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MORIKAWA Toshio

    Pharmaceutical Research and Technology Institute　Professor/Director
Last Updated :2024/04/23

Researcher Information

Degree

  • Ph. D（2002/09 Kyoto Pharmaceutical University）

J-Global ID

Research Interests

  • Pharmacognosy   Natural Products Chemistry   Medicinal Food Pharmaceutical Science   Chemical Biology   

Research Areas

  • Life sciences / Environmental and pharmaceutical development resources
  • Life sciences / Pharmaceuticals - chemistry and drug development

Academic & Professional Experience

  • 2024/04 - Today  Kindai University大学院実学社会起業イノベーション学位プログラム教授
  • 2023/04 - Today  Kindai Universityアンチエイジングセンターセンター長
  • 2022/04 - Today  Kobe Tokiwa University非常勤講師
  • 2020/04 - Today  Osaka UniversitySchool of Pharmaceutical Sciences非常勤講師，委託講師
  • 2015/04 - Today  近畿大学大学院薬学研究科教授
  • 2015/04 - Today  Kindai UniversityPharmaceutical Research and Technology InstituteProfessor
  • 2021/04 - 2023/03  Kindai Universityアンチエイジングセンター副センター長
  • 2007/06 - 2021/03  Kindai UniversityAntiaging CenterResearcher
  • 2011/04 - 2015/03  Kindai University大学院薬学研究科准教授
  • 2010/04 - 2015/03  Kinki UniversityPharmaceutical Research and Technology InstituteAssociate Professor
  • 2005/04 - 2010/03  Kinki UniversityPharmaceutical Research and Technology InstituteLecturer
  • 2001/04 - 2005/03  Kyoto Pharmaceutical UniversityResearch Associate

Published Papers

  • Morikawa, T.; Inoue, N.; Yamamoto, S.; Shiotani, M.; Manse, Y.; Ninomiya, K.
    Journal of Natural Medicines 1861-0293 2024/04
  • Morikawa, T.; Kubota, T.; Arai, M.
    Yakugaku Zasshi 144 (1) 19 - 19 1347-5231 2024
  • Miyasaka, K.; Takada, R.; Wu, J.; Takeda, S.; Manse, Y.; Morikawa, T.; Shimoda, H.
    Journal of Natural Medicines 1861-0293 2024
  • Takashima, K.; Nakamura, S.; Nagayama, M.; Marumoto, S.; Ishikawa, F.; Xie, W.; Nakanishi, I.; Muraoka, O.; Morikawa, T.; Tanabe, G.
    RSC Advances 14 (7) 2046-2069 2024
  • Akifumi Nagatomo; Mamiko Kohno; Hirosato Kawakami; Yoshiaki Manse; Toshio Morikawa
    Journal of Natural Medicines 78 (1) 180 - 190 1340-3443 2024/01 
    An acylated flavonol glycoside, trans-tiliroside (1), is found in certain parts of different herbs, including the seeds of Rosa canina (Rosaceae). Previous studies on compound 1 have focused on triglyceride (TG) metabolism, including its anti-obesity and intracellular TG reduction effects. In the present study, the effects of compound 1 on cholesterol (CHO) metabolism were investigated using human hepatocellular carcinoma-derived HepG2 cells and mice. Compound 1 decreased CHO secretion in HepG2 cells, which was enhanced by mevalonate in a concentration-dependent manner and decreased the secretion of apoprotein B (apoB)-100, a marker of very low-density lipoprotein (VLDL). Compound 1 also inhibited the activity of microsomal triglyceride transfer proteins, which mediate VLDL formation from cholesterol and triglycerides in the liver. In vivo, compound 1 inhibited the accumulation of Triton WR-1339-induced TG in the blood of fasted mice and maintained low levels of apoB-100. These results suggest that compound 1 inhibits the secretion of CHO as VLDL from the liver and has the potential for use for the prevention of dyslipidemia. Graphical abstract: [Figure not available: see fulltext.]
  • Takashima, K.; Asai, A.; Ashidate, M.; Suzuki, R.; Marumoto, S.; Ishikawa, F.; Morikawa, T.; Tanabe, G.
    Journal of Natural Products 86 (12) 1520-6025 2023/12
  • Hisashi Matsuda; Akifumi Nagatomo; Misaki Hatakeyama; Yoshiaki Manse; Masayuki Yoshikawa; Toshio Morikawa
    Traditional and Kampo Medicine 10 (2) 132 - 141 2023/08 
    Aim: Bombycis Feces (BF) and Bombyx Batryticatus (BB) are traditional medicines derived from silkworm. We investigated the suppressive effects of BF and BB extracts on elevated blood glucose levels in disaccharide-loaded rats. Methods: Effects of BF and BB extracts on serum glucose levels in sugar-loaded rats and streptozotocin (STZ)-induced diabetic mice were recorded, and several glucosidase inhibitory activities were determined in vitro by comparing with those of the natural medicines obtained from the mulberry plant (e.g., Mori Folium, Mori Cortex, and Mori Fructus). Results: BF and BB methanol extracts were found to suppress the elevated blood glucose level in sucrose-loaded mice, whereas they did not exhibit any activity in the glucose-loaded model and in the STZ-induced model. Through the bioassay-guided separation of the BF methanol extract using sucrase and maltase inhibitory activities, several pseudo-sugars, including 1-deoxynojirimycin (1), fagomine (2), and cis-5-hydroxy-L-pipecolic acid (3) were isolated as the active constituents. Oral administration (10 mg/kg) of constituent 1 simultaneous to sucrose loading in rats was found to significantly suppress elevation of the serum glucose level. Conclusion: BF and BB extracts were found to inhibit the elevated blood glucose level in disaccharides-loaded rats due to their α-glucosidase inhibitory activities. The suppressive effects of BF and BB extracts as well as of the active constituent 1 on the increase in blood glucose were estimated to dwindle at a limited time after administration. Therefore, it is suggested that BF and BB extracts might exert their effective antidiabetic effects when taken with meals.
  • Yusuke Sakamoto; Naoki Inoue; Yusuke Nakanishi; Kiyofumi Ninomiya; Masayuki Yoshikawa; Osamu Muraoka; Yoshiaki Manse; Toshio Morikawa
    Biological and Pharmaceutical Bulletin 46 (6) 848 - 855 0918-6158 2023/06 [Refereed]
     
    A methanol extract of rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) showed hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. We had previously isolated 46 compounds, including several types of iridoid glycosides, phenylethanoid glycosides, and aromatics, etc., from the extract. Among them, picroside II, androsin, and 4-hydroxy-3-methoxyacetophenone exhibited active hepatoprotective effects at doses of 50-100mg/kg, per os (p.o.) To characterize the mechanisms of action of these isolates and to clarify the structural requirements of phenylethanoid glycosides for their hepatoprotective effects, their effects were assessed in in vitro studies on (i) D-GalN-induced cytotoxicity in mouse primary hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. These isolates decreased the cytotoxicity caused by D-GalN without inhibiting LPS-induced macrophage activation and also reduced the sensitivity of hepatocytes to TNF-α. In addition, the structural requirements of phenylethanoids for the protective effects of D-GalN-induced cytotoxicity in mouse primary hepatocytes were evaluated.
  • 山口朋子; LUO Fenglin; 橋本統星; 赤木淳二; 萬瀬貴昭; 二宮清文; 二宮清文; 森川敏生
    診療と新薬 (株)医事出版社 60 (3) 179 - 187 0037-380X 2023/03 
    卵巣摘出によりエストロゲン分泌を低下させたマウスに,漢方エキス(防已黄耆湯エキス:BOT,防風通聖散エキス:BTS,大柴胡湯エキス:DST)を添加した高脂肪食を与えたところ,対照群(高脂肪食)と比べて体重増加が有意に抑えられ,血清中の総コレステロールや,AST,ALTなどの肝数値についても改善した。また,飼育6週間後の内臓脂肪量および皮下脂肪量を測定したところ対照群よりも有意に低く,これらの漢方エキスにエストロゲン低下に伴う脂肪蓄積の抑制効果が認められた。次に,エストロゲン依存的に増殖するMCF-7細胞を用いてBOT,BTSおよびDSTのエストロゲン様作用を検討したところ,BOTは10μg/mL以上の濃度において,BTSおよびDSTは100μg/mLの濃度においてMCF-7細胞の増殖が誘導され,これらの漢方エキスにエストロゲン様の活性が認められた。それぞれの漢方薬の構成生薬について検討した結果,カンゾウ,ダイオウ,キジツ,オウギ,オウゴン,マオウ,およびハッカから調製したエキスに活性が認められた。これらの結果から,肥満症に用いられる上記3種の漢方薬はいずれもエストロゲン様作用を有し,継続的な服用により,エストロゲン低下に伴う脂肪蓄積に対して抗肥満効果を発揮することを見出した。(著者抄録)
  • Fenglin Luo; Yoshiaki Manse; Saowanee Chaipech; Yutana Pongpiriyadacha; Osamu Muraoka; Toshio Morikawa
    Pharmaceuticals 16 (2) 2023/02 
    A methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) showed anti-proliferative activity against human prostate carcinoma LNCaP cells (IC50 = 2.0 µg/mL). Two new coumarin-related polysubstituted benzofurans, mammeasins P (1) and Q (2), and a known polysubstituted coumarin mammea B/AC cyclo F (39) were isolated from the extract along with 44 previously reported polysubstituted coumarin constituents (3–38 and 40–47). The structures of two new compounds (1 and 2) were determined based on their spectroscopic properties derived from the physicochemical evidence including NMR and MS analyses and taking the plausible generative pathway into account. Among the coumarin constituents, mammeasins A (3, IC50 = 1.2 µM) and B (4, 0.63 µM), sugangin B (18, 1.5 µM), kayeassamins E (24, 3.0 µM) and G (26, 3.5 µM), and mammeas E/BA (40, 0.88 µM), E/BB (41, 0.52 µM), and E/BC (42, 0.12 µM) showed relatively potent anti-proliferative activity.
  • Fenglin Luo; Yoshiaki Manse; Satoshi Ishikawa; Sakura Nishi; Anshin Chen; Tao Wang; Toshio Morikawa
    Journal of Natural Medicines 77 (2) 387 - 396 1340-3443 2023/01 
    Methanol extract from the capitula of Coreopsis tinctoria Nutt. (Asteraceae), which is also known as a flowering tea or blooming tea “Snow Chrysanthemum,” was found to inhibit the enzymatic activity of aromatase. A total of 24 known isolates (1–24) were identified from the extract, including three chalcones (1–3), an aurone (4), five flavanones (5–9), four flavanols (10–13), a flavonol (14), and two biflavanones (15, 16). Among them, okanin (1, Ki = 1.6 μM), (2S)-naringenin (5, 0.90 μM), isookanin (6, 0.81 μM), (2S)-7,3',5'-trihydroxyflavaone (7, 0.13 μM), and (2S)-5,7,3',5'-tetrahydroxyflavanone (8, 0.32 μM) exhibited relatively potent competitive inhibition. Specifically, the isolates 7 and 8, having a common 3',5'-resorcinol moiety at the B ring in their flavanone skeleton, exhibited potent inhibitory activities compared to those of a clinically applied aminoglutethimide (0.84 μM) and naturally occurring flavone, chrysin (0.23 μM), which is a common non-steroidal aromatase inhibitor. Importantly, the active flavonoid constituents (1 and 5–8) did not inhibit the activity of 5α-reductase enzyme, which normally reacts with the same substrate “testosterone,” thus, these compounds were suggested to be specific to aromatase.
  • Toshio Morikawa
    Chemical & pharmaceutical bulletin 71 (10) 756 - 765 0009-2363 2023 
    In this review, our resent pharmaceutical food science research for bio-functional molecules obtained from natural resources that contribute to i) suppression of postprandial blood glucose elevation and/or improvement of glucose tolerance and ii) reduction of visceral fat accumulation and improvement of lipid metabolism were summarized. Based on studies using MONOTORI science, salacinol (1), neokotalanol (4), and trans-tiliroside (20) have been approved or notified by the Consumer Affairs Agency in Japan as functional substances in food with health claims, Food for Specified Health Use and Food with Functional Claims.
  • Hisashi Matsuda; Toshio Morikawa; Seikou Nakamura; Osamu Muraoka; Masayuki Yoshikawa
    Journal of Natural Medicines 77 (4) 665 - 666 1340-3443 2023 
    In the current review, we describe the novel biofunctional effects of oleanane-type triterpene saponins, including elatosides, momordins, senegasaponins, camelliasaponins, and escins, obtained from Aralia elata (bark, root cortex, young shoot), Kochia scoparia (fruit), Polygala senega var. latifolia (roots), Camellia japonica (seeds), and Aesculus hippocastanum (seeds), considering the following biofunctional activities: (1) inhibitory effects on elevated levels of blood alcohol and glucose in alcohol and glucose-loaded rats, respectively, (2) inhibitory effects on gastric emptying in rats and mice, (3) accelerative effects on gastrointestinal transit in mice, and (4) protective effects against gastric mucosal lesions in rats. In addition, we describe (5) suppressive effects of the extract and chakasaponins from Camellia sinensis (flower buds) on obesity based on inhibition of food intake in mice. The active saponins were classified into the following three types: (1) olean-12-en-28-oic acid 3-O-monodesmoside, (2) olean-12-ene 3,28-O-acylated bisdesmoside, and (3) acylated polyhydroxyolean-12-ene 3-O-monodesmoside. Furthermore, common modes of action, such as involvements of capsaicin-sensitive nerves, endogenous NO and PGs, and possibly sympathetic nerves, as well as common structural requirements, were observed. Based on our findings, a common mechanism of action might mediate the pharmacological effects of active saponins. It should be noted that the gastrointestinal tract is an important action site of saponins, and the role of the saponins in the gastrointestinal tract should be carefully considered.
  • Shogo Takeda; Akari Yoneda; Kenchi Miyasaka; Yoshiaki Manse; Toshio Morikawa; Hiroshi Shimoda
    International Journal of Molecular Sciences 24 (1) 1661-6596 2022/12 
    Ceramide (Cer) plays an important role in skin barrier functions in the stratum corneum (SC). The ingestion of food-derived glucosylceramides (GlcCer) attenuates transepidermal water loss (TEWL). However, the moisturizing effects of single molecules of GlcCer and Cer remain unclear. Therefore, we herein purified 13 GlcCer and 6 Cer, including elasticamide, which has the same structure as human Cer[AP], from rice and compared their epidermal moisturizing effects in a reconstructed human epidermal keratinization model. The results obtained showed that 10 µM of 5 GlcCer[d18:2] with a 4E,8Z sphingadienine and C18 to C26 fatty acids and 10 µg/mL of 3 Cer with C23 or C24 fatty acids significantly reduced TEWL. The moisturizing effects of these GlcCer were dependent on the length of fatty acids. Furthermore, 10 µg/mL of elasticamide increased the SC Cer contents by promoting the expression of GlcCer synthase. Electron microscopic observations revealed that 1 µM of GlcCer[d18:2(4E,8Z)/26:0] increased the number of keratohyalin granules and desmosomes. Immunostaining and Western blotting indicated that 1 µM of GlcCer[d18:2(4E,8Z)/26:0] up-regulated the expression of filaggrin and corneodesmosin, which contribute to epidermal hydration. This comparative study on epidermal moisturization by GlcCer and Cer isolated from rice revealed differences in their hydration mechanisms.
  • 下田 博司; 森川 敏生
    FOOD Style 21 (株)食品化学新聞社 26 (11) 50 - 55 1343-9502 2022/11
  • 下田 博司; 森川 敏生
    FOOD Style 21 (株)食品化学新聞社 26 (11) 50 - 55 1343-9502 2022/11
  • Akifumi Nagatomo; Kiyofumi Ninomiya; Shinsuke Marumoto; Chie Sakai; Shuta Watanabe; Wakana Ishikawa; Yoshiaki Manse; Takashi Kikuchi; Takeshi Yamada; Reiko Tanaka; Osamu Muraoka; Toshio Morikawa
    International journal of molecular sciences 23 (21) 1661-6596 2022/10 
    The seed oil of Carapa guianensis Aublet (Andiroba) has been used in folk medicine for its insect-repelling, anti-inflammatory, and anti-malarial activities. This study aimed to examine the triglyceride (TG) reducing effects of C. guianensis-derived limonoids or other commercially available limonoids in human hepatoblastoma HepG2 cells and evaluate the expression of lipid metabolism or autophagy-related proteins by treatment with 7-deacetoxy-7-oxogedunin (DAOG; 1), a principal limonoid of C. guianensis. The gedunin-type limonoids, such as DAOG (% of control at 20 μM: 70.9 ± 0.9%), gedunin (2, 74.0 ± 1.1%), epoxyazadiradione (4, 73.4 ± 2.0%), 17β-hydroxyazadiradione (5, 79.9 ± 0.6%), 7-deacetoxy-7α-hydroxygedunin (6, 61.0 ± 1.2%), andirolide H (7, 87.4 ± 2.2%), and 6α-hydroxygedunin (8, 84.5 ± 1.1%), were observed to reduce the TG content at lower concentrations than berberine chloride (BBR, a positive control, 84.1 ± 0.3% at 30 μM) in HepG2 cells pretreated with high glucose and oleic acid. Andirobin-, obacunol-, nimbin-, and salannin-type limonoids showed no effect on the intracellular TG content in HepG2 cells. The TG-reducing effect of DAOG was attenuated by the concomitant use of compound C (dorsomorphin), an AMPK inhibitor. Further investigation on the detailed mechanism of action of DAOG at non-cytotoxic concentrations revealed that the expressions of autophagy-related proteins, LC3 and p62, were upregulated by treatment with DAOG. These findings suggested that gedunin-type limonoids from Andiroba could ameliorate fatty liver, and that the action of DAOG in particular is mediated by autophagy.
  • Katsuki Takashima; Miyu Teramachi; Shinsuke Marumoto; Fumihiro Ishikawa; Yoshiaki Manse; Toshio Morikawa; Genzoh Tanabe
    Bioorganic & Medicinal Chemistry Letters 78 129034 - 129034 0960-894X 2022/10 
    Although 4,5-didehydroguadiscine (12a), an alkaloid with potent melanogenesis-inhibitory activity isolated from Hornschuchia obliqua (Annonaceae), consists of an aporphine nucleus with an aromatized B-ring, to date, it has not been utilized as a template for structure-activity relationship (SAR) studies of pharmacological activities because of its exceptional structure. Accordingly, herein, five analogs (12b-12f) of 12a and five benzylisoquinoline analogs (13b-13f) lacking the C11a-C11b bond of 12b-12f were prepared. The inhibitory effects of 12b-12f and 13b-13f on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells were examined and compared with those of 12a. Melanogenesis-inhibitory activities of 12b-12f were the same as that of 12a, whereas the melanogenesis-inhibitory activities of 13b-13f were significantly inferior to those of 12a and 12b-12f. These results suggest that the C11a-C11b bond plays an essential role in the melanogenesis-inhibitory activities of 12a-12e.
  • Fenglin Luo; Yoshiaki Manse; Saowanee Chaipech; Yutana Pongpiriyadacha; Osamu Muraoka; Toshio Morikawa
    International journal of molecular sciences 23 (19) 1661-6596 2022/09 
    With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K (1), L (2), M (3), N (4), and O (5), were isolated from the methanolic extract of Mammea siamensis (Miq.) T. Anders. flowers (fam. Calophyllaceae), originating in Thailand. The stereostructures of 1-5 were elucidated based on their spectroscopic properties. Among the new compounds, 1 (IC50 = 7.6 µM) and 5 (9.1 µM) possessed relatively strong inhibitory activity against aromatase, which is a target of drugs already used in clinical practice for the treatment and prevention of estrogen-dependent breast cancer. The analysis through Lineweaver-Burk plots showed that they competitively inhibit aromatase (1, Ki = 3.4 µM and 5, 2.3 µM). Additionally, the most potent coumarin constituent, mammea B/AB cyclo D (31, Ki = 0.84 µM), had a competitive inhibitory activity equivalent to that of aminoglutethimide (0.84 µM), an aromatase inhibitor used in therapeutics.
  • Kenchi Miyasaka; Yoshiaki Manse; Akari Yoneda; Shogo Takeda; Norihito Shimizu; Wakana Yamada; Toshio Morikawa; Hiroshi Shimoda
    Journal of food biochemistry 46 (10) e14353  0145-8884 2022/08 
    Glucosylceramides (GlcCer), which are present in many edible plants, suppress melanin production in mouse melanocytes. Rice GlcCer consist of multiple molecules that comprise different types of sphingoid bases as well as diverse lengths and stereotypes of free fatty acids. Adjacent to the GlcCer fraction, there are free ceramides (Cer) as minor constituents. However, the anti-melanogenic activities of individual GlcCer and Cer remain unknown. Therefore, we herein isolated 13 GlcCer and elasticamide, a Cer [AP] from the gummy by-products of rice bran oil, and examined their anti-melanogenic activities. In theophylline-induced melanogenesis in B16 melanoma cells, GlcCer [d18:2(4E,8Z)/18:0], GlcCer [d18:2(4E,8Z)/20:0], and elasticamide significantly suppressed melanin production with IC50 values of 6.6, 5.2, and 3.9 μM, respectively. Elasticamide, but not GlcCer [d18:2 (4E,8Z)/20:0], suppressed melanogenesis in human 3D-cultured melanocytes and the expression of tyrosinase-related protein 1 in normal human melanocytes. Based on these results, we conducted a clinical trial on the effects of rice ceramide extract (Oryza ceramide®), containing 1.2 mg/day of GlcCer and 56 μg/day of elasticamide, on UV-B-induced skin pigmentation. The ingestion of Oryza ceramide® for 8 weeks significantly suppressed the accumulation of melanin 7 days after UV irradiation (1288 and 1546 mJ/cm2 ·S). Rice-derived GlcCer and elasticamide, which exhibited anti-melanogenic activities, were suggested to contribute to the suppressive effects of Oryza ceramide® on UV-induced skin pigmentation. Although the mechanisms underlying the anti-melanogenic activities of GlcCer remain unclear, elasticamide was identified as a promising Cer that exhibits anti-melanogenic activity. PRACTICAL APPLICATIONS: The anti-melanogenic activities of rice-derived GlcCer and elasticamide currently remain unclear. We herein demonstrated the inhibitory effects of individual GlcCer and elasticamide on melanogenesis in melanoma cells, melanocytes, and human skin.
  • Toshio Morikawa
    Molecules (Basel, Switzerland) 27 (16) 2022/08 
    Natural products remain important repositories of promising therapeutic candidates due to their rich chemical and biological diversity [...].
  • Tagami Takaomi; Ishida Akihiro; Ishihara Rie; Ito Michiho; Oi Itsuki; Okasaka Mamoru; Kawabata Akiko; Sakai Eiji; Tsutahara Ryota; Nishio Kayo; Matsuda Hisashi; Morikawa Toshio; Yamamoto Yutaka; Yokokura Tsuguo
    Shoyakugaku Zasshi The Japanese Society of Pharmacognosy 76 (2) 37 - 44 1349-9114 2022/08 
    The origin of ISODONIS HERBA in the Japanese standards for non-Pharmacopoeial crude drugs 2018 is the aerial parts of Isodon japonicus H. Hara (Plectranthus japonicus Koidzumi, Rabdosia japonica H. Hara) and Isodon trichocarpus Kudô (Plectranthus trichocarpus Maximowicz, Rabdosia trichocarpa H. Hara) (Labiatae). This herb is used as an ingredient for gastrointestinal agents, health foods, and cosmetics. ISODONIS HERBA contains ent-kaurane diterpenoids such as enmein. Enmein is a characteristic compound in ISODONIS HERBA. In order to help better understanding and facilitate quality control of ISODONIS HERBA, methods for quantitative analyses of enmein in ISODONIS HERBA were elaborated.
  • Yoshiaki Manse; Yusuke Sakamoto; Taiki Miyachi; Mitsuyo Nire; Yoshinori Hashimoto; Saowanee Chaipech; Yutana Pongpiriyadacha; Toshio Morikawa
    Separations {MDPI} {AG} 9 (5) 127 - 127 2022/05
  • Kosuke Kitahata; Kazuhiko Matsuo; Masako Sato; Yoko Susami; Yuta Hara; Toshio Morikawa; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama
    Experimental dermatology 31 (8) 1234 - 1242 1600-0625 2022/04 
    Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.
  • Souichi Nakashima; Yoshimi Oda; Moeko Morita; Ayako Ohta; Toshio Morikawa; Hisashi Matsuda; Seikou Nakamura
    Toxins 14 (3) 2022/03 
    We examined a two-step target protein binding strategy that uses cofilin as the target protein to analyze the active constituents in Bryonia cretica. In the first step, we prepared the target protein, and used it to analyze the compounds binding to it in the second step. We used the methanolic extract of B. cretica as a library of possible active compounds. We conducted LC-MS analysis using information from our previous study. The peaks in the HPLC profile were identified as cucurbitacin D, isocucurbitacin D, and cucurbitacin I. As far as we know, there is no known study of the activity of isocucurbitacin D in this research field. Therefore, we examined the effects of isocucurbitacin D on cell proliferation and cofilin protein in human fibrosarcoma cell line HT1080 to confirm the effectiveness of this strategy. The cytotoxicity assay, the fibrous/globular actin ratio assay, and the immunoblotting analysis revealed that isocucurbitacin D showed a cytotoxic effect with disruption of target protein cofilin. The target protein binding strategy is a direct and straightforward method for finding new drug seeds from crude sources, such as natural plant extracts.
  • Akifumi Nagatomo; Naoki Inoue; Takuya Konno; Yin Xu; Chinatsu Sakamoto; Mayuko Sone; Aya Shibasaka; Osamu Muraoka; Kiyofumi Ninomiya; Masayuki Yoshikawa; Yoshiaki Manse; Toshio Morikawa
    Journal of natural medicines 76 (3) 654 - 669 1861-0293 2022/03 
    The methanol extract from the leaves of Ilex paraguariensis A. St.-Hil. (Aquifoliaceae), popularly known as mate, maté, or yerba maté, inhibits the intracellular triglyceride accumulation in HepG2 cells and suppresses the plasma triglyceride elevation in olive oil-treated mice. Three new triterpene saponins, termed mateosides I (1), II (2), and III (3), were isolated from the extract along with 29 known compounds. The structures of 1-3 were elucidated based on chemical and spectroscopic evidence. Among the isolates, principal saponin constituents, 2 and matesaponins 1 (7) and 2 (9), potently inhibited the triglyceride accumulation in HepG2 cells simultaneously treated with oleic acid and high glucose. In vivo assay of the methanol extract of I. paraguariensis revealed that 7 and 9 showed anti-hyperlipidemic activities in olive oil-treated mice. These results suggested that the saponin constituents of I. paraguariensis could be valuable bioactive marker for the anti-obesogenic activity.
  • 森川敏生; 森川敏生
    JATAFFジャーナル 農林水産・食品産業技術振興協会 10 (3) 43 - 47 2187-4948 2022
  • Wei Zhang; Kun Ren; Shuangfeng Wu; Jingyan Guo; Shumeng Ren; Yingni Pan; Dongmei Wang; Toshio Morikawa; Huiming Hua; Xiaoqiu Liu
    Journal of Chromatography B Elsevier {BV} 1186 123040 - 123040 1873-376X 2021/12
  • Shogo Takeda; Kenchi Miyasaka; Sarita Shrestha; Yoshiaki Manse; Toshio Morikawa; Hiroshi Shimoda
    Molecules {MDPI} {AG} 26 (19) 5860 - 5860 1420-3049 2021/09 
    Tomatoes are widely consumed, however, studies on tomato seeds are limited. In this study, we isolated 11 compounds including saponins and flavonol glycosides from tomato seeds and evaluated their effects on epidermal hydration. Among the isolated compounds, tomato seed saponins (10 µM) significantly increased the mRNA expression of proteins related to epidermal hydration, including filaggrin, involucrin, and enzymes for ceramide synthesis, by 1.32- to 1.91-fold compared with the control in HaCaT cells. Tomato seed saponins (10 µM) also decreased transepidermal water loss by 7 to 13 g/m2·h in the reconstructed human epidermal keratinization (RHEK) models. Quantitative analysis of the ceramide content in the stratum corneum (SC) revealed that lycoperoside H (1-10 µM) is a promising candidate to stimulate ceramide synthesis via the upregulation of ceramide synthase-3, glucosylceramide synthase, and β-glucocerebrosidase, which led to an increase in the total SC ceramides (approximately 1.5-fold) in concert with ceramide (NP) (approximately 2-fold) in the RHEK models. Evaluation of the anti-inflammatory and anti-allergic effects of lycoperoside H demonstrated that lycoperoside H is suggested to act as a partial agonist of the glucocorticoid receptor and exhibits anti-inflammatory effects (10 mg/kg in animal test). These findings indicate that lycoperoside H can improve epidermal dehydration and suppress inflammation by increasing SC ceramide and steroidal anti-inflammatory activity.
  • Wei Zhang; Kun Ren; Shumeng Ren; Shuang Lv; Yingni Pan; Dongmei Wang; Toshio Morikawa; Xiaoqiu Liu
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1176 122772 - 122772 1873-376X 2021/06 
    Evodiae Fructus (EF) is generally divided into three categories: small flower EF (SEF), medium flower EF (MEF) and big flower EF (BEF) in commodity circulation according to the size of the fruit. It is a well-known and frequently used herbal medicine for treating gastrointestinal disorder-related stomachache and headache, which has aroused wide attention for its hepatotoxicity. However, reports about hepatotoxicity is controversial and hepatotoxic components are inconclusive. The study aimed to explain the controversial hepatotoxicity of EF and screen the components associated with hepatotoxicity of EF based on the spectrum-toxicity relationship. UPLC fingerprints of 39 batches of EF collected from different regions were established. Combined with the results of L02 cell viability assays, the spectrum-toxicity relationship was investigated on the basic of orthogonal partial least squares (OPLS). The results of the research demonstrated that the toxicity of EF was obviously various among the different categories, in particularly, SEF was with less toxicity, MEF except for adulterants and BEF had mild toxicity and adulterants of MEF (A-MEF) produced more damage to L02 cell and no regions specificity in hepatotoxicity of EF. Thereinto, samples, the contents of which do not meet the requirements of Chinese Pharmacopoeia, were adulterants. It was worth noting that P11, P17, P20 and P25 were closely related to hepatotoxicity of EF and they were respectively identified as limonin (LIM), evodiamine (EVO), 1-methyl-2-nonyl-4(1H)-quinolone (MNQ), and 1-methyl-2-undecyl-4(1H)-quinolone (MUQ) by UPLC-Q-Exactive-MS. The hepatoprotection of P11 and hepatotoxicity of P17 were consistent with the results of spectrum-toxicity relationship. In summary, A-MEF was more toxic than other categories and SEF was less toxic than the others. It was noteworthy that EVO was the main hepatotoxic component of EF and LIM was the main hepatoprotective component of EF. The results provided worthy evidence for better utilization and development of EF.
  • Yongli Guo; Qingling Cui; Shumeng Ren; Deguo Hao; Toshio Morikawa; Dongmei Wang; Xiaoqiu Liu; Yingni Pan
    Journal of natural medicines 75 (4) 784 - 797 1861-0293 2021/05 
    Echinacoside (ECH), acteoside (ACT), and isoacteoside (ISAT), the typical phenylethanoid glycosides (PhGs) in cistanches herba, have various pharmacological activities. However, the ECH, ACT and ISAT have extremely low oral bioavailability, which is related to their metabolism under the intestinal flora. Previous studies showed that intestinal metabolites were the hepatoprotective substances in vivo, but the research on whether PhGs has effects without intestinal bacteria has not been studied. In this paper, ECH, ACT and ISAT were incubated with human or rat intestinal bacteria for 36 h. After incubating with human bacteria for 36 h, three prototype compounds were not detected and were mainly biotransformed to 3-HPP and HT. In the network pharmacology, a total of 6 common targets were obtained by analysing the prototypes, the metabolites and the liver injury. It was found that the combinations of three metabolites and common targets were more stable than those of the prototypes and common targets by molecular docking. Meanwhile, hepatocellular apoptosis, proliferation, inflammation and oxidative responses might play important roles in the mechanisms of the metabolites exerting hepatoprotective activities. Then normal and pseudo-sterile mice experiments were adopted to further compare the hepatoprotective activities of prototypes and metabolites. Animal experiment results showed that the prototypes and the metabolites in the normal mice had significantly hepatoprotective activity. Interestingly, in the pseudo-germfree mice, the metabolites showed significant hepatoprotective effect, but the prototypes had not effect. It indicated that the prototype cannot exert liver protective activity without the effect of intestinal bacteria.
  • Morikawa, T.; Ninomiya, K.; Tanabe, G.; Matsuda, H.; Yoshikawa, M.; Muraoka, O.
    Journal of Natural Medicines Springer Science and Business Media {LLC} 75 (3) 449 - 466 1861-0293 2021/04 
    During our studies characterizing functional substances from food resources for the prevention and treatment of lifestyle-related diseases, we isolated the active constituents, salacinol (1) and neokotalanol (4), and related thiosugar sulfoniums, from the roots and stems of the genus Salacia plants [Celastraceae (Hippocrateaceae)] such as Salacia reticulata Wight, S. oblonga Wall., and S. chinensis L., and observed their antidiabetic effects. These plant materials have been used traditionally in Ayurvedic medicine as a specific remedy at the early stage of diabetes, and have been extensively consumed in Japan, the United States, and other countries as a food supplement for the prevention of obesity and diabetes. Here, we review our studies on the antidiabetic effects of plants from the genus Salacia, from basic chemical and pharmacological research to their application and development as new functional food ingredients.
  • Yoshiaki Manse; Fenglin Luo; Kazuhiro Kato; Akane Okazaki; Eriko Okada-Nishida; Mitsuhiro Yanagida; Sho Nakamura; Toshio Morikawa
    Journal of Natural Medicines Springer Science and Business Media {LLC} 141st (3) 326 - 338 0918-9823 2021/03 
    A methanol extract from Isodonis Herba demonstrated significant proliferative effect on human hair follicle dermal papilla cells (HFDPC, % of control: 150.0 ± 2.0% at 20 µg/mL, p < 0.01). From the extract, 14 ent-kaurane-type diterpenoids (1-14), two abietane-type diterpenoids (15 and 16) and four triterpenoids (17-20) were isolated. Among the isolates, enmein (1, 160.9 ± 3.0% at 20 µM, p < 0.01), isodocarpin (2, 169.3 ± 4.9% at 5 µM, p < 0.01), nodosin (4, 160.5 ± 12.4% at 20 µM, p < 0.01), and oridonin (8, 165.4 ± 10.6% at 10 µM, p < 0.01) showed the proliferative effects. The principal component enmein (1) activated the expression of vascular endothelial growth factor (VEGF) mRNA, upregulated the production of VEGF and increased levels of phospho-Akt, phospho-GSK-3β, and β-catenin accumulation in HFDPC, which could be the mechanism of these activate proliferation activity.
  • Katsuki Takashima; Mika Sakano; Eri Kinouchi; Shinya Nakamura; Shinsuke Marumoto; Fumihiro Ishikawa; Kiyofumi Ninomiya; Isao Nakanishi; Toshio Morikawa; Genzoh Tanabe
    Bioorganic & Medicinal Chemistry Letters Elsevier {BV} 33 127751 - 127751 1464-3405 2021/02 
    Four chain-extended analogs (12a-12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C3H7, b R = C6H13, c: R = C8H17, d: R = C10H21) to the side chains of salacinol (1), a natural α-glucosidase inhibitor from Ayurvedic traditional medicine "Salacia", were synthesized. The α-glucosidase inhibitory activities of all the synthesized analogs were evaluated in vitro. Against human intestinal maltase, the inhibitory activities of 12a and 13a with seven-carbon side chain were equal to that of 1. In contrast, analogs (12b-12d, and 13c) exhibited higher level of inhibitory activity against the same enzyme than 1 and had equal or higher potency than those of the clinically used anti-diabetics, voglibose, acarbose, and miglitol. Thus, elongation of the side chains of 1 was effective for specifically increasing the inhibitory activity against human intestinal maltase.
  • Takara, T.; Yamamoto, K.; Suzuki, N.; Yamashita, S.; Lio, S.-I.; Noguchi, H.; Kakinuma, T.; Baba, A.; Takeda, S.; Yamada, W.; Shrestha, S.; Manse, Y.; Morikawa, T.; Shimoda, H.
    Functional Foods in Health and Disease 11 (8) 2160-3855 2021
  • 森川敏生
    Foods & Food Ingredients Journal of Japan Editorial Board of Foods & Food Ingredients Journal of Japan 226 (4) 323 - 332 0919-9772 2021 
    Medicinal foods are used as resources of traditional, alternative, and/or complementary medicines and are known to have not only nutritive and taste values but also medicinal effects. Among them, we focused on exploring bio-functional molecules from plant resources with edible flower parts for the prevention and treatment of the early stages of lifestyle-related diseases. Here, we review our studies on evaluation of these biofunctional molecules obtained from the edible flower parts of chrysanthemum, everlasting, tea, and daisy, based on pharmaceutical food science.
  • Toshio Morikawa; Yoshiaki Manse; Fenglin Luo; Haruko Fukui; Yamato Inoue; Tsuyoshi Kaieda; Kiyofumi Ninomiya; Osamu Muraoka; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 69 (5) 464 - 471 1347-5223 2021 
    A methanol extract from the underground part of Calanthe discolor Lindl. (Orchidaceae) demonstrated significant proliferative activity on human hair follicle dermal papilla cells (HFDPC, % of control: 120.8 ± 0.2%) at 100 µg/mL against HFDPC. Through bioassay-guided separation of the extract, a new indole glycoside named 6'-O-β-D-apiofuranosylindican (1) was isolated along with six known compounds (2-7) including three indole glycosides. The stereostructure of 1 was elucidated based on its spectroscopic properties and chemical characteristics. Among the isolates, 1 (110.0 ± 1.0%), glucoindican (3, 123.9 ± 6.8%), and calanthoside (4, 158.6 ± 7.1%) showed significant proliferative activity at 100 µM. Furthermore, the active indole glycosides (1, 3, and 4) upregulated the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-7 (FGF-7) mRNA and protein in HFDPC, which could be the mechanism of their proliferative activity.
  • Fumihiro Ishikawa; Aiko Hirano; Yuuto Yoshimori; Kana Nishida; Shinya Nakamura; Katsuki Takashima; Shinsuke Marumoto; Kiyofumi Ninomiya; Isao Nakanishi; Weijia Xie; Toshio Morikawa; Osamu Muraoka; Genzoh Tanabe
    RSC Advances Royal Society of Chemistry ({RSC}) 11 (6) 3221 - 3225 2046-2069 2021 

    Salacinol-type α-glucosidase inhibitors are ligand-compatible with the GH 31 family. Salacinol and its 3′-O-benzylated analogs inhibit human lysosomal α-glucosidase at submicromolar levels.

  • Fenglin Luo; Hidemi Sugita; Kenichi Muraki; Shunsuke Saeki; Saowanee Chaipech; Yutana Pongpiriyadacha; Osamu Muraoka; Toshio Morikawa
    Fitoterapia Elsevier {BV} 148 104780 - 104780 0367-326X 2021/01
  • Masakazu Kobayashi; Junji Akaki; Kiyofumi Ninomiya; Masayuki Yoshikawa; Osamu Muraoka; Toshio Morikawa; Masato Odawara
    Journal of medicinal food 24 (1) 1557-7600 2020/12 
    The number of diabetes mellitus and borderline diabetes cases is increasing and poses a serious problem worldwide. Plants of the genus Salacia are known to have α-glucosidase inhibitory activity and to lower postprandial hyperglycemia. Two randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the efficacy of Salacia chinensis extract. Study 1 was a single-dose crossover study of 150, 300, or 600 mg of Salacia extract or placebo to determine the dose dependency of the effect on postprandial hyperglycemia. The duration of the washout period between each experimental day was a minimum of 6 days. Study 2 was a 12-week, multiple-dose, parallel-group study to evaluate the effects of 600 mg/day of Salacia extract on blood glucose parameters. In Study 1, Salacia induced significant dose-dependent suppression of postprandial blood glucose, insulin, and their incremental area under the curve values. The dose of 600 mg appeared to have the most significant effect. In Study 2, Salacia significantly improved several blood glucose-related parameters, such as hemoglobin A1c, and glucose tolerance after glucose challenge. These results suggest that S. chinensis extract may have beneficial effects in patients with diabetes.
  • Takara, T.; Yamamoto, K.; Suzuki, N.; Yamashita, S.; Iio, S.; Noguchi, H.; Kakinuma, T.; Baba, A.; Yamamoto, S.; Morikawa, T.; Takeda, S.; Shimoda, H.
    Functional Foods in Health and Disease Functional Food Center 10 (9) 2160-3855 2020/09 
    Background and objective: The fruit of Mauritia flexuosa (moriche palm), which is known as “Aguaje,” has been used for beverages and processed foods. Recently, we found that several methoxyflavans are contained in the fruit and they exhibit estrogenic activities. Therefore, moriche palm extract (MPE) may function as a phytoestrogen and improve the symptoms induced by estrogen deficiency. However, the clinical effects of MPE on females has not yet been reported. We conducted a clinical trial of MPE on undefined complaints related to premenstrual syndrome (PMS) in healthy Japanese females.Methods: This randomized, double-blind, placebo-controlled study examined the effects of MPE (100 mg daily) containing 12.6  g of 5,4'-dihydroxy-7-methoxy-6-methylflavan. Forty-four Japanese women with indefinite complaints in premenstrual and menstrual periods were enrolled in the study. All subjects were randomly allocated into either the MPE (100 mg) group (n=22) or the placebo group (n=22) using a computerized random-number generator. Capsules containing either MPE (100 mg) or placebo were administered for 8 weeks between October and December in 2018. The severity of uncertain complaints and emotional status were evaluated using the Japanese version of the menstrual distress questionnaire (MDQ) as a primary outcome, and Medical Outcomes Study Short-Form 36-Item Health (SF-36) questionnaire at 4 and 8 weeks of ingestion. Blood, urine, and body parameters were also evaluated.Results: Forty-three subjects completed the trial, and the per protocol set comprised 21 subjects in the MPE (100 mg) group and 22 subjects in the placebo group. After ingesting MPE for 4 weeks, arousal in the premenstrual period significantly improved in the MPE (100 mg) group. After 8 weeks, the summary score, water retention, impaired concentration and control during menstrual period significantly improved in the MPE (100 mg) group. Contrarily, among SF-36 domain scores, significant ameliorating effects of MPE were not observed compared with those of the placebo group. Laboratory tests revealed no abnormalities suggesting adverse effects of MPE.Conclusions: MPE (100 mg/day for 8 weeks) improved several indefinite complaint parameters related to mensuration. MPE was suggested to be useful for improving anxiety related to PMS.Keywords: Menstrual distress questionnaire; SF-36 questionnaire; moriche palm; methoxyflavan; indefinite complaint
  • Toshio Morikawa; Satoru Tamura; Tao Wang
    Frontiers in Chemistry Frontiers Media {SA} 8 650 - 650 2296-2646 2020/08
  • Wei Zhang; Jingyan Guo; Dongmei Wang; Shumeng Ren; Huiming Hua; Toshio Morikawa; Yingni Pan; Xiaoqiu Liu
    Chemico-Biological Interactions Elsevier {BV} 327 109146 - 109146 0009-2797 2020/08 [Refereed]
     
    Evodiae Fructus (EF), the dried nearly mature scented fruit of Tetradium ruticarpum (A.Juss.) T.G.Hartley, was typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It had been reported to be a mild toxic herb through metabolic activation mainly by CYP3A but was barely explained from pharmacokinetic interaction. The aim of the study was to investigate the role of CYP3A inducer/inhibitor in pharmacokinetics of five alkaloids (evodiamine (EVOD), rutaecarpine (RUTA), 1-methyl-2-undecyl-4(1H)-quinolone (MUDQ), 1-methyl-2-nonyl-4(1H)-quinolone (MNNQ) and evocarpine (EVOC)) associated with hepatotoxicity of EF in Sprague Dawley (SD) rats. The results demonstrated that the metabolism of the five alkaloids of EF were inhibited in presence of CYP3A inhibitor whereas the metabolism of the five alkaloids of EF were promoted in presence of CYP3A inducer. Therefore, the dose is required attention when EF is taken in conjunction with CYP3A inducer as there is an enhancement in drug metabolism, which might lead to toxicity.
  • Toshio Morikawa; Naoki Inoue; Yusuke Nakanishi; Yoshiaki Manse; Hideyuki Matsuura; Kenji Okino; Shinya Hamasaki; Masayuki Yoshikawa; Osamu Muraoka; Kiyofumi Ninomiya
    Fitoterapia Elsevier {BV} 143 104584 - 104584 0367-326X 2020/06 [Refereed]
     
    Three new acylated phenylethanoid glycosides, kurroaosides A (14), B (15), and C (16), and a new acylated cucurbitane-type triterpene glycoside, kurroaoside D (17), were isolated from a methanol extract of the rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) along with 29 known isolates including 10 acylated phenylethanoid glycosides (18-27), three cucurbitane-type triterpene glycosides (32-34), and a nortriterpene glycoside (35). The structures of these new compounds (14-17), including their stereochemistry, were determined based on chemical and physicochemical evidence derived from NMR and MS analysis. Among the isolates, acylated iridoid glycosides, picrosides I (8), II (9), III (10), and IV (11) and 6-feruloylcatalpol (12), phenylethanoid glycosides (14-16), triterpene glycosides, cucurbitacin B 2-O-β-D-glucopyranoside (32) and 25-acetoxy-2-β-D-glucopyranosyloxy-3,16,20-trihydroxy-9-methyl-19-norlanosta-5-en-22-one (35), and an acetophenone glycoside, picein (36), significantly promoted collagen synthesis at 10-30 μM, with no cytotoxicity being observed at the effective concentrations. Furthermore, acylated phenylethanoid glycosides, calceolarioside A (19, IC50 = 69.2 μM), plantamajoside (20, 51.8 μM), isoplantamajoside (21, 76.8 μM), and scroside E (23, 65.5 μM), exhibited collagenase inhibitory activity equivalent to that of positive agents caffeic acid (75.6 μM) and epigallocatechin 3-O-gallate (75.4 μM).
  • Toshio Morikawa; Fenglin Luo; Yoshiaki Manse; Hidemi Sugita; Shunsuke Saeki; Saowanee Chaipech; Yutana Pongpiriyadacha; Osamu Muraoka; Kiyofumi Ninomiya
    Frontiers in Chemistry Frontiers Media {SA} 8 199 - 199 2296-2646 2020/03 [Refereed]
     
    Geranylated coumarin constituents, kayeassamin I (1) and mammeasins E (2) and F (3) were newly isolated from the methanol extract of the flowers of Mammea siamensis (Calophyllaceae) originating in Thailand, along with five known isolates, such as mammea E/BC (23), deacetylmammea E/AA cyclo D (31), deacetylmammea E/BB cyclo D (32), mammea A/AA cyclo F (34), and mammea A/AC cyclo F (35). These compounds (1-3) were obtained as an inseparable mixture (ca. 1:1 ratio) of the 3″R and 3″S forms, respectively. Among the isolated coumarins from the extract, mammeasins E (2, 22.6 μM), A (4, 19.0 μM), and B (5, 24.0 μM), kayeassamins E (9, 33.8 μM), F (10, 15.9 μM), and G (11, 17.7 μM), surangin C (13, 5.9 μM), and mammeas A/AA (17, 19.5 μM), E/BB (22, 16.8 μM), and A/AA cyclo F (34, 23.6 μM), were found to inhibit testosterone 5α-reductase.
  • Morikawa, T.; Nakanishi, Y.; Inoue, N.; Manse, Y.; Matsuura, H.; Hamasaki, S.; Yoshikawa, M.; Muraoka, O.; Ninomiya, K.
    Phytochemistry 169 112185 - 112185 0031-9422 2020 [Refereed]
     
    Seven new acylated iridoid glycosides, picrorhizaosides A-G (1-7), were isolated from the methanol extract of the rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae), in addition to six known iridoid glycosides (8-13). The structures of these new iridoids, including their stereochemistry, were determined based on chemical and physicochemical evidence derived from NMR and MS analysis. Of the isolates, picrorhizaosides D (4, IC50 = 43.4 μM) and E (5, 35.8 μM); picrosides I (8, 60.7 μM), II (9, 22.3 μM), and IV (11, 59.2 μM); and minecoside (13, 57.2 μM), exhibited a similar or stronger hyaluronidase inhibitory activity than those of the antiallergic medicines disodium cromoglycate (64.8 μM), ketotifen fumarate (76.5 μM), and tranilast (227 μM).
  • Toshio Morikawa; Haihui Xie; Yingni Pan; Kiyofumi Ninomiya; Dan Yuan; Xiaoguang Jia; Masayuki Yoshikawa; Seikou Nakamura; Hisashi Matsuda; Osamu Muraoka
    Chemical and Pharmaceutical Bulletin Pharmaceutical Society of Japan 67 (7) 675 - 689 0009-2363 2019/07
  • Morikawa, T.; Okugawa, S.; Manse, Y.; Muraoka, O.; Yoshikawa, M.; Ninomiya, K.
    Natural Product Communications SAGE Publications 14 (6) 1934578X1985783 - 1934578X1985783 1934-578X 2019 [Refereed]
     
    Using a recently developed analytical protocol, distributions of 5 aporphine alkaloids, nuciferine (1), nornuciferine (2), N-methylasimilobine (3), asimilobine (4), and pronuciferine (5), and 5 benzylisoquinoline alkaloids, armepavine (6), norarmepavine (7), N-methylcoclaurine (8), coclaurine (9), and norjuziphine (10), in lotus flowers (the flower buds of Nelumbo nucifera) were analyzed. The flowers were collected at different blooming states (beginning of blooming, one-third in bloom, half in bloom, three-quarters in bloom, and in full bloom) from Saga prefecture, Japan (NN-S1–5). The samples from the beginning of blooming state (NN-S1, 16.35 mg/g in dried material) were found to possess the richest total alkaloid content (1-10). The samples of half in bloom (NN-S3, 52.69 mg per flower of dried material) had the highest total alkaloid content per flower. Among the alkaloid constituents, nornuciferine (2, IC50 = 22.5 µM), asimilobine (4, 11.7 μM), norarmepavine (7, 26.4 μM), coclaurine (9, 11.4 μM), and norjuziphine (10, 24.3 μM) exhibited hyaluronidase inhibitory activity, which was more potent than that of the antiallergic medicine disodium cromoglycate (DSCG, 64.8 μM).
  • Morikawa, T.
    Chemical and Pharmaceutical Bulletin 67 (7) 632 - 633 0009-2363 2019 [Refereed]
  • Morikawa, T.; Xie, H.; Pan, Y.; Ninomiya, K.; Yuan, D.; Jia, X.; Yoshikawa, M.; Nakamura, S.; Matsuda, H.; Muraoka, O.
    Chemical and Pharmaceutical Bulletin 67 (7) 675 - 689 0009-2363 2019 [Refereed]
     
    An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.
  • Kobayashi, M.; Akaki, J.; Yamaguchi, Y.; Yamasaki, H.; Ninomiya, K.; Pongpiriyadacha, Y.; Yoshikawa, M.; Muraoka, O.; Morikawa, T.
    Journal of Natural Medicines Springer Science and Business Media {LLC} 73 (3) 584 - 588 1340-3443 2019 [Refereed]
     
    The antidiabetic effects of a hot water extract of the stems of Salacia chinensis (SCE) were evaluated in vivo in ob/ob mice (genetically obese hyperglycemic mice). Administration of dietary feed containing 0.20 and 0.50% of SCE for 23 days to ob/ob mice significantly suppressed the elevation of both blood glucose and HbA1c levels, without significantly changing body weight and food intake. To characterize the antidiabetic effects of the thiosugar sulfonium constituent neokotalanol (1), which has potent α-glucosidase inhibitory activity, we performed a similar in vivo study. HbA1c levels were significantly suppressed in ob/ob mice after the administration of dietary feed containing 0.0003% of neokotalanol (1) for 20 days. These results indicate that SCE and neokotalanol (1) are potential leads for the development of novel antidiabetic agents.
  • Morikawa, T.; Nagatomo, A.; Oka, T.; Miki, Y.; Taira, N.; Shibano-Kitahara, M.; Hori, Y.; Muraoka, O.; Ninomiya, K.
    International Journal of Molecular Sciences 20 (24) 2019 [Refereed]
     
    An acylated flavonol glycoside, helichrysoside, at a dose of 10 mg/kg/day per os for 14 days, improved the glucose tolerance in mice without affecting the food intake, visceral fat weight, liver weight, and other plasma parameters. In this study, using hepatoblastoma-derived HepG2 cells, helichrysoside, trans-tiliroside, and kaempferol 3-O-β-D-glucopyranoside enhanced glucose consumption from the medium, but their aglycones and p-coumaric acid did not show this activity. In addition, several acylated flavonol glycosides were synthesized to clarify the structural requirements for lipid metabolism using HepG2 cells. The results showed that helichrysoside and related analogs significantly inhibited triglyceride (TG) accumulation in these cells. The inhibition by helichrysoside was more potent than that by other acylated flavonol glycosides, related flavonol glycosides, and organic acids. As for the TG metabolism-promoting activity in high glucose-pretreated HepG2 cells, helichrysoside, related analogs, and their aglycones were found to significantly reduce the TG contents in HepG2 cells. However, the desacyl flavonol glycosides and organic acids derived from the acyl groups did not exhibit an inhibitory impact on the TG contents in HepG2 cells. These results suggest that the existence of the acyl moiety at the 6'' position in the D-glucopyranosyl part is essential for glucose and lipid metabolism-promoting activities.
  • Toshio Morikawa; Akifumi Nagatomo; Kayako Kitazawa; Osamu Muraoka; Takashi Kikuchi; Takeshi Yamada; Reiko Tanaka; Kiyofumi Ninomiya
    Journal of Oleo Science Japan Oil Chemists{\textquotesingle} Society 67 (10) 1271 - 1277 1345-8957 2018
  • Tanabe, G.; Teramae, S.; Kunikata, Y.; Marumoto, S.; Okugawa, S.; Ishikawa, F.; Xie, W.; Morikawa, T.; Muraoka, O.
    Heterocycles 97 (1) 2018 [Refereed]
  • Tanabe, G.; Manse, Y.; Ogawa, T.; Sonoda, N.; Marumoto, S.; Ishikawa, F.; Ninomiya, K.; Chaipech, S.; Pongpiriyadacha, Y.; Muraoka, O.; Morikawa, T.
    Journal of Organic Chemistry 83 (15) 8250 - 8264 0022-3263 2018 [Refereed]
     
    A hitherto unreported member of γ-alkylidenebutenolides in Melodorum fruticosum (Annonaceae), (4 E)-6-benzoyloxy-7-hydroxy-2,4-heptadiene-4-olide, named as isofruticosinol (4) was isolated from the methanol extract of flowers, along with the known related butenolides, namely, the (4 Z)-isomer (3) of 4, melodrinol (1), and its (4 E)-isomer (2). To unambiguously determine the absolute configuration at the C-6 position in these butenolides, the first total syntheses of both enantiomers of 2-4 were achieved over 6-7 steps from commercially available D- or L-ribose (D- and L-5). Using the same protocol, both enantiomers of 1 were also synthesized. Based on chiral HPLC analysis of all synthetic compounds ( S- and R-1-4), all naturally occurring butenolides were assigned as partial racemic mixtures with respect to the chiral center at C-6 (enantiomeric ratio, 6 S/6 R = ∼83/17). Furthermore, the melanogenesis inhibitory activities of S- and R-1-4 were evaluated, with all shown to be potent inhibitors with IC50 values in the range 0.29-2.9 μM, regardless of differences in the stereochemistry at C-6. In particular, S-4 (IC50 = 0.29 μM) and R-4 (0.39 μM) showed potent inhibitory activities compared with that of reference standard arbutin (174 μM).
  • Taira, N.; Katsuyama, Y.; Yoshioka, M.; Muraoka, O.; Morikawa, T.
    International Journal of Molecular Sciences 19 (4) 2018 [Refereed]
     
    l-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin production, and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-l-ascorbic acid derivatives, highly stable vitamin C-alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-l-ascorbic acid derivatives (1-28) on theophylline-stimulated B16 melanoma 4A5 cells to determine if they inhibit melanogenesis and establish any structure-function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid (6, IC50 = 81.4 µM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid (20, IC50 = 117 µM) are deemed the best candidate derivatives based on their inhibitory activities and low toxicities. These derivatives are also found to be more stable than l-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-l-ascorbic acid derivatives are also determined: (i) alkylation of glyceryl-l-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivatives (2-14) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivatives (16-28); and (iii) derivatives with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that l-ascorbic acid derivatives exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1.
  • Morikawa, T.; Hachiman, I.; Ninomiya, K.; Hata, H.; Sugawara, K.; Muraoka, O.; Matsuda, H.
    Journal of Natural Medicines Springer Nature 72 (2) 464 - 473 1340-3443 2018 [Refereed]
     
    A methanol extract of mace, the aril of Myristica fragrans (Myristicaceae), was found to inhibit the release of β-hexosaminidase, a marker of antigen-IgE-stimulated degranulation in rat basophilic leukemia cells (RBL-2H3, IC50 = 45.7 μg/ml). From the extract, three new 8-O-4' type neolignans, maceneolignans I-K (1-3), were isolated, and the stereostructures of 1-3 were elucidated based on spectroscopic and chemical evidence. Among the isolates, maceneolignans A (5), D (6), and H (8), (-)-(8R)-∆8'-4-hydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan (13), (-)-(8R)-∆8'-3,4,5,3',5'-pentamethoxy-8-O-4'-neolignan (14), (-)-erythro-(7R,8S)-∆8'-7-acetoxy-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (24), verrucosin (25), and malabaricone C (29) were investigated as possible degranulation inhibitors (IC50 = 20.7-63.7 μM). These inhibitory activities were more potent than those of the antiallergic agents tranilast (282 μM) and ketotifen fumalate (158 μM). Compounds 5, 25, and 29 also inhibited antigen-stimulated tumor necrosis factor-α production (IC50 = 39.5-51.2 μM), an important process in the late phase of type I allergic reactions.
  • Morikawa, T.; Manse, Y.; Koda, M.; Chaipech, S.; Pongpiriyadacha, Y.; Muraoka, O.; Ninomiya, K.
    Journal of Natural Medicines Springer Nature 72 (2) 542 - 550 1340-3443 2018 [Refereed]
     
    Two new aromatic glycosides, elengiosides A (1) and B (2), were isolated from the methanolic extract of the flowers of Mimusops elengi (Sapotaceae) together with 26 known compounds. Their stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Among the isolates, a phenylethanoid glycoside, undatuside C (14), was found to exhibit hyaluronidase inhibitory activity.
  • Ishikawa, F.; Jinno, K.; Kinouchi, E.; Ninomiya, K.; Marumoto, S.; Xie, W.; Muraoka, O.; Morikawa, T.; Tanabe, G.
    Journal of Organic Chemistry American Chemical Society ({ACS}) 83 (1) 185 - 193 0022-3263 2018 [Refereed]
     
    A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus "Salacia", was developed using the S-alkylation of thiosugars with epoxides in HFIP (∼90%, dr, α/β = ∼ 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/β = ∼ 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3'-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose-loaded mice, at levels comparable to those of the antidiabetic agent, voglibose.
  • Morikawa, T.; Imura, K.; Akagi, Y.; Muraoka, O.; Ninomiya, K.
    Journal of Natural Medicines Springer Nature 72 (1) 317 - 325 1340-3443 2018 [Refereed]
     
    Two new gallic acid glycosides, potentillanosides G (1) and H (2), were newly isolated from the methanol extract of the tuberous roots of Potentilla anserina (Rosaceae), together with a known compound, ellagic acid 3-O-α-L-rhamnopyranoside (3). Their structures were elucidated on the basis of chemical and physicochemical evidence. Among the constituents, potentillanoside H (2, IC50 = 99.5 μM) was found to show hepatoprotective activity.
  • Morikawa, T.; Nagatomo, A.; Kitazawa, K.; Muraoka, O.; Kikuchi, T.; Yamada, T.; Tanaka, R.; Ninomiya, K.
    Journal of Oleo Science 67 (10) 1271 - 1277 1345-8957 2018 [Refereed]
     
    The seed oil of andiroba (Carapa guianensis, Meliaceae) was found to promote collagen synthesis in normal human dermal fibroblasts. To characterize the active constituents of this oil, the collagen synthesis-promoting activities of 10 principal limonoid constituents, gedunin (1), 6α-acetoxygedunin (2), 7-deacetoxy-7-oxogedunin (3), 7-deacetoxy-7α-hydroxygedunin (4), andirolide H (5), 6α-hydroxygedunin (6), methyl angolensate (7), 17β-hydroxyazadiradione (8), and carapanosides C (9) and R (10), were examined. Among them, 1-4, 6, 7, and 9 were found to significantly promote collagen synthesis without cytotoxicity at the effective concentrations.
  • Kikuchi, T.; Motoyashiki, N.; Yamada, T.; Shibatani, K.; Ninomiya, K.; Morikawa, T.; Tanaka, R.
    International Journal of Molecular Sciences {MDPI} {AG} 18 (11) 2479 - 2479 1422-0067 2017 [Refereed]
     
    Two new ergostane-type sterols; (22E)-5α,6α-epoxyergosta-8,14,22-triene-3β,7β-diol (1) and 5α,6α-epoxyergost-8(14)-ene-3β,7α-diol (2) were isolated from the fruiting bodies of king trumpet mushroom (Pleurotus eryngii), along with eight known compounds (3-10). All isolated compounds were evaluated for their inhibitory effects on aromatase. Among them, 4 and 6 exhibited comparable aromatase inhibitory activities to aminoglutethimide.
  • Manse, Y.; Ninomiya, K.; Nishi, R.; Hashimoto, Y.; Chaipech, S.; Muraoka, O.; Morikawa, T.
    Molecules {MDPI} {AG} 22 (12) 2279 - 2279 2017 [Refereed]
     
    In our continuing study of biologically active natural products from the fruit of Alpinia galanga (Zingiberaceae), we newly isolated three new labdane-type diterpenes, termed galangalditerpenes A-C (1-3), along with four known sesquiterpenes (4-7) and two diterpenes (8 and 9). The stereostructures of 1-3 were elucidated on the basis of their spectroscopic properties. The melanogenesis inhibitory activities in theophylline-stimulated murine B16 melanoma 4A5 cells of these isolates, including the new diterpenes (1-3, IC50 = 4.4, 8.6, and 4.6 μM, respectively), were found to be more than 6-87-fold higher than that of arbutin (174 μM), a commercially available positive control.
  • Tanabe, G.; Tsutsui, N.; Shibatani, K.; Marumoto, S.; Ishikawa, F.; Ninomiya, K.; Muraoka, O.; Morikawa, T.
    Tetrahedron PERGAMON-ELSEVIER SCIENCE LTD 73 (30) 4481 - 4486 0040-4020 2017 [Refereed]
     
    The first total syntheses of the geranylated pyranocoumarins, mameasins C (1) and D (2), aromatase inhibitors isolated from the flowers of Mammea siamensis, were accomplished in five steps, starting from phloroglucinol 3. In this strategy, the characteristic pyran ring-fused coumarin core of 1 and 2 was effectively constructed by Friedel-Crafts acylation of 3, followed by Reformatsky reaction of the resultant ketone to give a key coumarin intermediate 9. Compound 9 was converted to targets 1 and 2 in a stepwise manner by successive C-acylation and O-geranylation, followed by a [1,3]-sigmatropic geranyl shift. Furthermore, screening of intermediates obtained in the synthetic pathway to 1 and 2 revealed that de-geranylated pyranocoumarins (10 and 11) show superior aromatase inhibitory activity as compared to the natural products 1 and 2. (C) 2017 Elsevier Ltd. All rights reserved.
  • Manse, Y.; Ninomiya, K.; Okazaki, A.; Okada-Nishida, E.; Imagawa, T.; Imamura-Mizushima, M.; Yamano, Y.; Kaname, K.; Nakamura, S.; Morikawa, T.
    Natural Product Communications NATURAL PRODUCTS INC 12 (8) 1185 - 1188 1934-578X 2017 [Refereed]
     
    A methanol extract from the aerial part of Isodon trichocarpus (Labiatae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50 = 1.6 mu g/mL). From the extract, nine diterpenoids (1-9) and four triterpenoids (10-13) were isolated. Among the isolates, enmein (1, IC50 = 0.22 mu M), isodocarpin (2, 0.19 mu M), nodosin (4, 0.46 mu M), and oridonin (6, 0.90 mu M) showed an inhibitory effect without notable cytotoxicity at the effective concentrations. These diterpenoids (1, 2, 4, and 6) inhibited the expression of tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA, which could be the mechanism of melanogenesis inhibitory activity.
  • Shimada, H.; Urabe, Y.; Okamoto, Y.; Li, Z.; Kawase, A.; Morikawa, T.; Tu, P.; Muraoka, O.; Iwaki, M.
    Journal of Functional Foods ELSEVIER SCIENCE BV 39 91 - 95 1756-4646 2017 [Refereed]
     
    Echinacoside (ECH) and acteoside (ACT), the major constituents of Cistanche tubulosa, suppress the increase in postprandial blood glucose level. Although ECH and ACT have been reported to weakly inhibit alpha-glucosidases, the underlying mechanism remains unclear. Therefore, we focused on the regulatory mechanism of dietary glucose absorption: In this study, we aimed to clarify the inhibitory effects of ECH and ACT on sodium-dependent glucose cotransporter (SGLT) 1-mediated gastrointestinal glucose absorption. Uptake experiments were performed using human intestinal Caco-2 cells and the fluorescence glucose analogue, 2-deoxy-2-[(7-nitro-2,1,3benzoxadiazol-4-yDaminc]-n-glucose (2-NBDG). Sodium-dependent 2-NBDG uptake was successfully estimated and this uptake was completely inhibited by an SGLT inhibitor phlorizin. ECH and ACT inhibited sodium-dependent 2-NBDG uptake in a concentration-dependent manner. However, this inhibition was not observed under sodium-free condition. This study suggested that the inhibitory effects of ECH and ACT on SGLT1-mediated glucose uptake contribute to suppression of increased postprandial blood glucose level.
  • Ninomiya, K.; Chaipech, S.; Kunikata, Y.; Yagi, R.; Pongpiriyadacha, Y.; Muraoka, O.; Morikawa, T.
    International Journal of Molecular Sciences {MDPI} {AG} 18 (2) 451 - 451 1422-0067 2017 [Refereed]
     
    A simultaneous quantitative analytical method for 13 stilbenoids including (-)-hopeaphenol (1), (+)-isohopeaphenol (2), hemsleyanol D (3), (-)-ampelopsin H (4), vaticanols A (5), E (6), and G (7), (+)-α-viniferin (8), pauciflorol A (9), hopeafuran (10), (-)-balanocarpol (11), (-)-ampelopsin A (12), and trans-resveratrol 10-C-β-d-glucopyranoside (13), and two dihydroisocoumarins, phayomphenols A₁ (14) and A₂ (15) in the extract of Shorea roxburghii (dipterocarpaceae) was developed. According to the established protocol, distributions of these 15 polyphenols (1-15) in the bark and wood parts of S. roxburghii and a related plant Cotylelobium melanoxylon were evaluated. In addition, the principal polyphenols (1, 2, 8, 13-15) exhibited hepatoprotective effects against d-galactosamine (d-galN)/lipopolysaccharide (LPS)-induced liver injury in mice at a dose of 100 or 200 mg/kg, p.o. To characterize the mechanisms of action, the isolates were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes; (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages; and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of these polyphenols (1, 2, and 8) were suggested to be dependent on the inhibition of LPS-induced macrophage activation and reduction of sensitivity of hepatocytes to TNF-α. However, none of the isolates reduced the cytotoxicity caused by d-GalN.
  • 森川敏生; 森川敏生
    大阪府薬雑誌 68 (6) 51‐58 - 58 0475-0683 2017
  • 森川敏生; 森川敏生
    月刊ファインケミカル シーエムシー出版 46 (6) 13‐19 - 19 0913-6150 2017
  • Morikawa, T.; Matsuda, H.; Yoshikawa, M.
    Journal of Oleo Science 66 (8) 805 - 814 1345-8957 2017 [Refereed]
     
    Frankincense and myrrh have been used as incense in religious and cultural ceremonies since the beginning of written history. Their common medicinal properties are used in the treatment for inflammatory conditions, some cancerous diseases, and wound healing. In the course of our characterization of the anti-inflammatory constituents from frankincense and myrrh, several terpenoid constituents were found to inhibit nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages. Here we review the structure of those terpenoid constituents from the gum resins of frankincense and myrrh and evaluate their anti-inflammatory effects by their nitric oxide production inhibitory activity.
  • 矢作忠弘; 石内勘一郎; 渥美聡孝; 三宅克典; 森永紀; 伏見裕利; 大山雅義; 森川敏生; 田中謙; 有田正規; 有田正規; 牧野利明
    生薬学雑誌 The Japanese Society of Pharmacognosy 71 (1) 1 - 19 1349-9114 2017 
    The usage of Kampo medicine has been expanding in hospitals and pharmacies, and systematic education on Kampo medicines and their ingredients, crude drugs, is urgently needed. The National Examination for Pharmacists in Japan sets questions on the pharmacology and efficacy of crude drugs. Although the efficacies of Kampo formulations are approved at the national level, those of crude drugs are not approved individually except for some cases. Consequently, the efficacy description of individual crude drug in textbooks differs much depending on the authors. To clarify this situation, we developed a database for the description of the efficacy of 129 crude drugs used in ethical Kampo formulation in major textbooks from 1887 to the present, to explore the possibility of standardizing the efficacy of crude drugs. For the national examination, for example, the efficacy can be estimated by the length and the abundance of description in the textbook. Part I describes the efficacies of 67 early crude drugs in katakana order.
  • 矢作忠弘; 石内勘一郎; 渥美聡孝; 三宅克典; 森永紀; 伏見裕利; 大山雅義; 森川敏生; 田中謙; 有田正規; 有田正規; 牧野利明
    生薬学雑誌 The Japanese Society of Pharmacognosy 71 (1) 20 - 36 1349-9114 2017 
    The usage of Kampo medicine has been expanding in hospitals and pharmacies, and systematic education on Kampo medicines and their ingredients, crude drugs, is urgently needed. The National Examination for Pharmacists in Japan sets questions on the pharmacology and efficacy of crude drugs. Although the efficacies of Kampo formulations are approved at the national level, those of crude drugs are not approved individually except for some cases. Consequently, the efficacy description of individual crude drug in textbooks differs much depending on the authors. To clarify this situation, we developed a database for the description of the efficacy of 129 crude drugs used in ethical Kampo formulation in major textbooks from 1887 to the present, to explore the possibility of standardizing the efficacy of crude drugs. For example, the efficacy can be estimated by the length and the abundance of description in the textbook. Part II describes the efficacies of 62 late crude drugs in katakana order.
  • Ninomiya, K.; Shibatani, K.; Sueyoshi, M.; Chaipech, S.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.; Morikawa, T.
    Chemical and Pharmaceutical Bulletin 64 (7) 880 - 5 0009-2363 2016 [Refereed]
     
    A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit enzymatic activity against aromatase (IC50=16.5 µg/mL). From the extract, two new geranylated coumarins, mammeasins C (1) and D (2), were isolated together with seven coumarins: 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(2-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (9), 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(3-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (10), mammeas A/AA (14), A/AB (15), A/AA cyclo D (18), E/BA (23), and E/BC cyclo D (25). The structures of 1 and 2 were elucidated on the basis of spectroscopic evidence. Among the isolates including 17 previously reported coumarins, 1 (IC50=2.7 µM), 2 (3.6 µM), and mammea B/AB cyclo D (21, 3.1 µM) showed relatively strong inhibitory activities comparable to the activity of the synthetic nonsteroidal aromatase inhibitor aminoglutethimide (2.0 µM).
  • Moriyama, H.; Moriyama, M.; Ninomiya, K.; Morikawa, T.; Hayakawa, T.
    Biological and Pharmaceutical Bulletin 39 (10) 1675 - 1682 0918-6158 2016 [Refereed]
     
    Human malignant melanomas remain associated with dismal prognosis due to their resistance to apoptosis and chemotherapy. There is growing interest in plant oligostilbenoids owing to their pleiotropic biological activities, including anti-inflammatory, antioxidant, and anticancer effects. Recent studies have demonstrated that resveratrol, a well-known stilbenoid from red wine, exhibits cell cycle-disrupting and apoptosis-inducing activities on melanoma cells. The objective of our study was to evaluate the anti-melanoma effect of oligostilbenoids isolated from the bark of Shorea roxburghii. Among the isolates, four resveratrol oligomers, i.e., (-)-hopeaphenol, vaticanol B, hemsleyanol D, and (+)-α-viniferin, possessed more potent antiproliferative action than did resveratrol against SK-MEL-28 melanoma cells. Cell cycle analysis revealed that (-)-hopeaphenol, hemsleyanol D, and (+)-α-viniferin arrested cell division cycle at the G1 phase, whereas vaticanol B had little effect on the cell cycle. In addition, cell proliferation assay also revealed that (+)-α-viniferin induced DNA damage followed by induction of apoptosis in SK-MEL-28 cells, which was confirmed by an increased expression of γ-H2AX and cleaved caspase-3, respectively. The compounds vaticanol B, hemsleyanol D, and resveratrol significantly increased the expression of p21, suggesting that they are able to block cell cycle progression. Moreover, these oligostilbenoids downmodulated cylin D1 expression and extracellular signal-regulated kinase (ERK) activation. Furthermore, hemsleyanol D, (+)-α-viniferin, and resveratrol significantly decreased the expression of cyclin B1, which could also suppress cell cycle progression. The present study thus suggests that these plant oligostilbenoids are effective as therapeutic or chemopreventive agents against melanoma.
  • Kitagawa, N.; Ninomiya, K.; Okugawa, S.; Motai, C.; Nakanishi, Y.; Yoshikawa, M.; Muraoka, O.; Morikawa, T.
    Natural Product Communications 11 (7) 953 - 956 1934-578X 2016 [Refereed]
     
    A quantitative analytical method has been-developed for four alkaloids (1-4), identified as constituents responsible for the melanogenesis inhibitory activity of the.extracts of wintersweet, the flower buds of Chimonanthus praecox (L.) Link (Calycanthaceae). Concurrently, a quantitative analytical protocol has been developed for five flavonoids (5-9), which also exhibited inhibitory activity. To approve the validity of the developed protocols, five extracts of the flower buds collected in Chinese market were evaluated. The optimum conditions of separation and detection of these alkaloids (1-4) and flavonoids (5-9) were achieved on a common ODS column using a MeOH-H₂0 mobile phase with different additives [Et₂NH for alkaloids (1-4); acetic acid for flavonoids (5-9)]. The results. indicated that these assays were reproducible and precise, and could be readily utilized for evaluation of the melanogenesis inhibitory activity of -wintersweet on the basis of the content of the functional species. The principal flavonoid constituents (5-9) also exhibited lipid accumulation inhibitory activity.
  • 小林正和; 赤木淳二; 山口康代; 山崎寛生; 森川敏生; 二宮清文; 吉川雅之; 村岡修
    薬理と治療 ライフサイエンス出版(株) 44 (3) 399 - 408 0386-3603 2016 
    サラシナエキス配合食品を試験食、同エキス未配合食品をプラセボ食としてプラセボ対照二重盲検試験を行い、その長期(12週)摂取時、過剰(5倍量4週間)摂取時の安全性について検討した。長期摂取試験被験者は42名(男女各21名、平均年齢49.3歳)で、理学的検査項目は両群間に有意差はなかった。血液・生化学的検査では両群とも標準値範囲内の軽微変動で、尿検査では両群とも異常変動はなかった。血糖関連では試験食群で1,5-アンヒドロ-D-グルシトールの有意な高値を認め、両群でグリコアルブミンの有意な低下を認めた。HbA1cは両群とも大きな変動はなかった。過剰摂取試験被験者は41名(男性28名、女性13名、平均年齢48.7歳)で、理学的検査項目は両群間に有意差はなかった。血液・生化学的検査は両群とも標準値範囲内の軽微な変動であった。尿検査で異常な変動はなかった。長期摂取時・過剰摂取時とも試験食摂取と関連した有害事象は認めず、安全性を確認した。
  • Kitagawa, N.; Morikawa, T.; Motai, C.; Ninomiya, K.; Okugawa, S.; Nishida, A.; Yoshikawa, M.; Muraoka, O.
    International Journal of Molecular Sciences 17 (12) 1661-6596 2016 [Refereed]
     
    Acylated oleanane-type triterpene saponins, namely chakasaponins I (1) and II (2), floratheasaponin A (3), and their analogs, together with catechins-including (-)-epigallocatechin 3-O-gallate (4), flavonoids, and caffeine-have been isolated as characteristic functional constituents from the extracts of "tea flower", the flower buds of Camellia sinensis (Theaceae), which have common components with that of the leaf part. These isolates exhibited antiproliferative activities against human digestive tract carcinoma HSC-2, HSC-4, MKN-45, and Caco-2 cells. The antiproliferative activities of the saponins (1-3, IC50 = 4.4-14.1, 6.2-18.2, 4.5-17.3, and 19.3-40.6 µM, respectively) were more potent than those of catechins, flavonoids, and caffeine. To characterize the mechanisms of action of principal saponin constituents 1-3, a flow cytometric analysis using annexin-V/7-aminoactinomycin D (7-AAD) double staining in HSC-2 cells was performed. The percentage of apoptotic cells increased in a concentration-dependent manner. DNA fragmentation and caspase-3/7 activation were also detected after 48 h. These results suggested that antiproliferative activities of 1-3 induce apoptotic cell death via activation of caspase-3/7.
  • Manse, Y.; Ninomiya, K.; Nishi, R.; Kamei, I.; Katsuyama, Y.; Imagawa, T.; Chaipech, S.; Muraoka, O.; Morikawa, T.
    Bioorganic and Medicinal Chemistry 24 (23) 6215 - 6224 0968-0896 2016 [Refereed]
     
    An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50=7.3μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC50=2.5μM), 1'S-1'-acetoxychavicol acetate (2, 5.0μM), and 1'S-1'-acetoxyeugenol acetate (3, 5.6μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1'-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9'-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1' (IC50=1.9μM) and 2' (4.5μM)] and racemic mixtures [(±)-1 (2.2μM) and (±)-2 (4.4μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1-3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.
  • Ninomiya, K.; Motai, C.; Nishida, E.; Kitagawa, N.; Yoshihara, K.; Hayakawa, T.; Muraoka, O.; Li, X.; Nakamura, S.; Yoshikawa, M.; Matsuda, H.; Morikawa, T.
    Journal of Natural Medicines 70 (3) 435 - 51 1861-0293 2016 [Refereed]
     
    Seven oleanane-type triterpene saponin bisdesmosides, perennisaponins N-T (1-7), were newly isolated from a methanol extract of daisy, the flowers of Bellis perennis L. (Asteraceae). The structures were determined based on chemical and physicochemical data and confirmed using previously isolated related compounds as references. The isolates, including 13 previously reported perennisaponins A-M (8-20), exhibited anti-proliferative activities against human digestive tract carcinoma HSC-2, HSC-4, and MKN-45 cells. Among them, perennisaponin O (2, IC50 = 11.2, 14.3, and 6.9 μM, respectively) showed relatively strong activities. The mechanism of action of 2 against HSC-2 was found to involve apoptotic cell death.
  • Tanabe, G.; Xie, W.; Balakishan, G.; Amer, M.F.A.; Tsutsui, N.; Takemura, H.; Nakamura, S.; Akaki, J.; Ninomiya, K.; Morikawa, T.; Nakanishi, I.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 24 (16) 3705 - 15 0968-0896 2016 [Refereed]
     
    Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3'-O-position in salacinol (1), a highly potent natural α-glucosidase inhibitor from Ayurvedic traditional medicine 'Salacia', were designed and synthesized. In order to verify the computational SAR assessments, their α-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a-8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal α-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3'-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1.
  • Matsuo, K.; Koizumi, K.; Fujita, M.; Morikawa, T.; Jo, M.; Shibahara, N.; Saiki, I.; Yoshie, O.; Nakayama, T.
    Frontiers in Cell and Developmental Biology 4 (JUN) 54 - 54 2016 [Refereed]
     
    Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. Taken together, our data suggest that these crude drugs/herbs might be useful sources to develop new drugs targeting TH2-mediated allergic diseases.
  • Matsuda, H.; Nakamura, S.; Morikawa, T.; Muraoka, O.; Yoshikawa, M.
    Journal of Natural Medicines 70 (4) 689 - 701 1340-3443 2016 [Refereed]
     
    We review the biofunctional effects of the flower buds of Camellia sinensis and C. sinensis var. assamica, such as antihyperlipidemic, antihyperglycemic, antiobesity, and gastroprotective effects in vivo, and antiallergic, pancreatic lipase inhibitory, and amyloid β (Aβ) aggregation inhibitory activities in vitro. Although the biofunctional effects of tea leaves have been extensively studied, less attention has been given to those of the flowers and seeds of the tea plant. Our studies focused on the saponin constituents of the extracts of the flower buds of C. sinensis cultivated in Japan and China, and C. sinensis var. assamica cultivated in India, and we review their beneficial biofunctions for health promotion.
  • Morikawa, T.; Hachiman, I.; Matsuo, K.; Nishida, E.; Ninomiya, K.; Hayakawa, T.; Yoshie, O.; Muraoka, O.; Nakayama, T.
    Journal of Natural Products 79 (8) 2005 - 13 1520-6025 2016 [Refereed]
     
    CC chemokine receptor 3 (CCR3) is expressed selectively in eosinophils, basophils, and some Th2 cells and plays a major role in allergic diseases. A methanol extract from the arils of Myristica fragrans inhibited CC chemokine ligand 11-induced chemotaxis in CCR3-expressing L1.2 cells at 100 μg/mL. From this extract, eight new neolignans, maceneolignans A-H (1-8), were isolated, and their stereostructures were elucidated from their spectroscopic values and chemical properties. Of those constituents, compounds 1, 4, 6, and 8 and (+)-erythro-(7S,8R)-Δ(8')-7-hydroxy-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (11), (-)-(8R)-Δ(8')-3,4-methylenedioxy-3',5'-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (25), verrucosin (26), and myristicin (27) inhibited CCR3-mediated chemotaxis at a concentration of 1 μM. Among them, 1 (EC50 1.6 μM), 6 (1.5 μM), and 8 (1.4 μM) showed relatively strong activities, which were comparable to that of a synthetic CCR3 selective antagonist, SB328437 (0.78 μM).
  • Morikawa, T.; Kitagawa, N.; Tanabe, G.; Ninomiya, K.; Okugawa, S.; Motai, C.; Kamei, I.; Yoshikawa, M.; Lee, I.-J.; Muraoka, O.
    Molecules {MDPI} {AG} 21 (7) 930 - 930 1420-3049 2016 [Refereed]
     
    A quantitative analytical method for five aporphine alkaloids, nuciferine (1), nornuciferine (2), N-methylasimilobine (3), asimilobine (4), and pronuciferine (5), and five benzylisoquinoline alkaloids, armepavine (6), norarmepavine (7), N-methylcoclaurine (8), coclaurine (9), and norjuziphine (10), identified as the constituents responsible for the melanogenesis inhibitory activity of the extracts of lotus flowers (the flower buds of Nelumbo nucifera), has been developed using liquid chromatography-mass spectrometry. The optimum conditions for separation and detection of these 10 alkaloids were achieved on a πNAP column, a reversed-phase column with naphthylethyl group-bonded silica packing material, with CH₃CN-0.2% aqueous acetic acid as the mobile phase and using mass spectrometry equipped with a positive-mode electrospray ionization source. According to the protocol established, distributions of these 10 alkaloids in the petal, receptacle, and stamen parts, which were separated from the whole flower, were examined. As expected, excellent correlations were observed between the total alkaloid content and melanogenesis inhibitory activity. Among the active alkaloids, nornuciferine (2) was found to give a carbamate salt (2'') via formation of an unstable carbamic acid (2') by absorption of carbon dioxide from the air.
  • Ninomiya, K.; Miyazawa, S.; Ozeki, K.; Matsuo, N.; Muraoka, O.; Kikuchi, T.; Yamada, T.; Tanaka, R.; Morikawa, T.
    International Journal of Molecular Sciences 17 (4) 1661-6596 2016 [Refereed]
     
    Three gedunin-type limonoids, gedunin (1), 6α-acetoxygedunin (2), and 7-deacetoxy-7-oxogedunin (3), which were isolated from the seed and flower oils of andiroba (Carapa guianensis Aublet, Meliaceae), exhibited hepatoprotective effects at doses of 25 mg/kg, p.o. against d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. To characterize the mechanisms of action of 1-3 and clarify the structural requirements for their hepatoprotective effects, 17 related limonoids (1-17) isolated from the seed and/or flower oils of C. guianensis were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of 1-3 are likely to involve the inhibition of LPS-induced macrophage activation and reduced sensitivity of hepatocytes to TNF-α; however, these compounds did not decrease the cytotoxicity caused by d-GalN. In addition, the structural requirements of limonoids (1-17) for inhibition of LPS-induced NO production in mouse peritoneal macrophages and TNF-α-induced cytotoxicity in L929 cells were evaluated.
  • Ninomiya, K.; Matsumoto, T.; Chaipech, S.; Miyake, S.; Katsuyama, Y.; Tsuboyama, A.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.; Morikawa, T.
    Journal of Natural Medicines 70 (2) 179 - 89 1861-0293 2016 [Refereed]
     
    A methanol extract from the rhizomes of Kaempferia parviflora Wall. ex Baker (Zingiberaceae) has shown inhibitory effects against melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50 = 9.6 μg/mL). Among 25 flavonoids and three acetophenones isolated previously (1-28), several constituents including 5-hydroxy-7,3',4'-trimethoxyflavone (6, IC50 = 8.8 μM), 5,7,3',4'-tetramethoxyflavone (7, 8.6 μM), 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (12, 2.9 μM), and 5-hydroxy-3,7,3',4'-tetramethoxyflavone (13, 3.5 μM) showed inhibitory effects without notable cytotoxicity at the effective concentrations. Compounds 6, 7, 12, and 13 inhibited the expression of tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA, which could be the mechanism of their melanogenesis inhibitory activity. In addition, a quantitative analytical method for 12 methoxyflavones (1, 2, 4-11, 13, and 14) in the extract was developed using HPLC. The optimal condition for separation and detection of these constituents were achieved on an ODS column (3 μm particle size, 2.1 mm i.d. × 100 mm) with MeOH-0.1 % aqueous acetic acid solvent systems as the mobile phase, and the detection and quantitation limits of the method were estimated to be 0.08-0.66 ng and 0.22-2.00ng, respectively. The relative standard deviation values of intra- and interday precision were lower than 0.95 and 1.08 %, respectively, overall mean recoveries of all flavonoids were 97.9-102.9 %, and the correlation coefficients of all the calibration curves showed good linearity within the test ranges. For validation of the protocol, extracts of three kinds of the plant's rhizomes collected from different regions in Thailand (Leoi, Phetchabun, and Chiang Mai provinces) were evaluated. The results indicated that the assay was reproducible, precise, and could be readily utilized for the quality evaluation of the plant materials.
  • Morikawa, T.; Ninomiya, K.; Kuramoto, H.; Kamei, I.; Yoshikawa, M.; Muraoka, O.
    Journal of Natural Medicines 70 (1) 89 - 101 1340-3443 2016 [Refereed]
     
    A methanol extract of the flowers of Narcissus tazetta var. chinensis Roem. (Amaryllidaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. From the extract, four new phenylethanoid glycosides, tazettosides A–D (1–4), and a new phenylpropanoid glycoside, tazettoside E (5), were isolated along with 23 known compounds (6–28). Of the isolates, 1 (IC50 = 22.0 μM) and 4 (82.5 μM), 3-methoxy-8,9-methylenedioxy-3,4-dihydrophenanthridine (13, IC50 = 28.5 μM), 5,6-dihydrobicolorine (14, 23.7 μM), tazettine (16, 60.8 μM), benzyl β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (18, 27.8 μM), 2-(3,4-dimethoxyphenyl)ethyl β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (21, 74.6 μM), 3-phenylpropyl β-D-glucopyranoside (22, 59.0 μM), and cinnamyl β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (24, 88.0 μM) showed inhibitory effects without notable cytotoxicity at the effective concentrations.
  • Inoue, T.; Matsui, Y.; Kikuchi, T.; Yamada, T.; In, Y.; Muraoka, O.; Sakai, C.; Ninomiya, K.; Morikawa, T.; Tanaka, R.
    Tetrahedron PERGAMON-ELSEVIER SCIENCE LTD 71 (18) 2753 - 2760 0040-4020 2015 [Refereed]
     
    Five novel phragmalin-type limonoids, carapanolides M-Q (1-5), together with two mexicanolide-type limonoids, carapanolides R-S (6-7), were isolated from the oil of Carapa guianensis A(UBLET) (Meliaceae) seeds, a traditional medicine in Brazil and Latin American countries. Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR techniques and a Single-crystal X-ray diffraction analysis. Compounds 1-7 along with 12 known limonoids, 8-19, isolated from the flower and seed oil of C. guianensis were assayed to determine their triglyceride metabolism-promoting activities in the high glucose-pretreated human hepatocellular carcinoma cell line, HepG2. Gedunin-type limonoid: 14 (% of control at 10 mu M: 35.4 +/- 3.9), 13 (55.0 +/- 3.6 at 10 mu M), and 18 (75.4 +/- 4.2 at 10 mu M) significantly reduced TG levels in hepatocytes. (C) 2015 Elsevier Ltd. All rights reserved.
  • 中村恭子; 赤木淳二; 赤木淳二; 石伏史明; 谷恭輔; 森川敏生; 森川敏生; YUTANA Pongpiriyadacha; 村岡修; 村岡修; 村岡修; 早川尭夫; 角谷晃司; 角谷晃司
    生薬学雑誌 (一社)日本生薬学会 69 (2) 53 - 58 1349-9114 2015 
    rDNA ITS領域の塩基配列によるSalacia chinensisの鑑別について検討した。S.reticulata 3株(SR-1～3)、S.oblonga 1株(SO-1)、S.chinensis 7株(SC-1～7)を使用した。S.reticulataとS.oblongaはITS領域の配列が類似しているため鑑別困難であったが、S.chinensisはS.reticulataとS.oblongaと区別可能な特徴的な遺伝子タイプを示すことから、これらの特徴がS.chinensisの鑑別に利用可能と考えられた。
  • Tanabe, G.; Sugano, Y.; Shirato, M.; Sonoda, N.; Tsutsui, N.; Morikawa, T.; Ninomiya, K.; Yoshikawa, M.; Muraoka, O.
    Journal of Natural Products 78 (7) 1536 - 42 0163-3864 2015 [Refereed]
     
    The first total synthesis of the 7,7-dimethylaporphinoid, 4,5-didehydroguadiscine (6), originally isolated from the stems and roots of Hornschuchia oblique (Annonaceae), was achieved by the condensation of homopiperonylamine (7) with an α,α-dimethylphenylacetic acid derivative (8) and subsequent Pschorr reaction of the resulting benzylisoquinoline intermediate (22). The reported (13)C NMR data were partially revised on the basis of the analysis of HMBC spectra measured under different conditions. The melanogenesis inhibitory activity (IC50 = 4.7 μM) of 6 was 40 times stronger than that of arbutin (174 μM), which was used as reference standard. Furthermore, 6 was the most potent natural melanogenesis inhibitor within this class of compounds.
  • Morikawa, T.; Ninomiya, K.; Takamori, Y.; Nishida, E.; Yasue, M.; Hayakawa, T.; Muraoka, O.; Li, X.; Nakamura, S.; Yoshikawa, M.; Matsuda, H.
    Phytochemistry Elsevier {BV} 116 (1) 203 - 212 0031-9422 2015 [Refereed]
     
    The methanol extract from Bellis perennis (Asteraceae) flowers was found to promote collagen synthesis in normal human dermal fibroblasts (NHDFs). Seven oleanane-type triterpene saponins, perennisosides XIII-XIX, and two known saponins, bellissaponins BS5 and BS9, were isolated from the methanol extract. The structures were determined based on chemical and physicochemical data, and confirmed using previously isolated related compounds as references. Among the isolates, including 19 previously reported saponins, perennisosides XVIII, I, II, VII, IX, and XI, asterbatanoside D, bernardioside B2, and bellissaponins BS5 and BS9 significantly promoted collagen synthesis at 3-30μM without cytotoxicity.
  • Morikawa, T.; Ninomiya, K.; Akaki, J.; Kakihara, N.; Kuramoto, H.; Matsumoto, Y.; Hayakawa, T.; Muraoka, O.; Wang, L.-B.; Wu, L.-J.; Nakamura, S.; Yoshikawa, M.; Matsuda, H.
    Journal of Natural Medicines 69 (4) 494 - 506 1340-3443 2015 [Refereed]
     
    A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 μg/ml), but did not show intestinal α-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V-VII (2-4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2-4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2'-O-β-D-glucopyranoside (16, IC50 = 23.1 μM) and aureusidin 6-O-β-D-glucopyranoside (35, 24.3 μM) showed relatively strong inhibitory activities.
  • Morikawa, T.; Akaki, J.; Ninomiya, K.; Kinouchi, E.; Tanabe, G.; Pongpiriyadacha, Y.; Yoshikawa, M.; Muraoka, O.
    Nutrients 3 7 (3) 1480 - 93 2072-6643 2015 [Refereed]
     
    The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-Ay mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-Ay mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-Ay mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, α-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the α-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human α-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9-4.9 μM for maltase) as they inhibited rat small intestinal α-glucosidase. The principal sulfonium constituents (1-4) were highly stable in an artificial gastric juice. In addition, 1-4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents.
  • Sakamoto, A.; Tanaka, Y.; Yamada, T.; Kikuchi, T.; Muraoka, O.; Ninomiya, K.; Morikawa, T.; Tanaka, R.
    Fitoterapia 100 81 - 7 0367-326X 2015 [Refereed]
     
    Three new limonoids, andirolides W-Y (1-3), were isolated from the flower oil of Carapa guianasis AUBLET (Meliaceae). Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR spectra and FABMS. Seven known limonoids: 7-deacetoxy-7-oxogedunin (4), 6α-acetoxygedunin (5), methylangolensate (6), 6α-hydroxygedunin (7), 6α-acetoxy-7α-deacetoxy-7α-hydroxygedunin (8), gedunin (9), and 7-deacetoxy-7-hydroxygedunin (10) from this flower oil were evaluated for the effects on the production of NO in LPS-activated mouse peritoneal macrophages.
  • Nakamura, S.; Xu, F.; Ninomiya, K.; Nakashima, S.; Oda, Y.; Morikawa, T.; Muraoka, O.; Yoshikawa, M.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin 10 62 (10) 1026 - 31 0009-2363 2014 [Refereed]
     
    An 80% aqueous acetone extract of Cassia auriculata leaves was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the 80% aqueous acetone extract, we isolated a new benzocoumarin glycoside, avaraoside I (1), and a new flavanol dimer, avaraol I (2), together with 29 known constituents. The structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. In addition, three isolated compounds, pseudosemiglabrin (15, 0.0011%), (2S)-7,4'-dihydroxyflavan(4β→8)-catechin (22, 0.00075%), and (2S)-7,4'-dihydroxyflavan(4β→8)-gallocatechin (23, 0.092%), displayed hepatoprotective effects equivalent to that of the hepatoprotective agent, silybin.
  • Morikawa, T.; Ninomiya, K.; Imura, K.; Yamaguchi, T.; Akagi, Y.; Yoshikawa, M.; Hayakawa, T.; Muraoka, O.
    Phytochemistry 102 169 - 81 0031-9422 2014 [Refereed]
     
    A methanol extract from the tuberous roots of Potentilla anserina (Rosaceae) exhibited hepatoprotective effects against d-galactosamine (d-GalN)/lipopolysaccharide-induced liver injuries in mice. Six triterpene 28-O-monoglucopyranosyl esters, potentillanosides A-F, were isolated from the extract along with 32 known compounds, including 15 triterpenes. The structures of potentillanosides A-F were determined on the basis of spectroscopic properties and chemical evidence. Four ursane-type triterpene 28-O-monoglycosyl esters, potentillanoside A (IC50=46.7μM), 28-O-β-d-glucopyranosyl pomolic acid (IC50=9.5μM), rosamutin (IC50=35.5μM), and kaji-ichigoside F1 (IC50=14.1μM), inhibited d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes. Among these four triterpenes, potentillanoside A, rosamutin, and kaji-ichigoside F1 exhibited in vivo hepatoprotective effects at doses of 50-100mg/kg, p.o. The mode of action was ascribable to the reduction in cytotoxicity caused by d-GalN.
  • Akaki, J.; Morikawa, T.; Miyake, S.; Ninomiya, K.; Okada, M.; Tanabe, G.; Pongpiriyadacha, Y.; Yoshikawa, M.; Muraoka, O.
    Phytochemical Analysis WILEY-BLACKWELL 25 (6) 544 - 550 0958-0344 2014 [Refereed]
     
    IntroductionStems and roots of Salacia genus plants have been used in Ayurveda as a specific remedy for early stage diabetes. Previous investigations identified four sulphonium sulphates, that is, salacinol (1), kotalanol (3), ponkoranol (5) and salaprinol (7), as the compounds responsible for the anti-diabetic activity. Their desulphonates (2, 4, 6 and 8) were also isolated as active constituents. Two separate quantitative analytical protocols, that is, for 1 and 3 and for 2 and 4, have been developed recently. ObjectiveTo: validate the two analytical protocols with respect to all eight sulphoniums; evaluate the quality of a variety of Salacia samples collected in different geographical regions, that is, Thailand, Sri Lanka and India; and determine their distribution in each part of the plant, that is, stems/roots, leaves and fruits. MethodsAnalyses of four sulphonium sulphates in 32 Salacia extracts were carried out on an Asahipak NH2P-50 column, and those of the corresponding desulphonates were conducted on an Inertsil ODS-3 column. ResultsNeokotalanol (4) was the major constituent in Salacia samples from Thailand, whereas 1 was the primary constituent in extracts of the stems/roots of plants from Sri Lanka and India. These sulphoniums were only present in trace amounts in leaves and fruits of the plants. ConclusionTwo analytical protocols were successfully applied to analyse 32 Salacia samples, and revealed that sulphoniums (1-8) had characteristic distributions due to the plant part and/or due to geographical region. Copyright (c) 2014 John Wiley & Sons, Ltd. Using the recently developed two analytical protocols, the distributions of eight sulphoniums (1-8) responsible for the anti-diabetic activity of Salacia, a specific remedy for the treatment of early stage diabetes in Ayurveda, were examined in 32 extracts of Salacia samples collected in Thailand, Sri Lanka and India. The distribution of these sulphoniums in the different plant parts was also examined. Each constituent had characteristic distributions in the different plant parts and different geographical regions.
  • Morikawa, T.; Nakanishi, Y.; Ninomiya, K.; Matsuda, H.; Nakashima, S.; Miki, H.; Miyashita, Y.; Yoshikawa, M.; Hayakawa, T.; Muraoka, O.
    Journal of Natural Medicines 3 68 (3) 539 - 49 1340-3443 2014 [Refereed]
     
    A methanol extract of the flower buds of Chimonanthus praecox (L.) Link (Calycanthaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. From the extract, five dimeric pyrrolidinoindoline alkaloids and four sesquiterpenes were isolated, together with 16 known compounds. Among them, (-)-chimonanthine (1, IC50 = 0.93 μM), (-)-folicanthine (2, 1.4 μM), and (-)-calycanthidine (3, 1.8 μM) showed potent inhibitory effects without notable cytotoxicity at the effective concentrations. The most potent alkaloid (1) inhibited both tyrosinase and tyrosine-related protein-1 mRNA expressions, to which the melanogenesis inhibitory activity would be ascribable.
  • Morikawa, T.; Ninomiya, K.; Imamura, M.; Akaki, J.; Fujikura, S.; Pan, Y.; Yuan, D.; Yoshikawa, M.; Jia, X.; Li, Z.; Muraoka, O.
    Journal of Natural Medicines 3 68 (3) 561 - 6 1340-3443 2014 [Refereed]
     
    Acylated phenylethanoid glycosides, echinacoside (1) and acteoside (2), principal constituents in stems of Cistanche tubulosa (Orobanchaceae), inhibited the increase in postprandial blood glucose levels in starch-loaded mice at doses of 250-500 mg/kg p.o. These compounds (1 and 2) also significantly improved glucose tolerance in starch-loaded mice after 2 weeks of continuous administration at doses of 125 and/or 250 mg/kg/day p.o. without producing significant changes in body weight or food intake. In addition, several constituents from C. tubulosa, including 1 (IC50 = 3.1 μM), 2 (1.2 μM), isoacteoside (3, 4.6 μM), 2'-acetylacteoside (4, 0.071 μM), tubulosides A (5, 8.8 μM) and B (9, 4.0 μM), syringalide A 3-O-α-L-rhamnopyranoside (10, 1.1 μM), campneoside I (13, 0.53 μM), and kankanoside J1 (14, 9.3 μM), demonstrated potent rat lens aldose reductase inhibitory activity. In particular, the potency of compound 4 was similar to that of epalrestat (0.072 μM), a clinical aldose reductase inhibitor.
  • Weijia Xie; Genzoh Tanabe; Jinyi Xu; Xiaoming Wu; Toshio Morikawa; Masayuki Yoshikawa; Osamu Muraoka
    MINI-REVIEWS IN ORGANIC CHEMISTRY BENTHAM SCIENCE PUBL LTD 10 (2) 141 - 159 1570-193X 2013/05 [Refereed]
     
    Salacinol was isolated as the first naturally occurring sulfonium type alpha-glucosidase inhibitor from Salacia reticulata, a large woody, climbing plant widely distributed in Sri Lanka and South India, in 1997. This compound presents a quite unique zwitterionic sulfonium sulfate structure and its alpha-glucosidase inhibitory activity (in vitro) was revealed to be as potent as those of anti-diabetics used in clinic. Since then, great efforts have been made to discover other bioactive ingredients as potent -glucosidase inhibitors from the same genus of plants, which directly led to the identification of several side chain analogs of salacinol such as kotalanol, salaprinol and ponkoranol together with their de-()-sulfonated analogs. In the mean time, much attention has been focused on the total syntheses, structure activity relationship (SAR) studies on this group of natural products in order to design molecules with improved activities. Thus, as a possible result of present findings, this class of natural products has the potential to become lead compounds with potent glucosidase inhibitory activities, which could be further developed to a new class of hypoglycemic drug candidates. The present review was developed as a summary of the recent researches of total synthesis and SAR of this series of natural products. In addition, several important structural determinants including the most recent discoveries on SAR are summarized, which may provide new insights into the development of novel anti-diabetic agents.
  • Morikawa, T.; Ninomiya, K.; Xu, F.; Okumura, N.; Matsuda, H.; Muraoka, O.; Hayakawa, T.; Yoshikawa, M.
    Phytochemistry Letters ELSEVIER SCIENCE BV 6 (2) 198 - 204 1874-3900 2013 [Refereed]
     
    Two new acylated dolabellane-type diterpenes, nigellamines B-3 (9) and D (10), were isolated from Nigella sativa (Ranunculaceae) seeds using column chromatography and preparative HPLC. Their structures were determined based on chemical and physicochemical evidence, and confirmed using previously isolated related compounds as reference. Of the seed constituents, nigellamines A(2) (2), A(3) (3), A(5) (5), B-1 (6), and B-2 (7) had in vitro triglyceride metabolism-promoting activities in the high glucose-pretreated human liver carcinoma cell line, HepG2. (C) 2013 Phytochemical Society of Europe. Published by Elsevier B. V. All rights reserved.
  • Xie, W.; Tanabe, G.; Xu, J.; Wu, X.; Morikawa, T.; Yoshikawa, M.; Muraoka, O.
    Mini-Reviews in Organic Chemistry BENTHAM SCIENCE PUBL LTD 10 (2) 141 - 159 1570-193X 2013 [Refereed]
     
    Salacinol was isolated as the first naturally occurring sulfonium type alpha-glucosidase inhibitor from Salacia reticulata, a large woody, climbing plant widely distributed in Sri Lanka and South India, in 1997. This compound presents a quite unique zwitterionic sulfonium sulfate structure and its alpha-glucosidase inhibitory activity (in vitro) was revealed to be as potent as those of anti-diabetics used in clinic. Since then, great efforts have been made to discover other bioactive ingredients as potent -glucosidase inhibitors from the same genus of plants, which directly led to the identification of several side chain analogs of salacinol such as kotalanol, salaprinol and ponkoranol together with their de-()-sulfonated analogs. In the mean time, much attention has been focused on the total syntheses, structure activity relationship (SAR) studies on this group of natural products in order to design molecules with improved activities. Thus, as a possible result of present findings, this class of natural products has the potential to become lead compounds with potent glucosidase inhibitory activities, which could be further developed to a new class of hypoglycemic drug candidates. The present review was developed as a summary of the recent researches of total synthesis and SAR of this series of natural products. In addition, several important structural determinants including the most recent discoveries on SAR are summarized, which may provide new insights into the development of novel anti-diabetic agents.
  • Morikawa, T.; Lee, I.-J.; Okugawa, S.; Miyake, S.; Miki, Y.; Ninomiya, K.; Kitagawa, N.; Yoshikawa, M.; Muraoka, O.
    Natural Product Communications 11 8 (11) 1553 - 7 1934-578X 2013 [Refereed]
     
    Using the recently developed two analytical protocols, distributions were analyzed of five catechins (1-5), ten flavonoids (6-15), caffeine (16), and nine saponins (17-25) in 12 samples of flower buds of Camellia sinensis (L.) O. Kuntze, collected at different points in Taiwan. Characteristic tendencies with respect to the distribution of these constituents were observed according to the region of collection. Among the catechins, (-)-epigallocatechin 3-O-gallate (5) was the major constituent in all the samples. Notably, the content of 5 was higher in samples from the mountain regions in the middle and northern Taiwan than in samples from other regions. As for the principal flavonoids, the content of 10 was higher than that of 11 in most of the samples except those of Sijichun tea. For the saponin contents, the following trends were observed: (1) contents of chakasaponins I-III (17-19) were higher in samples from the mountain region in the middle and northern areas; and (2) contents of floratheasaponins A-F (20-25) were higher in the samples from central and southern areas.
  • Morikawa, T.; Ninomiya, K.; Miyake, S.; Miki, Y.; Okamoto, M.; Yoshikawa, M.; Muraoka, O.
    Food Chemistry 1-2 140 (1-2) 353 - 60 0308-8146 2013 [Refereed]
     
    A simultaneous quantitative analytical method for 15 major polyphenols, e.g. five catechins (1-5) and 10 flavonols (6-15), as functional constituents in the extracts of "tea flowers", the flower buds of Camellia sinensis (Theaceae), has been developed. The content of caffeine (16), which showed similar chromatographic behaviour under the analytical conditions, was also determined. To approve the validity of the newly developed protocol, thirteen extracts of the plant's flower buds collected from different regions, i.e. China, Taiwan, Japan and India, were evaluated. The results indicated that the assay was reproducible and precise, and could be readily underutilised for the quality evaluation of tea flowers on the basis of polyphenols' contents. It was noteworthy that the contents of two major constituents, kaempferol 3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (10) and kaempferol 3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranoside (11), varied by region where the flower buds were produced. A new flavonol glycoside, chakaflavonoside B (17), which was isolated in the course of this analytical study, was found to show oleic acid-albumin-induced lipid accumulation inhibitory activity.
  • Yoichiro Ohara; Takahiro Ohara; Takashi Ohrui; Toshio Morikawa; Takaaki Asamura; Hidetada Sasaki; Hiroyuki Arai
    Pediatrics international : official journal of the Japan Pediatric Society 54 (2) 227 - 32 2012/04 
    BACKGROUND: The concentration of exhaled carbon monoxide (eCO) in young children with stable asthma and during acute asthma attack is not known. METHODS: A sampling bag was developed to collect the exhaled air of preschool children. A total of 257 preschool-age children (≥ 3 years and ≤ 6 years old) were studied; 111 had a diagnosis of asthma (43 suffering a mild asthma attack and 68 without active asthmatic symptom), 99 had upper respiratory infection (URI) and 47 were healthy. RESULTS: In preschool-age children, eCO levels of those with asthma attacks (mean ± SE, 2.7 ± 0.3 p.p.m., n= 43) were significantly higher than those of subjects with asymptomatic asthma (0.5 ± 0.1 p.p.m., P < 0.05), URI (0.8 ± 0.1 p.p.m., P < 0.05) and healthy children (0.4 ± 0.1 p.p.m., P < 0.05). A multivariate linear regression model showed that eCO was higher in children with asthma attacks independent of age and gender. In 33 asthmatic children followed before and after treatment, eCO levels during asthma attacks significantly decreased after inhalation therapy with a combination of salbutamol and sodium cromoglycate (before therapy, 2.9 ± 0.4 p.p.m.; after therapy, 0.6 ± 0.1 p.p.m., P < 0.0001). CONCLUSIONS: The measurement of eCO using a novel collecting system is useful in the recognition of asthma in preschool children.
  • Chaipech, S.; Morikawa, T.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.
    Chemical and Pharmaceutical Bulletin 1 60 (1) 62 - 9 0009-2363 2012 [Refereed]
     
    Two new phenolic glycosides, kaempferiaosides A and B were isolated from the rhizomes of Kaempferia parviflora (Zingiberaceae) together with 24 known compounds. Their structures including absolute stereochemistry were elucidated on the basis of chemical and spectroscopic evidence. Among the isolates, 5,3'-dihydroxy-3,7,4'-trimethoxyflavone showed higher activity than silybin, a commercial hepatoprotective agent.
  • Morikawa, T.; Ninomiya, K.; Zhang, Y.; Yamada, T.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Hayakawa, T.; Yoshikawa, M.
    Phytochemistry Letters ELSEVIER SCIENCE BV 5 (1) 53 - 58 1874-3900 2012 [Refereed]
     
    Three new flavonol glycosides, sarmenosides V-VII (1-3), were isolated from the whole plant of Sedum sarmentosum (Crassulaseae). The structures of 1-3 were determined on the basis of spectroscopic analysis. Among the flavonoid constituents from S. sarmentosum, 1 and 3 were found to show oleic acid-albumin-induced lipid accumulation inhibitory activity. (C) 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
  • Morikawa, T.; Sueyoshi, M.; Chaipech, S.; Matsuda, H.; Nomura, Y.; Yabe, M.; Matsumoto, T.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 16 20 (16) 4968 - 77 0968-0896 2012 [Refereed]
     
    A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells. From the extract, two new geranylated coumarins, mammeasins A (1) and B (2), were isolated together with 17 known compounds including 15 coumarins. The structures of 1 and 2 were determined on the basis of their spectroscopic properties as well as of their chemical evidence. Among the isolates, 1 (IC(50) = 1.8 μM), 2 (6.4 μM), surangins B (3, 5.0 μM), C (4, 6.8 μM), and D (5, 6.2 μM), kayeassamins E (7, 6.1 μM), F (8, 6.0 μM), and G (9, 0.8 μM), mammea A/AD (11, 1.3 μM), and mammea E/BB (16, 7.9 μM) showed NO production inhibitory activity. Compounds 1, 9, and 11 were found to inhibit induction of inducible nitric oxide synthase (iNOS). With regard to mechanism of action of these active constituents (1, 9, and 11), suppression of STAT1 activation is suggested to be mainly involved in their suppression of iNOS induction.
  • Morikawa, T.; Miyake, S.; Miki, Y.; Ninomiya, K.; Yoshikawa, M.; Muraoka, O.
    Journal of Natural Medicines 4 66 (4) 608 - 13 1340-3443 2012 [Refereed]
     
    A quantitative analytical method was developed for the determination of acylated oleanane-type triterpene saponins, chakasaponins I-III (1-3) and floratheasaponins A-F (4-9), found in Camellia sinensis (Theaceae). The practical conditions for separation and detection of these saponins were established on an ODS column with methanol containing 5 mM trifluoroacetic acid as a mobile phase, and the detection and quantitation limits of the method were estimated to be 1.1-3.8 and 3.5-12.5 ng, respectively. The relative standard deviation values of intra- and interday precision were lower than 2.35 and 6.12%, respectively, overall mean recoveries of all saponins being 94.7-108.8%, and the correlation coefficients of all the calibration curves showed good linearity within the test ranges. To approve the validity of the protocol, extracts of 13 kinds of C. sinensis collected in China, Taiwan, Japan, and India were evaluated. The results indicated that the assay was reproducible and precise, and could be readily utilized for the quality evaluation of tea flowers. It was noteworthy that the distinct regional difference was observed with respect to the content of chakasaponins and floratheasaponins, more chakasaponins being contained in the extracts of tea flowers from Fujian and Sichuan provinces, China than those from Japan, Taiwan, and India. Optimum conditions for the extraction process were also established.
  • Morikawa, T.; Imura, K.; Miyake, S.; Ninomiya, K.; Matsuda, H.; Yamashita, C.; Muraoka, O.; Hayakawa, T.; Yoshikawa, M.
    Journal of Natural Medicines 1 66 (1) 39 - 48 1340-3443 2012 [Refereed]
     
    A novel sugar ester poacynose (1) was isolated from the flowers of Poacynum hendersonii together with 31 known compounds. The structure of 1 was established mainly on the basis of 1D and 2D NMR spectral data. Among the isolates, several constituents, such as kaempferol 3-O-sophoroside (5), picein (16), and 4-hydroxybenzoic acid 4-O-β-D-glucopyranoside (17) moderately promoted adipogenesis of 3T3-L1 cells. In addition, simultaneous quantitative analysis of eight flavonoid constituents from the flower and leaf parts of P. hendersonii was developed.
  • Chaipech, S.; Morikawa, T.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.
    Journal of Natural Medicines 3 66 (3) 486 - 92 1340-3443 2012 [Refereed]
     
    Two new flav-3-en-3-ol glycosides, kaempferiaosides C (3) and D(4), and two new acetophenone glycosides, kaempferiaosides E (5) and F (6), were isolated from the Thai natural medicine Krachai Dum, the rhizomes of Kaempferia parviflora Wall. ex Baker. Their structures were established mainly on the basis of 1D and 2D NMR spectral data.
  • Tanabe, G.; Nakamura, S.; Tsutsui, N.; Balakishan, G.; Xie, W.; Tsuchiya, S.; Akaki, J.; Morikawa, T.; Ninomiya, K.; Nakanishi, I.; Yoshikawa, M.; Muraoka, O.
    Chemical Communications 69 48 (69) 8646 - 8 1359-7345 2012 [Refereed]
     
    With the aid of an in silico method, α-glucosidase inhibitors with far more potent activities than salacinol (1), a potent natural α-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, have been developed.
  • Morikawa, T.; Chaipech, S.; Matsuda, H.; Hamao, M.; Umeda, Y.; Sato, H.; Tamura, H.; Kon'I, H.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 2 20 (2) 832 - 40 0968-0896 2012 [Refereed]
     
    A methanol extract of the bark of Shorea roxburghii (Dipterocarpaceae) was found to inhibit plasma glucose elevation in sucrose-loaded mice. From the extract, three new 3-ethyl-4-phenyl-3,4-dihydroisocoumarins, 1'S-dihydrophayomphenol A(2) (1) and phayomphenols B(1) (2) and B(2) (3), were isolated together with 24 known compounds including 20 stilbenoids and oligostilbenoids. The structures of 1-3 were determined on the basis of their spectroscopic properties as well as of chemical evidences. Among the isolates, (-)-hopeaphenol (6), hemsleyanol D (8), (+)-α-viniferin (15), and (-)-balanocarpol (18) showed inhibitory activity against plasma glucose elevation in sucrose-loaded rats at doses of 100-200mg/kg, p.o. To clarify the mode of action of the antihyperglycemic property, effects of these oligostilbenoids on gastric emptying in mice, those on glucose uptake in isolated intestinal tissues as well as inhibitory activities against rat intestinal α-glucosidase and rat lens aldose reductase were examined.
  • Morikawa, T.; Chaipech, S.; Matsuda, H.; Hamao, M.; Umeda, Y.; Sato, H.; Tamura, H.; Ninomiya, K.; Yoshikawa, M.; Pongpiriyadacha, Y.; Hayakawa, T.; Muraoka, O.
    Journal of Natural Medicines 3 66 (3) 516 - 24 1340-3443 2012 [Refereed]
     
    The methanol extract from the bark of Shorea roxburghii (Dipterocarpaceae, "Phayom" in Thai) was found to suppress plasma triglyceride elevation in olive oil-treated mice, and also to inhibit pancreatic lipase activity (IC(50) = 31.6 μg/ml). From the extract, two new 3-acetyl-4-phenyl-3,4-dihydroisocoumarins, phayomphenols A(1) (1) and A(2) (2) were isolated, together with 22 known compounds. The structures of 1 and 2 were elucidated on the basis of chemical and spectroscopic evidence, including X-ray crystallographic analysis. Among the isolates, several oligostilbenoids, including (-)-hopeaphenol (3) and (+)-isohopeaphenol (4), showed inhibitory effects on plasma triglyceride elevation at a dose of 200 mg/kg p.o. and pancreatic lipase inhibitory activity (IC(50) = 32.9 and 26.5 μM, respectively).
  • Morikawa, T.; Li, X.; Nishida, E.; Nakamura, S.; Ninomiya, K.; Matsuda, H.; Hamao, M.; Muraoka, O.; Hayakawa, T.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 7 59 (7) 889 - 95 0009-2363 2011 [Refereed]
     
    Five new triterpene saponins perennisosides VIII (1), IX (2), X (3), XI (4), and XII (5) were isolated from the MeOH-eluated fraction of the methanolic extract from the flowers of Bellis perennis. The MeOH-eluted fraction of the methanolic extract from the flowers of B. perennis was found to inhibit gastric emptying in olive oil-loaded mice at a dose of 200 mg/kg, per os (p.o.). The stereostructures of 1-5 were elucidated on the basis of chemical and spectroscopic evidence.
  • Muraoka, O.; Morikawa, T.; Miyake, S.; Akaki, J.; Ninomiya, K.; Pongpiriyadacha, Y.; Yoshikawa, M.
    Journal of Natural Medicines 1 65 (1) 142 - 8 1340-3443 2011 [Refereed]
     
    A quantitative analytical method for the highly polar sulfonium pseudo-sugar constituents neosalacinol (3) and neokotalanol (4), another two potent α-glucosidase inhibitors isolated from Ayurvedic traditional medicine Salacia species, was developed by employing an ion pair reagent upon chromatographic separation. The optimum conditions for separation and detection of these two constituents were achieved on an ODS column (3-µm particle size, 2.1-mm i.d. × 100 mm) with 5 mM undecafluorohexanoic acid-MeOH (99:1, v/v) as the mobile phase and using MS equipped with an electrospray ionization source. More than ten samples of Salacia from different origins were analyzed, and the results indicated that the assay was reproducible and precise and could be readily utilized for evaluation of α-glucosidase inhibitory activity of Salacia species. By combining this assay with the quantitative analytical method previously developed for salacinol (1) and kotalanol (2), a more precise and strict evaluation of α-glucosidase inhibitory activities of extracts from Salacia species (R = 0.959 for maltase and 0.795 for sucrase) was achieved.
  • Morikawa, T.; Oominami, H.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Medicines 1 65 (1) 129 - 34 1340-3443 2011 [Refereed]
     
    A new prenylaromadendrane-type diterpene, olibanumol D (1), and three new oleanane- and lupane-type triterpenes, olibanumols E (2), F (3), and G (4), were isolated from the traditional Egyptian medicine olibanum, the exuded gum-resin from Boswellia carterii Birdw. Their structures were established mainly on the basis of 1D and 2D NMR spectral data. Compounds 1 and 2 exhibited nitric oxide production inhibitory activity in lipopolysaccharide-activated mouse peritoneal macrophages.
  • Xie, W.; Tanabe, G.; Akaki, J.; Morikawa, T.; Ninomiya, K.; Minematsu, T.; Yoshikawa, M.; Wu, X.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 6 19 (6) 2015 - 22 0968-0896 2011 [Refereed]
     
    Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal α-glucosidases were evaluated. Among them, 3'-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.
  • 小林正和; 赤木淳二; 山下耕作; 森川敏生; 二宮清文; 吉川雅之; 村岡修
    薬理と治療 ライフサイエンス出版(株) 38 (6) 545 - 550 0386-3603 2010/06 
    サラシアエキス配合食品の単回摂取における食後血糖値上昇抑制効果について評価した。糖尿病境界型および空腹時血糖値正常高値者32名を対象として、クロスオーバー法による二重盲検試験にて米飯負荷試験を行い、摂食終了から0.5、1、2、3時間後の血糖値とインスリンを測定した。その結果、試験食を摂取すると糖負荷30分後の血糖値上昇が有意に抑制され、糖負荷後3時間までの血糖値の曲線下面積(AUC)も有意に低下した。また、インスリン値についても糖負荷30分後と2時間後でそれぞれ有意な上昇抑制効果が認められ、AUCも有意に低値を示した。サラシアエキス配合食品は正常にコントロールされている血糖値を下げないことが確認されており、糖尿病境界型や空腹時血糖値正常高値者が食事の際に摂取することで、食後の血糖値やインスリンの上昇を抑制できる有用な食品であると考えられた。
  • Toshio Morikawa; Osamu Muraoka; Masayuki Yoshikawa
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 130 (5) 673 - 678 0031-6903 2010/05 [Refereed]
     
    Among a variety of food materials, some are being used as resources of traditional, alternative, and/or complementary medicines all over the world. These medicinal foods are known to have not only nutritive and taste values but also medicinal effects, and they are prescribed in various traditional preparations. Regarding this point, we focused on exploring bioactive constituents in these medicinal foods, which would be applicable to remedy so-called metabolic syndrome. In this review, our recent studies on anti-hyperlipidemic saponin constituents from flowers of Bellis perennis are described.
  • MORIKAWA Toshio; MURAOKA Osamu; YOSHIKAWA Masayuki
    YAKUGAKU ZASSHI The Pharmaceutical Society of Japan 130 (5) 673 - 678 0031-6903 2010/05 
    Among a variety of food materials, some are being used as resources of traditional, alternative, and/or complementary medicines all over the world. These medicinal foods are known to have not only nutritive and taste values but also medicinal effects, and they are prescribed in various traditional preparations. Regarding this point, we focused on exploring bioactive constituents in these medicinal foods, which would be applicable to remedy so-called metabolic syndrome. In this review, our recent studies on anti-hyperlipidemic saponin constituents from flowers of Bellis perennis are described.
  • Hisashi Matsuda; Souichi Nakashima; Osama Bashir Abdel-Halim; Toshio Morikawa; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 5 58 (5) 747 - 51 0009-2363 2010/05 [Refereed]
     
    The 90% aqueous ethanol extract of an Egyptian natural medicine, the roots of Bryonia cretica L., was found to exhibit a strong inhibitory effect on the proliferation of human leukemia U937 cells. By bioassay-guided fractionation, we isolated two new cucurbitane-type triterpene glycosides, bryoniaosides A and B, were isolated from the roots of Bryonia cretica L. together with 16 known cucurbitane-type triterpenes and glycosides. The chemical structures of bryoniaosides A and B were determined on the basis of chemical and spectroscopic evidence. Effects of principal cucurbitane-type triterpenes (cucurbitacins B, D, E, and J, 23,24-dihydrocucurbitacins B and E, and hexanorcucurbitacin D) on proliferation of the cells were examined. Cucurbitacins B and E showed the greater cytotoxic effects with IC(50) values of 9.2 and 16 nM after 72 h, and their IC(50) values were equivalent to that of camptothecin. An alpha,beta-conjugated ketone moiety at the 22-24-positions and an acetoxy group at the 25-position are essential for the strong activity.
  • Osamu Muraoka; Weijia Xie; Satomi Osaki; Ayumi Kagawa; Genzoh Tanabe; Mumen F. A. Amer; Toshie Minematsu; Toshio Morikawa; Masayuki Yoshikawa
    TETRAHEDRON PERGAMON-ELSEVIER SCIENCE LTD 66 (21) 3717 - 3722 0040-4020 2010/05 
    Stereochemical structure of kotalanol (2), a highly potent a-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, was proved by alkaline catalyzed degradation of natural kotalanol (2), in which characteristic stereospecific cyclization of the degradative side chain leading to anhydroheptitols (10 and 11) was involved. (C) 2010 Elsevier Ltd. All rights reserved.
  • Yingni Pan; Toshio Morikawa; Kiyofumi Ninomiya; Katsuya Imura; Dan Yuan; Masayuki Yoshikawa; Osamu Muraoka
    Chemical & pharmaceutical bulletin 4 58 (4) 575 - 8 0009-2363 2010/04 [Refereed]
     
    Four new acylated phenylethanoid oligoglycosides, kankanosides J(1) (1), J(2) (2), K(1) (3), and K(2) (4), were isolated from stems of Cistanche tubulosa (Orobanchaceae) together with isocampneoside I (5). Their structures were elucidated on the basis of chemical and physicochemical evidence. Among them, 3-5 were found to inhibit D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Acylated Oleanane-Type Triterpene Bisdesmosides: Perennisaponins G, H, I, J, K, L, and M with Pancreatic Lipase Inhibitory Activity from the Flowers of Bellis perennis
    Morikawa T; Nishida E; Ninomiya K; Muraoka O; Li X; Nakamura S; Matsuda H; Oda Y; Yoshikawa M
    Helv. Chim. Acta 93 (3) 573 - 586 2010/03
  • Toshio Morikawa; Xuezheng Li; Eriko Nishida; Seikou Nakamura; Kiyofumi Ninomiya; Hisashi Matsuda; Yoshimi Oda; Osamu Muraoka; Masayuki Yoshikawa
    HELVETICA CHIMICA ACTA WILEY-BLACKWELL 93 (3) 573 - 586 0018-019X 2010 [Refereed]
     
    The MeOH extract from the flowers of Bellis perennis was found to show pancreatic-lipase inhibitory activity (IC(50) 455 mu g/ml). From the extract, seven new triterpene saponins named perennisaponins 0 (1; IC(50) 163 mu M), H (2; 137 mu M), 1(3: 147 mu M), J (4; 148 mu M), K (5; 223 mu M), L (6; 81.4 mu M), and M (7; 195 mu M) were isolated as pancreatic lipase inhibitors. The stereostructures of 1-7 were elucidated on the basis of chemical and spectroscopic evidence.
  • Pan, Y.; Morikawa, T.; Ninomiya, K.; Imura, K.; Yuan, D.; Yoshikawa, M.; Muraoka, O.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 58 (4) 575 - 578 0009-2363 2010 [Refereed]
     
    Four new acylated phenylethanoid oligoglycosides, kankanosides J(1) (1), J(2) (2), K-1 (3), and K-2 (4), were isolated from stems of Cistanche-tubulosa (Orobanchaceae) together with isocampneoside I (5). Their structures were elucidated on the basis of chemical and physicochemical evidence. Among them, 3-5 were found to inhibit D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Muraoka, O.; Xie, W.; Osaki, S.; Kagawa, A.; Tanabe, G.; Amer, M.F.A.; Minematsu, T.; Morikawa, T.; Yoshikawa, M.
    Tetrahedron PERGAMON-ELSEVIER SCIENCE LTD 66 (21) 3717 - 3722 0040-4020 2010 [Refereed]
     
    Stereochemical structure of kotalanol (2), a highly potent a-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, was proved by alkaline catalyzed degradation of natural kotalanol (2), in which characteristic stereospecific cyclization of the degradative side chain leading to anhydroheptitols (10 and 11) was involved. (C) 2010 Elsevier Ltd. All rights reserved.
  • Matsuda, H.; Nakashima, S.; Abdel-Halim, O.B.; Morikawa, T.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 58 (5) 747 - 751 0009-2363 2010 [Refereed]
     
    The 90% aqueous ethanol extract of an Egyptian natural medicine, the roots of Bryonia cream L., was found to exhibit a strong inhibitory effect on the proliferation of human leukemia U937 cells. By bioassay-guided fractionation, we isolated two new cucurbitane-type triterpene glycosides, bryoniaosides A and B, were isolated from the roots of Bryonia cretica L. together with 16 known cucurbitane-type triterpenes and glycosides. The chemical structures of bryoniaosides A and B were determined on the basis of chemical and spectroscopic evidence. Effects of principal cucurbitane-type triterpenes (cucurbitacins B, D, E, and J, 23,24-dihydrocucurbitacins B and E, and hexanorcucurbitacin D) on proliferation of the cells were examined. Cucurbitacins B and E showed the greater cytotoxic effects with IC50 values of 9.2 and 16 nM after 72 h, and their IC50 values were equivalent to that of camptothecin. An alpha,beta-conjugated ketone moiety at the 22-24-positions and an acetoxy group at the 25-position are essential for the strong activity.
  • Morikawa, T.; Li, X.; Nishida, E.; Nakamura, S.; Ninomiya, K.; Matsuda, H.; Oda, Y.; Muraoka, O.; Yoshikawa, M.
    Helvetica Chimica Acta WILEY-BLACKWELL 93 (3) 573 - 586 0018-019X 2010 [Refereed]
     
    The MeOH extract from the flowers of Bellis perennis was found to show pancreatic-lipase inhibitory activity (IC(50) 455 mu g/ml). From the extract, seven new triterpene saponins named perennisaponins 0 (1; IC(50) 163 mu M), H (2; 137 mu M), 1(3: 147 mu M), J (4; 148 mu M), K (5; 223 mu M), L (6; 81.4 mu M), and M (7; 195 mu M) were isolated as pancreatic lipase inhibitors. The stereostructures of 1-7 were elucidated on the basis of chemical and spectroscopic evidence.
  • 小林正和; 赤木淳二; 山下耕作; 森川敏生; 二宮清文; 吉川雅之; 村岡修
    薬理と治療 38 (6) 545 - 550 0386-3603 2010 [Refereed]
  • 森川敏生
    薬学雑誌 6 130 (6) 785 - 91 0031-6903 2010 [Refereed]
     
    Eighty percent (80%) aqueous acetone extract from fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: i) the amide moiety was essential for strong activity; ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effect at a dose of 5 mg/kg, p.o. and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
  • 森川敏生; 村岡修; 吉川雅之; 吉川雅之
    薬学雑誌 5 130 (5) 673 - 8 0031-6903 2010 [Refereed]
     
    Among a variety of food materials, some are being used as resources of traditional, alternative, and/or complementary medicines all over the world. These medicinal foods are known to have not only nutritive and taste values but also medicinal effects, and they are prescribed in various traditional preparations. Regarding this point, we focused on exploring bioactive constituents in these medicinal foods, which would be applicable to remedy so-called metabolic syndrome. In this review, our recent studies on anti-hyperlipidemic saponin constituents from flowers of Bellis perennis are described.
  • Morikawa, T.; Xu, F.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 10 58 (10) 1379 - 85 0009-2363 2010 [Refereed]
     
    The methanolic extract of the whole plant of Cyperus longus originating in Egypt was found to show antiallergic effect on ear passive cutaneous anaphylaxis reactions in mice. By bioassay-guided separation, 11 stilbenes and stilbene dimers including a novel norstilbene dimer, longusone A, and three new stilbene dimers, longusols A, B, and C, were isolated. Their structures were elucidated on the basis of chemical and physicochemical evidence. Among the isolates, longusol B (IC(50)=96 µM), luteolin (3.0 µM), resveratrol (17 µM), piceatannol (24 µM), and cassigarols E (84 µM) and G (84 µM) were found to inhibit the release of β-hexosaminidase, as a marker of antigen-induced degranulations, in rat basophilic leukemia (RBL-2H3) cells. In addition, the methanolic extract and the constituents showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (SC(50)=22 µg/ml and 2.8-29 µM, respectively).
  • Muraoka, O.; Morikawa, T.; Miyake, S.; Akaki, J.; Ninomiya, K.; Yoshikawa, M.
    Journal of Pharmaceutical and Biomedical Analysis 5 52 (5) 770 - 3 0731-7085 2010 [Refereed]
     
    A practical HPLC-MS method for the quantitative determination of salacinol (1) and kotalanol (2), potent alpha-glucosidase inhibitors from Salacia species (Hippocrateaceae) as a specific remedy for diabetes in Ayurvedic system, was developed. The optimum conditions of separation and detection of these two constituents were achieved on a Asahipak NH2P-50 column (5 mcirom particle size, 2.0 mm i.d. x 150 mm) with a CH(3)CN-H(2)O mobile phase, associated with MS using electrospray ionization source. The overall recoveries of 1 (85.8-112.6%) and 2 (99.7-106.1%), and relative standard deviation values of intra- and inter-day precision were lower than 6.8 and 8.5%, respectively. The detection (S/N=3) and quantitation limits (S/N=10) were established to be 0.015 and 0.050 ng for 1, and 0.030 and 0.10 ng for 2, respectively. The correlation coefficients of all the calibration curves showed good linearity within test ranges. The extraction process was also optimized as 2 h immersion in water under reflux. The method was applied to evaluate extracts of three kinds of Salacia species, i.e. S. reticulata, S. oblonga, and S. chinensis, and those of four different parts, i.e. roots, stems, leaves and fruits of the same material, revealing that the extract from the roots of S. reticulata had the highest contents of these compounds. The results indicated that the assay was reproducible and precise and could be readily utilized for the evaluation of Salacia species.
  • Morikawa, T.; Pan, Y.; Ninomiya, K.; Imura, K.; Yuan, D.; Yoshikawa, M.; Hayakawa, T.; Muraoka, O.
    Chemical and Pharmaceutical Bulletin 10 58 (10) 1403 - 7 0009-2363 2010 [Refereed]
     
    Three iridoid glycosides, kankanosides L, M, and N, and two acyclic monoterpene glycosides, kankanosides O and P, were isolated from fresh stems of Cistanche tubulosa (Orobanchaceae) together with eight iridoid glycosides, five acyclic monoterpene glycosides, three phenylpropanoid glycosides, and four lignan glycosides. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Morikawa, T.; Xie, Y.; Ninomiya, K.; Okamoto, M.; Muraoka, O.; Yuan, D.; Yoshikawa, M.; Hayakawa, T.
    Chemical and Pharmaceutical Bulletin 9 58 (9) 1276 - 80 0009-2363 2010 [Refereed]
     
    Four new acylated acyclic sesquiterpene oligoglycosides (1-4) were isolated from the pericarps of Sapindus rarak DC. together with four known acyclic sesquiterpene oligoglycosides, mukuroziosides Ia (5), Ib (6), IIa (7), and IIb (8). Their structures were elucidated on the basis of chemical and physicochemical evidence. These newly isolated compounds (1-4) were found to show inhibitory effects on tumor necrosis factor-alpha-induced cytotoxicity in L929 cells at concentrations of 30-100 microM.
  • Morikawa, T.; Oominami, H.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 11 58 (11) 1541 - 4 0009-2363 2010 [Refereed]
     
    Four new ursane-type triterpenes, olibanumols K (1), L (2), M (3), and N (4), were isolated from traditional Egyptian medicine olibanum, the exuded gum-resin from Boswellia carterii BIRDW. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Nakamura, S.; Takahira, K.; Tanabe, G.; Morikawa, T.; Sakano, M.; Ninomiya, K.; Yoshikawa, M.; Muraoka, O.; Nakanishi, I.
    Bioorganic and Medicinal Chemistry Letters 15 20 (15) 4420 - 3 0960-894X 2010 [Refereed]
     
    Salacinol is a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to alpha-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure-activity relationships of salacinol derivatives.
  • Morikawa, T.; Pan, Y.; Ninomiya, K.; Imura, K.; Matsuda, H.; Yoshikawa, M.; Yuan, D.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 5 18 (5) 1882 - 90 0968-0896 2010 [Refereed]
     
    The methanolic extract from fresh stems of Cistanche tubulosa (Orobanchaceae) was found to show hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the extract, three new phenylethanoid oligoglycosides, kankanosides H(1) (1), H(2) (2), and I (3), were isolated together with 16 phenylethanoid glycosides (4-19) and two acylated oligosugars (20, 21). The structures of 1-3 were determined on the basis of spectroscopic properties as well as of chemical evidence. Among the isolates, echinacoside (4, IC(50)=10.2 microM), acteoside (5, 4.6 microM), isoacteoside (6, 5.3 microM), 2'-acetylacteoside (8, 4.8 microM), and tubuloside A (10, 8.6 microM) inhibited D-GalN-induced death of hepatocytes. These five isolates, 4 (31.1 microM), 5 (17.8 microM), 6 (22.7 microM), 8 (25.7 microM), and 10 (23.2 microM), and cistantubuloside B(1) (11, 21.4 microM) also reduced TNF-alpha-induced cytotoxicity in L929 cells. Moreover, principal constituents (4-6) exhibited in vivo hepatoprotective effects at doses of 25-100mg/kg, po.
  • Toshio Morikawa; Itadaki Yamaguchi; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 11 57 (11) 1292 - 5 0009-2363 2009/11 [Refereed]
     
    A new amide, piperchabamide F (1), and two new phenylpropanoid glycosides, piperchabaosides A (2) and B (3), were isolated from 80% aqueous acetone extract from fruit of Piper chaba. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence.
  • Masayuki Yoshikawa; Toshio Morikawa; Hideo Oominami; Hisashi Matsuda
    Chemical & pharmaceutical bulletin 9 57 (9) 957 - 64 0009-2363 2009/09 [Refereed]
     
    Three new monoterpenes, olibanumols A (1), B (2), and C (3), and three new triterpenes, olibanumols H (4), I (5), and J (6), were isolated from olibanum, the exuded gum-resin from Boswellia carterii BIRDW. Their structures including the absolute configuration were determined by chemical and physicochemical evidence. Among the constituents, olibanumols A (1), H (4), and I (5), and isofouquierol (12) exhibited nitric oxide production inhibitory activity in lipopolysaccharide-activated mouse peritoneal macrophages.
  • Toshio Morikawa; Li-Bo Wang; Kiyofumi Ninomiya; Seikou Nakamura; Hisashi Matsuda; Osamu Muraoka; Li-Jun Wu; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 8 57 (8) 853 - 9 0009-2363 2009/08 [Refereed]
     
    Eight new glycosides, everlastosides F (1), G (2), H (3), I (4), J (5), K (6), L (7), and M (8), were isolated from the methanolic extract of the flowers of Helichrysum arenarium. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Osamu Muraoka; Toshio Morikawa; Yi Zhang; Kiyofumi Ninomiya; Seikou Nakamura; Hisashi Matsuda; Masayuki Yoshikawa
    TETRAHEDRON PERGAMON-ELSEVIER SCIENCE LTD 65 (21) 4142 - 4148 0040-4020 2009/05 
    Four novel megastigmanes, neosedumosides I (1), II (2), III(3), and IV (4) were isolated from the whole plant of Sedum sarmentosum (Crassulaceae). Absolute stereostructures of these constituents were determined on the basis of chemical and physicochemical evidence. Among them, 1-3 were found to show lipid accumulation inhibitory activity in HepG2 cells. Furthermore, 2 and 3 were found to also show lipid metabolism-promoting activity. (C) 2009 Elsevier Ltd. All rights reserved.
  • Li-Bo Wang; Toshio Morikawa; Seikou Nakamura; Kiyofumi Ninomiya; Hisashi Matsuda; Osamu Muraoka; Li-Jun Wu; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 78 (5) 1235 - 1242 0385-5414 2009/05 
    Five new glycosides, everlastosides A (1), B (2), C (3), D (4). and E (5), were isolated from the methanolic extract of the flowers of Helichrysum arenarium. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Kohei Yamauchi; Gen Tamura; Toru Akasaka; Toshihiko Chiba; Kohei Honda; Motoji Kishi; Hitoshi Kobayashi; Tadayuki Kuronuma; Atsushi Matsubara; Toshio Morikawa; Hiroshi Ogawa; Nobuo Ohta; Masahiko Okada; Masahiro Sasaki; Junpei Saito; Kunio Sano; Morito Satoh; Yoko Shibata; Yoshihiro Takahashi; Shingo Takanashi; Hiroshi Inoue
    Allergology international : official journal of the Japanese Society of Allergology 58 (1) 55 - 61 2009/03 
    BACKGROUND: Bronchial asthma (BA) and allergic rhinitis (AR) are thought to share a common pathogenesis. However, reports concerning the comorbidity of the two diseases in a large-scaled population are rare in Japan. In the present study, we performed an analysis on the two diseases using questionnaires that addressed the diagnosis, symptoms and period of occurrence in more than 10,000 patients with BA or AR. METHODS: Patients with BA (adult: n = 2,781, childhood: n = 3,283) and AR (n = 3,945) were enrolled in the present study during the 3 months from August 1, 2006 to October 31, 2006. RESULTS: Sixty one percent of the patients with adult BA showed symptoms of AR. Among them, 68% of the patients were diagnosed with AR. Among the patients with childhood BA, 68% showed AR symptoms and 60% were diagnosed with AR. On the other hand, 49% of AR patients showed BA symptoms and 35% of them were diagnosed with BA. The symptoms of both BA and AR in the BA and AR patients were frequent in two seasons, March and April, and September and October. In addition, BA and AR symptoms often co-occurred in the patients with BA and AR. CONCLUSIONS: Comorbidity of BA and AR was high in both populations of BA and AR. The symptoms of both BA and AR co-occurred on both a daily and seasonal basis. These results suggested that BA and AR share a common immuno-pathogenesis in the airway and need to be treated as a single airway disease.
  • Toshio Morikawa; Haihui Xie; Tao Wang; Hisashi Matsuda; Masayuki Yoshikawa
    Chemistry & biodiversity 6 (3) 411 - 20 1612-1872 2009/03 [Refereed]
     
    Six new acylated flavonol bisdesmosides, sinocrassosides A(3), A(4), A(5), A(6), A(7), and B(3) (1-6, resp.), were isolated from the MeOH extract of the whole plant of Sinocrassula indica. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Among them, 2 and 6 which have an acyl group in the 3'''-position were found to show strong inhibitory effects on aminopeptidase N activity, which were stronger than that of curcumin.
  • Morikawa, T.; Yamaguchi, I.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 57 (11) 1292 - 1295 0009-2363 2009 [Refereed]
     
    A new amide, piperchabamide F (1), and two new phenylpropanoid glycosides, piperchabaosides A (2) and B (3). were isolated front 80% aqueous acetone extract from fruit of Piper chaba. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence.
  • Yoshikawa, M.; Morikawa, T.; Oominami, H.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 57 (9) 957 - 964 0009-2363 2009 [Refereed]
     
    Three new monoterpenes, olibanumols A (1), B (2), and C (3), and three new triterpenes, olibanumols H (4), I (5), and J (6), were isolated from olibanum, the exuded gum-resin from Boswellia carterii BIRDW. Their structures including the absolute configuration were determined by chemical and physicochemical evidence. Among the constituents, olibanumols A (1), H (4), and I (5), and isofouquierol (12) exhibited nitric oxide production inhibitory activity in lipopolysaccharide-activated mouse peritoneal macrophages.
  • Wang, L.-B.; Morikawa, T.; Nakamura, S.; Ninomiya, K.; Matsuda, H.; Muraoka, O.; Wu, L.-J.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 78 (5) 1235 - 1242 0385-5414 2009 [Refereed]
     
    Five new glycosides, everlastosides A (1), B (2), C (3), D (4). and E (5), were isolated from the methanolic extract of the flowers of Helichrysum arenarium. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Morikawa, T.; Wang, L.-B.; Ninomiya, K.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Wu, L.-J.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 57 (8) 853 - 859 0009-2363 2009 [Refereed]
     
    Eight new glycosides, everlastosides F (1), G (2), H (3), I (4), J (5), K (6), L (7), and M (8), were isolated from the methanolic extract of the flowers of Helichrysum arenarium. Their structures were elucidated on the basis of chemical and physicochemical evidence.
  • Muraoka, O.; Morikawa, T.; Zhang, Y.; Ninomiya, K.; Nakamura, S.; Matsuda, H.; Yoshikawa, M.
    Tetrahedron 65 (21) 4142 - 4148 0040-4020 2009 [Refereed]
  • Asao, Y.; Morikawa, T.; Yuanyuan, X.I.E.; Okamoto, M.; Hamao, M.; Matsuda, H.; Muraoka, O.; Yuan, D.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 2 57 (2) 198 - 203 0009-2363 2009 [Refereed]
     
    The methanolic extract and its saponin fraction (methanol-eluted fraction) of the pericarps of Sapindus rarak DC. were found to suppress plasma triglyceride elevation in olive oil-treated mice. From the active fraction, three new acylated oleanane-type triterpene saponins, rarasaponins IV (1), V (2), and VI (3), were isolated. The structures of 1-3 were elucidated on the basis of chemical and spectroscopic evidence. The principle saponin constituents, hederagenin 3-O-alpha-L-arabinopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside (4) and hederagenin 3-O-(3,4-di-O-acetyl-alpha-L-arabinopyranosyl)-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside (5), showed inhibitory effects on plasma triglyceride elevation at a dose of 200 mg/kg, per os.
  • Morikawa, T.; Xie, Y.; Asao, Y.; Okamoto, M.; Yamashita, C.; Muraoka, O.; Matsuda, H.; Pongpiriyadacha, Y.; Yuan, D.; Yoshikawa, M.
    Phytochemistry 9 70 (9) 1166 - 1172 0031-9422 2009 [Refereed]
     
    The methanolic extract from the pericarps of Sapindus rarak DC. was found to show pancreatic lipase inhibitory activity (IC50=ca. 614 microg/mL). From the extract, oleanane-type triterpene oligoglycosides, rarasaponins I-III (1-3), and raraoside A (4), were isolated together with 13 known saponins and four known sesquiterpene glycosides. Among them, several saponin constituents including rarasaponins I (1, IC50=131microM) and II (2, 172microM), and raraoside A (4, 151microM) inhibited pancreatic lipase activity, which were stronger than that of theasaponin E(1) (270microM).
  • Toshio Morikawa; Li-Bo Wang; Seikou Nakamura; Kiyofumi Ninomiya; Eri Yokoyama; Hisashi Matsuda; Osamu Muraoka; Li-Jun Wu; Masayuki Yoshikawa
    Chemical and Pharmaceutical Bulletin 4 57 (4) 361 - 367 0009-2363 2009 [Refereed]
     
    The methanolic extract from the flowers of Helichrysum arenarium L. Moench was found to show inhibitory effect on tumor necrosis factor-α (TNF-α, 1 ng/ml)-induced cytotoxicity in L929 cells. From the methanolic extract, 50 constituents including four new flavanone and chalcone glycosides named arenariumosides I (1), II (2), III (3), and IV (4) were isolated. The stereostructures of 1-4 were elucidated on the basis of chemical and physicochemical evidence. Among the constituents, naringenin 7-O-β-D-glucopyranoside (7), apigenin 7-O-β-dglucopyranoside (14), apigenin 7-O-gentiobioside (16), and apigenin 7,4'-di-O-β-D-glucopyranoside (17) significantly inhibited TNF-α-induced cytotoxicity in L929 cells at 30 μM. © 2009 Pharmaceutical Society of Japan.
  • Matsuda, H.; Ninomiya, K.; Morikawa, T.; Yasuda, D.; Yamaguchi, I.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 20 17 (20) 7313 - 23 0968-0896 2009 [Refereed]
     
    The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
  • Morikawa, T.; Xie, H.; Wang, T.; Matsuda, H.; Yoshikawa, M.
    Chemistry and Biodiversity WILEY-BLACKWELL 6 (3) 411 - 420 1612-1872 2009 [Refereed]
     
    Six new acylated flavonol bisdesmosides, sinocrassosides A(3), A(4), A(5), A(6), A(7) and B-3 (1-6, resp.), were isolated from the MeOH extract of the whole plant of Sinocrassida indica. The Structures Of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Among them, 2 and 6 which have an acyl group in the 3'''-position were found to show strong inhibitory effects on aminopeptidase N activity, which were stronger than that of curcumin.
  • Toshio Morikawa; Haihui Xie; Tao Wang; Hisashi Matsuda; Masayuki Yoshikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 56 (10) 1438 - 1444 0009-2363 2008/10 [Refereed]
     
    From the methanolic extract of the whole plant of Sinocrassula indica (Crassulaceae), six new, flavonol glycosides, sinocrassosides B. (1), B, (2), C, (3), 1), (4), D-2 (5), and D., (6), were isolated together with 30 compounds. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. In addition, several constituents were found to show inhibitory effects on aminopeptidase N and aldose reductase.
  • Kiyofumi Ninomiya; Toshio Morikawa; Haihui Xie; Hisashi Matsuda; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 75 (8) 1983 - 1995 0385-5414 2008/08 [Refereed]
     
    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new acylated flavonol glycosides, sinocrassosides A(8) (1), A(9) (2), A(10) (3), A(11) (4), and A(12) (5), were isolated together with 25 compounds. The structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated compounds, sinocrassosides A(1) (6), A(2) (7), and B(2) (14) were found to show potent hepatoprotective effect.
  • Kiyofumi Ninomiya; Toshio Morikawa; Haihui Xie; Hisashi Matsuda; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 75 (8) 1983 - 1995 0385-5414 2008/08 
    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new acylated flavonol glycosides, sinocrassosides A(8) (1), A(9) (2), A(10) (3), A(11) (4), and A(12) (5), were isolated together with 25 compounds. The structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated compounds, sinocrassosides A(1) (6), A(2) (7), and B(2) (14) were found to show potent hepatoprotective effect.
  • Masayuki Yoshikawa; Toshio Morikawa; Kanako Funakoshi; Momotaro Ochi; Yutana Pongpiriyadacha; Hisashi Matsuda
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 75 (7) 1639 - 1650 0385-5414 2008/07 [Refereed]
     
    The methanolic extract from the rhizomes of Boesenbergia rotunda (Zingiberaceae) was found to exhibit potent inhibitory activities on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Through the bioassay-guided separation, six new optically active Diels-Alder type addition prenylcalcones, (+)-panduratin A (1a), (-)-panduratin A (1b), (+)-4-hydroxypanduratin A (2a), (-)-4-hydroxypanduratin A (2b), (+)-isopanduratin A (3a), and (-)-isopanduratin A (3b) were isolated to-ether with 12 known compounds [(4-14) and geraniol]. The absolute stereostrucutures of six new Compounds were elucidated on the basis of physicochemical evidence including CD spectra. Among them, the enantiomeric mixtures of panduratin A (1a, 1b) and 4-hydroxypanduratin A (2a, 2b), and pinocembrin (4) showed gastroprotective effects on ethanol- or indomethacin-induced gastric mucosal in rats.
  • 村岡修; 二宮清文; 森川敏生; 若山広子; 松田久司; 吉川雅之; 李征
    食品と開発 43 (10) 82 - 83 0911-3932 2008
  • Ninomiya, K.; Morikawa, T.; Xie, H.; Matsuda, H.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 75 (8) 1983 - 1995 0385-5414 2008 [Refereed]
     
    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new acylated flavonol glycosides, sinocrassosides A(8) (1), A(9) (2), A(10) (3), A(11) (4), and A(12) (5), were isolated together with 25 compounds. The structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated compounds, sinocrassosides A(1) (6), A(2) (7), and B(2) (14) were found to show potent hepatoprotective effect.
  • Morikawa, T.; Xie, H.; Wang, T.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 56 (10) 1438 - 44 0009-2363 2008 [Refereed]
     
    From the methanolic extract of the whole plant of Sinocrassula indica (Crassulaceae), six new flavonol glycosides, sinocrassosides B(4) (1), B(5) (2), C(1) (3), D(1) (4), D(2) (5), and D(3) (6), were isolated together with 30 compounds. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. In addition, several constituents were found to show inhibitory effects on aminopeptidase N and aldose reductase.
  • 森川敏生
    ファルマシア 公益社団法人日本薬学会 44 (6) 562 - 563 0014-8601 2008
  • Matsuda, H.; Ninomiya, K.; Morikawa, T.; Yasuda, D.; Yamaguchi, I.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 6 18 (6) 2038 - 42 0960-894X 2008 [Refereed]
     
    The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
  • Morikawa, T.; Li, X.; Nishida, E.; Ito, Y.; Matsuda, H.; Nakamura, S.; Muraoka, O.; Yoshikawa, M.
    Journal of Natural Products 5 71 (5) 828 - 35 0163-3864 2008 [Refereed]
     
    The methanolic extract and its saponin fraction (methanol-eluted fraction) of the flowers of Bellis perennis were found to suppress serum triglyceride elevation in olive oil-treated mice. From the saponin fraction, seven new triterpene saponins, perennisosides I (1), II (2), III (3), IV (4), V (5), VI (6), and VII (7), were isolated together with four known saponins, bellidioside A (8), asterbatanoside D (9), bernardioside B 2 (10), and bellissaponin BS6 (11). The stereostructures of 1- 7 were elucidated on the basis of chemical and spectroscopic evidence. Among these saponins, perennisosides I (1) and II (2) showed inhibitory effects on serum triglyceride elevation at doses of 25-50 mg/kg, po.
  • Morikawa, T.; Funakoshi, K.; Ninomiya, K.; Yasuda, D.; Miyagawa, K.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 7 56 (7) 956 - 62 0009-2363 2008 [Refereed]
     
    The methanolic extract from the rhizomes of Boesenbergia rotunda (Zingiberaceae) was found to show inhibitory effect on tumor necrosis factor-alpha (TNF-alpha)-induced cytotoxicity in L929 cells (IC(50)=6.1 microg/ml). By bioassay-guided separation, four new prenylcalcones, (+)-krachaizin A (1a), (-)-krachaizin A (1b), (+)-krachaizin B (2a), and (-)-krachaizin B (2b), and four new prenylflavanones, rotundaflavones Ia (3a), Ib (3b), IIa (4a), and IIb (4b), were isolated together with 18 known constituents (5a-7b and 8-19). The structures of eight new compounds were elucidated on the basis of physicochemical evidence. Among them, (+)-krachaizin B (2a), (-)-krachaizin B (2b), (+)-4-hydroxypanduratin A (6a), (-)-4-hydroxypanduratin A (6b), (+)-isopanduratin A (7a), (-)-isopanduratin A (7b), alpinetin (10), cardamonin (14), and 2,6-dihydroxy-4-methoxydihydrochalcone (15) significantly inhibited TNF-alpha-induced cytotoxicity in L929 cells at 10 microM. In addition, 2a, 2b, (+)-panduratins A (5a), (-)-panduratin A (5b), 6a, 7b, and geranyl-2,4-dihydroxy-6-phenylbenzoate (17) were found to show strong inhibitory effects on aminopeptidase N activity.
  • Nakamura, S.; Okazaki, Y.; Ninomiya, K.; Morikawa, T.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 12 56 (12) 1704 - 9 0009-2363 2008 [Refereed]
     
    The 80% aqueous acetone extract from the flowers of Hedychium coronarium was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. On the other hand, two new labdane-type diterpene glycosides, coronalactosides I (1) and II (2), and a new labdane-type trinorditerpene, coronadiene (3), were isolated together with 8 known compounds from the extracts, which were obtained with chloroform and 80% aqueous acetone from the flowers of H. coronarium. The structures of new constituents were elucidated on the basis of chemical and physicochemical evidence. In addition, the principal constituents, coronaririn C and 15-hydroxylabda-8(17),11,13-trien-16,15-olide, displayed hepatoprotective effects, which were stronger than that of the hepatoprotective agent, silybin.
  • Xie, Y.; Morikawa, T.; Ninomiya, K.; Imura, K.; Muraoka, O.; Yuan, D.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 11 56 (11) 1628 - 31 0009-2363 2008 [Refereed]
     
    The methanolic extract from the flowers of Punica granatum L. (Punicaceae) was found to show inhibitory effect on tumor necrosis factor-alpha (TNF-alpha, 1 ng/ml)-induced cytotoxicity in L929 cells. By bioassay-guided separation, a new taraxastane-type triterpene, punicanolic acid (1), was isolated from the active fraction (ethyl acetate-soluble fraction) together with four triterpenes (2--5), two galloyl glucoses (6, 7), two flavones (8, 9), and beta-sitosterol. Among the constituents, 1, oleanolic acid (2), maslinic acid (4), 1,2,6-tri-O-galloyl beta-D-glucopyranoside (6), 1,2-di-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl beta-D-glucopyranoside (7), and luteolin (8) significantly inhibited TNF-alpha-induced cytotoxicity in L929 cells at 30 microM.
  • Yoshikawa, M.; Li, X.; Nishida, E.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Morikawa, T.
    Chemical and Pharmaceutical Bulletin 4 56 (4) 559 - 68 0009-2363 2008 [Refereed]
     
    Six new acylated oleanane-type triterpene oligoglycosides, perennisaponins A (1), B (2), C (3), D (4), E (5), and F (6), were isolated from the flowers of Bellis perennis (Daisy flower) together with 14 saponins, nine flavonoids, and two glycosides. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence.
  • Yoshikawa, M.; Morikawa, T.; Funakoshi, K.; Ochi, M.; Pongpiriyadacha, Y.; Matsuda, H.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 75 (7) 1639 - 1650 0385-5414 2008 [Refereed]
     
    The methanolic extract from the rhizomes of Boesenbergia rotunda (Zingiberaceae) was found to exhibit potent inhibitory activities on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Through the bioassay-guided separation, six new optically active Diels-Alder type addition prenylcalcones, (+)-panduratin A (1a), (-)-panduratin A (1b), (+)-4-hydroxypanduratin A (2a), (-)-4-hydroxypanduratin A (2b), (+)-isopanduratin A (3a), and (-)-isopanduratin A (3b) were isolated to-ether with 12 known compounds [(4-14) and geraniol]. The absolute stereostrucutures of six new Compounds were elucidated on the basis of physicochemical evidence including CD spectra. Among them, the enantiomeric mixtures of panduratin A (1a, 1b) and 4-hydroxypanduratin A (2a, 2b), and pinocembrin (4) showed gastroprotective effects on ethanol- or indomethacin-induced gastric mucosal in rats.
  • Shin-ichi Nakaki; Daiki Hino; Miki Miyoshi; Hideki Nakayama; Hiroyuki Moriyoshi; Toshio Morikawa; Koji Itohara
    Forensic science international 173 (2-3) 97 - 102 2007/12 
    We developed a simple method for animal species identification of humans, dogs and cats, using a multiplex single-base primer extension reaction in the cytochrome b gene. Using this method, three points of a single nucleotide in the cytochrome b gene were examined in these species using primers of different lengths. Our method was found to be able to successfully identify humans (26 samples), dogs (21 samples) and cats (9 samples), and no differences were found among the samples from each animal species in this study. The amount of template DNA required was over 0.01 ng for humans and dogs, and over 0.1 ng for cats. The present method was able to identify animal species from hair shaft (2 cm) and forensic casework samples (blood stains and hair shafts), and is thus a useful tool for animal species (human, dog and cat) identification in forensic science.
  • Seikou Nakamura; Xuezheng Li; Hisashi Matsuda; Kiyofutni Ninomiya; Toshio Morikawa; Kikuji Yamaguti; Masayuki Yoshikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 55 (10) 1505 - 1511 0009-2363 2007/10 
    The methanolic extract from the roots of Rhodiola sachalinensis was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new glycosides, two monoterpene glycosides, two flavonol bisdesmosides, and a cyanogenic glycoside, were isolated together with 34 known compounds. The structures of new constituents were elucidated on the basis of chemical and physicochemical evidence. In addition, the principal constituents, sachalosides III and IV, rhodiosin, and trans-caffeic acid, displayed hepatoprotective effects.
  • Masayuki Yoshikawa; Tao Wang; Toshio Morikawa; Halhul Xie; Hisashi Matsuda
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 55 (9) 1308 - 1315 0009-2363 2007/09 [Refereed]
     
    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to inhibit the increase in serum glucose levels in oral administration of sucrose and glucose in rats at a dose of 250 mg/kg (p.o.). However, the extract did not inhibit the increase in serum glucose levels after intraperitoneal administration of glucose in these animals but did partly inhibit the gastric emptying. On the other hand, this extract significantly inhibited the increase in serum glucose levels after administration for 2 weeks in KK-A(y) mice, a genetically type 11 diabetic mice, at a dose of 250 mg/kg/d (p.o.) without significant changes of the weights of body, liver, and visceral fat. From the extract, four new acylated flavonol glycosides, sinocrassosides A, A, 13, and B, were isolated together with 11 flavonoids and 2 megastigmanes. The absolute stereostructures of the four new compounds were elucidated on the basis of chemical and physicochemical evidence.
  • Yi Zhang; Toshio Morikawa; Seikou Nakamura; Kiyofumi Ninomiya; Hisashi Matsuda; Osamu Muraoka; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 71 (7) 1565 - 1576 0385-5414 2007/07 [Refereed]
     
    Four new flavonol bisdesmosides, sarmenosides I, II, III, and IV, were isolated from the whole plant of Sedum sarmentosum (Crassulaceae). Their structures were elucidated on the basis of chemical and physicochemical evidence. Among them, sarmenoside III was found to show potent hepatoprotective effect (IC50 = 4.4 mu m) on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Ning Li; Toshio Morikawa; Hisashi Matsuda; Kiyofumi Ninomiya; Xian Li; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 71 (5) 1193 - 1201 0385-5414 2007/05 
    Four new flavanone oligoglycosides, theaflavanosides I, II, III, and IV, were isolated from the seeds of Camellia sinensis. The structures of theaflavanosides were elucidated on the basis of chemical and physicochemical evidence. Among them, theaflavanoside III was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Masayuki Yoshikawa; Seikou Nakamura; Kenichi Ozaki; Akira Kumahara; Toshio Morikawa; Hisashi Matsuda
    JOURNAL OF NATURAL PRODUCTS AMER CHEMICAL SOC 70 (2) 210 - 214 0163-3864 2007/02 [Refereed]
     
    In the course of our studies on antidiabetogenic compounds from natural medicines and medicinal foodstuffs, a methanolic extract of the fruits of Solanum lycocarpum showed an inhibitory effect on the increase of serum glucose levels in oral sucrose-loaded rats. Through bioassay-guided separation, three known steroidal alkaloid oligoglycosides, solamargine (1), solasonine (3), and 12-hydroxysolasonine (5), were isolated from the active fraction together with two new steroidal alkaloid oligoglycosides, robeneosides A (2) and B (4). The major constituents, solamargine (1) and solasonine (3), exhibited an inhibitory effect on the increase of serum glucose levels in oral sucrose-loaded rats. In addition, these compounds suppressed gastric emptying in mice. However, this methanolic extract from S. lycocarpum fruits did not have any effect on intestinal alpha-glucosidase (sucrase and maltase) in vitro. It was concluded that these steroidal alkaloid oligoglycosides, 1 and 3, inhibited the increase of rat serum glucose levels by suppressing the transfer of sucrose from the stomach to the small intestine.
  • Masayuki Yoshikawa; Fengming Xu; Toshio Morikawa; Yutana Pongpiriyadacha; Seikou Nakamura; Yasunobu Asao; Akira Kumahara; Hisashi Matsuda
    Chemical & pharmaceutical bulletin 2 55 (2) 308 - 16 0009-2363 2007/02 [Refereed]
     
    The methanolic extract from the male flowers of Borassus flabellifer was found to inhibit the increase of serum glucose levels in sucrose-loaded rats at a dose of 250 mg/kg, p.o. From the methanolic extract, six new spirostane-type steroid saponins, borassosides A-F (1-6), were isolated together with 23 known constituents. The structures of borassosides (1-6) were elucidated on the basis of chemical and physicochemical evidences. In addition, the principal steroid saponin, dioscin (13), inhibited the increase of serum glucose levels in sucrose-loaded rats at a dose of 50 mg/kg, p.o.
  • Toshio Morikawa; Seikou Nakamura; Yasuyo Kato; Osamu Muraoka; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 2 55 (2) 293 - 8 0009-2363 2007/02 [Refereed]
     
    New triterpene saponins, foliatheasaponins I-V, were isolated from the methanolic extract of Tencha [the leaves of Camellia sinensis (L.) O. KUNTZE (Theaceae)]. The chemical structures of these new saponins were elucidated on the basis of chemical and physicochemical evidence. Among the new saponins, foliatheasaponins II and III, were found to inhibit release of beta-hexosaminidase, as a marker of antigen-induced degranulation, in RBL-2H3 cells.
  • Fumiaki Kamada; Yoichi Mashimo; Hiroki Inoue; Chenchen Shao; Tomomitsu Hirota; Satoru Doi; Makoto Kameda; Hiroshi Fujiwara; Kimie Fujita; Tadao Enomoto; Sei Sasaki; Hiroko Endo; Reiko Takayanagi; Chifuyu Nakazawa; Toshio Morikawa; Miki Morikawa; Shigeaki Miyabayashi; Yasushi Chiba; Gen Tamura; Taro Shirakawa; Yoichi Matsubara; Akira Hata; Mayumi Tamari; Yoichi Suzuki
    International archives of allergy and immunology 144 (4) 275 - 86 2007 
    BACKGROUND: Bronchial asthma is a chronic airway disorder characterized by bronchial inflammation. Oxidative stress is a key component of inflammation. Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays a key role in cellular protection against oxidative stress. Several studies have shown that the GSTP1 geneis involved in the pathogenesis of asthma and a gene-gene interaction may occur within the GST gene superfamily. METHODS: We screened single-nucleotide polymorphisms (SNPs) at the GSTP1 locus and performed an association study in the Japanese population using two independent case-control groups (group 1: 391 pediatric patients with asthma, 462 adult patients with asthma, and 639 controls, and group 2: 115 pediatric patients with asthma and 184 controls). The effect of GSTM1 null/present genotype on the association between GSTP1 Ile105Val and asthma was also investigated. RESULTS: We identified 20 SNPs at this locus and found this region consisted of one linkage disequilibrium block represented by four SNPs (tag SNPs). The association between the Ile105Val polymorphism in the GSTP1 gene and childhood asthma was significant in both groups (p = 0.047 in group 1, and p = 0.021 in group 2). This association was only significant in patients with GSTM1-positive genotype in both groups (group 1: GSTM1 present p = 0.013 and GSTM1 null p = 0.925, and group 2: GSTM1 present p = 0.015 and GSTM1 null p = 0.362). CONCLUSIONS: These findings suggest that the GSTP1 gene is a childhood asthma susceptible gene, and the GSTM1 gene is a modifier gene of GSTP1 for the risk of childhood asthma in the Japanese population.
  • NINOMIYA KIYOFUMI; MORIKAWA TOSHIO; WAKAYAMA HIROKO; MATSUDA HISAJI; MURAOKA OSAMU; YOSHIKAWA MASAYUKI
    J Tradit Med (一社)和漢医薬学会 24 (Supplement) 80 - 80 1880-1447 2007
  • 村岡修; 二宮清文; 森川敏生; 若山広子; 松田久司; 吉川雅之
    薬学雑誌 PHARMACEUTICAL SOC JAPAN 127 (Suppl.4) 49 - 51 0031-6903 2007 [Refereed]
     
    The orobanceae parasitic plant, Cistanche tubulosa (Schrenk) R. Wight, is widely distributed in North Africa, Arabia, and Asian countries. During the course of our characterization studies on bioactive constituents from Chinese natural medicines, we have reported the isolation and structure elucidation of nine new compounds (kankanosides A-G, kankanol and kankanose) and vasorelaxant activity of the constituents.(1-2) In this study, we found that the methanolic extract from the stems of C. tubulosa showed a hepatoprotective activity on D-galactosamine (GaIN) and lipopolysaccharide (LPS)-induced liver injury in mice. Principal constituents, echinacoside, acteoside and isoacteoside also showed hepatoprotective activity in vivo. To determine the mode of action, we studied the effects of the constituents on LPS-activated macrophage and GaIN- or TNF-alpha-induced cytotoxicity. As the results, many phenyl ethanoidglycosides from C. tubulosa showed inhibitory activity on GaIN- or TNF-alpha-induced cytotoxicity and several structural requirements for the activity were suggested.
  • Toshio Morikawa; Hisashi Matsuda; Ning Li; Xian Li; Masayuki Yoshikawa
    HELVETICA CHIMICA ACTA WILEY-V C H VERLAG GMBH 90 (12) 2342 - 2348 0018-019X 2007 [Refereed]
     
    Three new acylated oleanane-type triterpene saponins, theasaponins A(6) (1), A(7) (2), and B-5 (3), were isolated from the saponin fraction of the seeds of the Japanese tea plant Camellia smensis together with the known constituent foliatheasaponin III (4). The structures of the glycosides 1-3 were elucidated on the basis of spectroscopic, chemical, and physico-chemical evidence.
  • Hisashi Matsuda; Sachiko Sugimoto; Toshio Morikawa; Koudai Matsuhira; Eri Mizuguchi; Seikou Nakamura; Masayuki Yoshikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 55 (1) 106 - 110 0009-2363 2007/01 [Refereed]
     
    The ethyl acetate-soluble fraction of the methanolic extract from the seeds of Psoralea corylifolia was found to inhibit the release of beta-hexosaminidase, as a marker of antigen-IgE-induced degranulation in RBL-2H3 cells. Sixteen constituents were isolated from the ethyl acetate-soluble fraction and several constituents, Delta(1),3-hydroxybakuchiol (IC50 = 49 mu M), Delta(3),2-hydroxybakuchiol (69 mu M, bavachin (58 mu M), and psoralidin (ca. 100 mu M), showed inhibitory activities against the antigen-induced degranulation.
  • Zhang, Y.; Morikawa, T.; Nakamura, S.; Ninomiya, K.; Matsuda, H.; Muraoka, O.; Yoshikawa, M.
    Heterocycles 71 (7) 1565 - 1576 2007 [Refereed]
  • Morikawa, T.; Matsuda, H.; Li, N.; Li, X.; Yoshikawa, M.
    Helvetica Chimica Acta WILEY-V C H VERLAG GMBH 90 (12) 2342 - 2348 0018-019X 2007 [Refereed]
     
    Three new acylated oleanane-type triterpene saponins, theasaponins A(6) (1), A(7) (2), and B-5 (3), were isolated from the saponin fraction of the seeds of the Japanese tea plant Camellia smensis together with the known constituent foliatheasaponin III (4). The structures of the glycosides 1-3 were elucidated on the basis of spectroscopic, chemical, and physico-chemical evidence.
  • Morikawa, T.; Nakamura, S.; Kato, Y.; Muraoka, O.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 55 (2) 293 - 298 0009-2363 2007 [Refereed]
     
    New triterpene saponins, foliatheasaponins I-V, were isolated from the methanolic extract of Tencha [the leaves of Camellia sinensis (L.) O. KUNTZE (Theaceae)]. The chemical structures of these new saponins were elucidated on the basis of chemical and physicochernical evidence. Among the new saponins, foliatheasaponins II and III, were found to inhibit release of beta-hexosaminidase, as a marker of antigen-induced degranulation, in RBL-2H3 cells.
  • Yoshikawa, M.; Xu, F.; Morikawa, T.; Pongpiriyadacha, Y.; Nakamura, S.; Asao, Y.; Kumahara, A.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 55 (2) 308 - 316 0009-2363 2007 [Refereed]
     
    The methanolic extract from the male flowers of Borassus flabellifer was found to inhibit the increase of serum glucose levels in sucrose-loaded rats at a dose of 250 mg/kg, p.o. From the methanolic extract, six new spirostane-type steroid saponins, borassosides A-F (1-6), were isolated together with 23 known constituents. The structures of borassosides (1-6) were elucidated on the basis of chemical and physicochemical evidences. In addition, the principal steroid saponin, dioscin (13), inhibited the increase of serum glucose levels in sucroseloaded rats at a dose of 50 mg/kg, p.o.
  • Li, N.; Morikawa, T.; Matsuda, H.; Ninomiya, K.; Li, X.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 71 (5) 1193 - 1201 0385-5414 2007 [Refereed]
     
    Four new flavanone oligoglycosides, theaflavanosides I, II, III, and IV, were isolated from the seeds of Camellia sinensis. The structures of theaflavanosides were elucidated on the basis of chemical and physicochemical evidence. Among them, theaflavanoside III was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Yoshikawa, M.; Nakamura, S.; Ozaki, K.; Kumahara, A.; Morikawa, T.; Matsuda, H.
    Journal of Natural Products 2 70 (2) 210 - 4 0163-3864 2007 [Refereed]
     
    In the course of our studies on antidiabetogenic compounds from natural medicines and medicinal foodstuffs, a methanolic extract of the fruits of Solanum lycocarpum showed an inhibitory effect on the increase of serum glucose levels in oral sucrose-loaded rats. Through bioassay-guided separation, three known steroidal alkaloid oligoglycosides, solamargine (1), solasonine (3), and 12-hydroxysolasonine (5), were isolated from the active fraction together with two new steroidal alkaloid oligoglycosides, robeneosides A (2) and B (4). The major constituents, solamargine (1) and solasonine (3), exhibited an inhibitory effect on the increase of serum glucose levels in oral sucrose-loaded rats. In addition, these compounds suppressed gastric emptying in mice. However, this methanolic extract from S. lycocarpum fruits did not have any effect on intestinal alpha-glucosidase (sucrase and maltase) in vitro. It was concluded that these steroidal alkaloid oligoglycosides, 1 and 3, inhibited the increase of rat serum glucose levels by suppressing the transfer of sucrose from the stomach to the small intestine.
  • Morikawa, T.
    Journal of Natural Medicines SPRINGER TOKYO 61 (2) 112 - 126 1340-3443 2007 [Refereed]
     
    In the course of our characterization studies on bioactive constituents from medicinal herbs, several medicinal foods and their constituents were found to show the following biological activities: (1) hepato-protective sesquiterpenes from Zedoariae Rhizoma (2) alpha-glucosidase and aldose reductase inhibitors form Salacia spices and the flowers of Chrysanthemum indicum, and (3) anti-allergic and antiinflammatory diaryloheptanoids from the barks of Myrica rubra and Acer nikoense.
  • Ninomiya, K.; Matsuda, H.; Kubo, M.; Morikawa, T.; Nishida, N.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 11 17 (11) 3059 - 64 0960-894X 2007 [Refereed]
     
    The 80% aqueous acetone extracts from the fruit (50 mg/kg/d) and seeds (12.5 and 25 mg/kg/d) of Rosa canina L., but not from the pericarps, were found to show substantial inhibitory effect on the gain of body weight and/or weight of visceral fat without affecting food intake in mice for 2 weeks after administration of the extracts. With regard to the active constituents, the principal constituent, trans-tiliroside (0.1-10 mg/kg/d), potently inhibited the gain of body weight, especially visceral fat weight, and significantly reduced blood glucose levels after glucose loading (1 g/kg, ip) in mice. On the other hand, kaempferol and p-coumaric acid lacked such effect and kaempferol 3-O-beta-D-glucopyranoside tended to reduce the gain of body weight and visceral fat weight, but not significantly, at a dose of 10 mg/kg/d. These results indicate the importance of both kaempferol 3-O-beta-D-glucopyranoside and p-coumaroyl moieties for anti-obese effects. Furthermore, a single oral administration of trans-tiliroside at a dose of 10 mg/kg increased the expression of PPAR-alpha mRNA of liver tissue in mice.
  • Yoshikawa, M.; Morikawa, T.; Zhang, Y.; Nakamura, S.; Muraoka, O.; Matsuda, H.
    Journal of Natural Products 4 70 (4) 575 - 83 0163-3864 2007 [Refereed]
     
    Two new megastigmanes, sarmentoic acid (1) and sarmentol A (2), and six new megastigmane glucosides, sedumosides A1 (3), A2 (4), A3 (5), B (6), C (7), and D (8), were isolated from the whole plant of Sedum sarmentosum together with eight known megastigmanes (9-16). The absolute stereostructures of 1-8 were elucidated on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method.
  • Yoshikawa, M.; Morikawa, T.; Asao, Y.; Fujiwara, E.; Nakamura, S.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin 4 55 (4) 606 - 12 0009-2363 2007 [Refereed]
     
    The methanolic extract from the flowers buds of Camellia japonica L. (Theaceae) were found to exhibit potent inhibitory activities on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Through bioassay-guided separation, 28-noroleanane-type triterpene oligoglycosides, camelliosides A, B, and C, and an oleanane-type triterpene oligoglycoside, camellioside D, were isolated from the methanolic extract together with five known compounds. The absolute stereostructures of camelliosides were determined on the basis of chemical and physicochemical evidence, which included the structure revision of the nortriterpene aglycons (camellenodiol and camelledionol). The principal oligoglycosides, camelliosides A and B, showed platelet aggregation activity in addition to the gastroprotective effects on ethanol- or indomethacin-induced gastric mucosal lesions in rats.
  • Yoshikawa, M.; Morikawa, T.; Kobayashi, H.; Nakamura, A.; Matsuhira, K.; Nakamura, S.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin 3 55 (3) 428 - 34 0009-2363 2007 [Refereed]
     
    The methanolic extract from the fruit of Citrullus colocynthis showed an inhibitory effect on ear passive cutaneous anaphylaxis reactions as a type I allergic model in mice. From the methanolic extract, two new cucurbitane-type triterpene glycosides, colocynthosides A and B, were isolated together with 17 known constituents. The structures of colocynthosides A and B were elucidated on the basis of chemical and physicochemical evidence. In addition, the principal cucurbitane-type triterpene glycoside, cucurbitacin E 2-O-beta-D-glucopyranoside, and its aglycon, cucurbitacin E, exhibited the antiallergic activity at a dose of 100 and 1.25 mg/kg, p.o., respectively.
  • Yoshikawa, M.; Morikawa, T.; Nakamura, S.; Li, N.; Li, X.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin 1 55 (1) 57 - 63 0009-2363 2007 [Refereed]
     
    Seven new acylated oleanane-type triterpene oligoglycosides, theasaponins A(4) (1), A(5) (2), C(1) (3), E(8) (4), E(9) (5), G(1) (6), and H(1) (7), were isolated from the seeds of Japanese tea plant (Camellia sinensis). The structures of 1-7 were elucidated on the basis of chemical and physicochemical evidence.
  • Nakamura, S.; Li, X.; Matsuda, H.; Ninomiya, K.; Morikawa, T.; Yamaguti, K.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 10 55 (10) 1505 - 11 0009-2363 2007 [Refereed]
     
    The methanolic extract from the roots of Rhodiola sachalinensis was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new glycosides, two monoterpene glycosides, two flavonol bisdesmosides, and a cyanogenic glycoside, were isolated together with 34 known compounds. The structures of new constituents were elucidated on the basis of chemical and physicochemical evidence. In addition, the principal constituents, sachalosides III and IV, rhodiosin, and trans-caffeic acid, displayed hepatoprotective effects.
  • Ninomiya, K.; Morikawa, T.; Zhang, Y.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 8 55 (8) 1185 - 91 0009-2363 2007 [Refereed]
     
    The methanol-eluted fraction of the hot water extract from the whole plant of Sedum sarmentosum (Crassulaceae) was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the active fraction, five new megastigmane glycosides, sedumosides A(4), A(5), A(6), H, and I, were isolated together with 22 megastigmane constituents. Their absolute stereostructures were elucidated on the basis of chemical and physicochemical evidence. Among them, sedumoside F(1) (IC(50)=47 microM), (3S,5R,6S,9R)-megastigmane-3,9-diol (61 microM), and myrsinionosides A (52 microM) and D (62 microM) were found to show the strong hepatoprotective activity.
  • Morikawa, T.; Zhang, Y.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 3 55 (3) 435 - 41 0009-2363 2007 [Refereed]
     
    Six new megastigmane glycosides, sedumosides E1, E2, E3, F1, F2, and G, were isolated from the whole plant of Sedum sarmentosum (Crassulaceae). The structures of new constituents including the absolute configuration were elucidated on the basis of chemical and physicochemical evidence.
  • Matsuda, H.; Sugimoto, S.; Morikawa, T.; Matsuhira, K.; Mizuguchi, E.; Nakamura, S.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 1 55 (1) 106 - 10 0009-2363 2007 [Refereed]
     
    The ethyl acetate-soluble fraction of the methanolic extract from the seeds of Psoralea corylifolia was found to inhibit the release of beta-hexosaminidase, as a marker of antigen-IgE-induced degranulation in RBL-2H3 cells. Sixteen constituents were isolated from the ethyl acetate-soluble fraction and several constituents, Delta(1),3-hydroxybakuchiol (IC(50) = 49 microM), Delta(3),2-hydroxybakuchiol (69 microM, bavachin (58 microM), and psoralidin (ca. 100 microM), showed inhibitory activities against the antigen-induced degranulation.
  • Toshio Morikawa; Hisashi Matsuda; Ning Li; Xian Li; Masayuki Yoshikawa
    Helvetica Chimica Acta 90 (12) 2342 - 2348 0018-019X 2007 
    Three new acylated oleanane-type triterpene saponins, theasaponins A 6 (1), A7 (2), and B5 (3), were isolated from the saponin fraction of the seeds of the Japanese tea plant Camellia sinensis together with the known constituent foliatheasaponin III (4). The structures of the glycosides 1-3 were elucidated on the basis of spectroscopic, chemical, and physico-chemical evidence. © 2007 Verlag Helvetica Chimica Acta AG.
  • Yoshikawa, M.; Wang, T.; Morikawa, T.; Xie, H.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin 55 (9) 1308 - 15 0009-2363 2007 [Refereed]
     
    The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to inhibit the increase in serum glucose levels in oral administration of sucrose and glucose in rats at a dose of 250 mg/kg (p.o.). However, the extract did not inhibit the increase in serum glucose levels after intraperitoneal administration of glucose in these animals but did partly inhibit the gastric emptying. On the other hand, this extract significantly inhibited the increase in serum glucose levels after administration for 2 weeks in KK-A(y) mice, a genetically type II diabetic mice, at a dose of 250 mg/kg/d (p.o.) without significant changes of the weights of body, liver, and visceral fat. From the extract, four new acylated flavonol glycosides, sinocrassosides A(1), A(2), B(1), and B(2), were isolated together with 11 flavonoids and 2 megastigmanes. The absolute stereostructures of the four new compounds were elucidated on the basis of chemical and physicochemical evidence.
  • Masayuki Yoshikawa; Toshio Morikawa; Junji Tanaka; Hiroshi Shimoda
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 68 (11) 2335 - 2342 0385-5414 2006/11 [Refereed]
     
    Novel sesquiterpene glycoside sulfate, fukinoside A, was isolated as the potassium salt from the aerial parts of Petasites japonicus. The absolute sterostructure of fukinoside A was elucidated on the basis of chemical and physicochemical evidence. In addition, fukinoside A was found to inhibit release of beta-hexosaminidase, as a marker of antigen-induced degranulation, in RBL-2H3 cells.
  • Toshio Morikawa; Fengming Xu; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 11 54 (11) 1530 - 4 0009-2363 2006/11 [Refereed]
     
    A new flavanol, erycibenin D, and two new flavans, erycibenins E and F, were isolated from the stems of Erycibe expansa originating in Thailand. The structures of new flavonoids were elucidated on the basis of chemical and physicochemical evidence. In addition, the inhibitory activities of the isolated constituents from E. expansa on lipopolysaccharide-activated nitric oxide production in mouse peritoneal macrophages were examined. Among the principal constituents, two isoflavones, clycosin (IC50 = 13 microM) and erythrinin B (18 microM), and two rotenoids, deguelin (26 microM) and rotenone (27 microM), were found to show potent inhibitory activity.
  • Masayuki Yoshikawa; Toshio Morikawa; Junji Tanaka; Hiroshi Shimoda
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 68 (11) 2335 - 2342 0385-5414 2006/11 
    Novel sesquiterpene glycoside sulfate, fukinoside A, was isolated as the potassium salt from the aerial parts of Petasites japonicus. The absolute sterostructure of fukinoside A was elucidated on the basis of chemical and physicochemical evidence. In addition, fukinoside A was found to inhibit release of beta-hexosaminidase, as a marker of antigen-induced degranulation, in RBL-2H3 cells.
  • Nakamura Seikou; Morikawa Toshio; Xie Haihui; Matsuda Hisashi; Muraoka Osamu; Yoshikawa Masayuki
    International Symposium on the Chemistry of Natural Products Symposium on the chemistry of natural products 2006 "P - 466" 2006/07
  • Morikawa Toshio; Yasuhara Tomohisa; Morimoto Tomoyuki; Manse Takaaki; Muraoka Osamu; Wang Qilong; Kubo Mizuho; Matsuda Hisashi; Yoshikawa Masayuki
    International Symposium on the Chemistry of Natural Products Symposium on the chemistry of natural products 2006 "P - 469" 2006/07
  • Matsuda Hisashi; Sugimoto Sachiko; Nakamura Seikou; Morikawa Toshio; Ninomiya Kiyofumi; Yoshikawa Masayuki
    International Symposium on the Chemistry of Natural Products Symposium on the chemistry of natural products 2006 "P - 483" 2006/07
  • Yoshikawa Masayuki; Kato Yasuyo; Morikawa Toshio; Nakamura Seikou; Nagatomo Akifumi; Matsuda Hisashi
    International Symposium on the Chemistry of Natural Products Symposium on the chemistry of natural products 2006 "P - 484" 2006/07
  • Morikawa Toshio; Xu Fengming; Matsuda Hisashi; Ninomiya Kiyofumi; Yoshikawa Masayuki
    International Symposium on the Chemistry of Natural Products Symposium on the chemistry of natural products 2006 "P - 482" 2006/07
  • Toshio Morikawa; Shin-Ichi Nakaki; Hiroyuki Moriyoshi; Hideki Nakayama; Daiki Hino; Miki Miyoshi; Koji Itohara
    Journal of forensic sciences 51 (4) 941 - 4 0022-1198 2006/07 [Refereed]
  • Toshio Morikawa; Osama Bashir Abdel-Halim; Hisashi Matsuda; Shin Ando; Osamu Muraoka; Masayuki Yoshikawa
    TETRAHEDRON PERGAMON-ELSEVIER SCIENCE LTD 62 (26) 6435 - 6442 0040-4020 2006/06 
    Three new pseudoguaiane-type sesquiterpenes, dichrocepholides A-C, and two new pseudoguaiane-type sesquiterpene dimers, dichrocepholides D and E, were isolated from the aerial part of Dichrocephala integrifolia. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, the extract and its principal sesquiterpene constituent, parthenin, showed an inhibitory activity on nitric oxide (NO) production and on induction of inducible NO synthase. (c) 2006 Published by Elsevier Ltd.
  • Toshio Morikawa; Hisashi Matsuda; Ning Li; Seikou Nakamura; Xian Li; Masayuki Yoshikawa
    HETEROCYCLES PERGAMON-ELSEVIER SCIENCE LTD 68 (6) 1139 - + 0385-5414 2006/06 
    New triterpene saponins, theasaponins E-10, E-11, E-12, E-13, and G(2), were isolated from the saponin fraction of the seeds of Camellia sinesis. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence.
  • Yoichiro Ohara; Takashi Ohrui; Toshio Morikawa; Mei He; Hiroyasu Yasuda; Mutsuo Yamaya; Hidetada Sasaki
    Pediatric pulmonology 41 (5) 470 - 4 8755-6863 2006/05 
    Carbon monoxide (CO) can be detected in exhaled air and is increased in adult and childhood persistent asthmatic patients. However, little is known about the exhaled CO concentration in episodic childhood asthma. This study aimed to clarify whether measurement of exhaled CO is useful in monitoring disease activity in children with episodic asthma. We measured exhaled CO concentration by modified Micro-Smokerlyzer in 217 elementary school children (132 boys; mean age, 10 +/- 1 (SE) years; range, 9-12 years), in whom 29 had infrequent episodic asthma without current exacerbations. We also measured exhaled CO concentrations in 22 children with episodic asthma (13 boys; mean age, 10 +/- 3 years; range, 8-12 years), who had acute mild asthmatic attacks during examination. In these patients with mild asthmatic attacks, exhaled CO was measured both before and after combination therapy with salbutamol and sodium cromoglycate (SCG) by powered nebulizer. Among 217 schoolchildren, exhaled CO levels in infrequent episodic asthmatic children (1.1 +/- 0.1 parts per million (ppm), n = 29) were not significantly different from those in healthy schoolchildren (1.0 +/- 0.1 ppm, n = 188, P > 0.68). The exhaled CO concentrations during asthma attacks in children with episodic asthma were significantly higher (5.1 +/- 0.4 ppm, n = 22) compared with those in healthy children (P < 0.001) or those in asymptomatic asthmatic children (P < 0.001). The elevated exhaled CO levels were significantly decreased after inhalation therapy of a combination of salbutamol and SCG (3.2 +/- 0.5 ppm, n = 22, P < 0.02). In conclusion, exhaled CO levels were significantly elevated during acute asthma exacerbations, and partially recovered after treatment with beta(2)-agonist and SCG in children with mild episodic asthma. These findings indicate that measurement of exhaled CO might provide another noninvasive measurement of asthma exacerbations that would be suitable for use in children with acute mild episodic asthma.
  • Haihui Xie; Toshio Morikawa; Hisashi Matsuda; Seikou Nakamura; Osamu Muraoka; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 5 54 (5) 669 - 75 0009-2363 2006/05 [Refereed]
     
    Four new iridoid glycosides, kankanosides A (1), B (2), C (3), and D (4), a chlorinated iridoid, kankanol (5), and an acyclic monoterpene glycoside, kankanoside E (6), were isolated from the methanolic extract of dried stems of Cistanche tubulosa (SCHRENK) R. WIGHT (Orobanchaceae) together with 16 known compounds. The structures of these new compounds (1-6) were determined on the basis of the chemical and physicochemical evidence.
  • Toshio Morikawa; Haihui Xie; Hisashi Matsuda; Tao Wang; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 4 54 (4) 506 - 13 0009-2363 2006/04 [Refereed]
     
    The methanol-eluted fraction of the methanolic extract from the tubers of Gymnadenia conopsea was found to show radical scavenging activities for DPPH and super oxide anion (.O2-) radicals. Three new glucosyloxybenzyl 2-isobutylmalates, gymnosides VIII, IX, and X, were isolated from this natural medicine together with 58 known constituents. The stereostructures of gymnosides were elucidated on the basis of chemical and physicochemical evidence. In addition, the phenanthrene and dihydrostilbene constituents showed radical scavenging activities and suggested the following structural requirements on radical scavenging activities; a) phenanthrenes: 1) dihydrogenation at the 9,10-positions enhances the activities, 2) the 1 or 3-p-hydroxybenzyl group enhances the activities; b) dihydrostilbenes: 1) methylation of the 3'-position reduces the activities, 2) the 2- and/or 6-p-hydroxybenzyl groups enhance the activities.
  • Morikawa, T.; Xie, H.; Matsuda, H.; Wang, T.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 54 (4) 506 - 513 0009-2363 2006 [Refereed]
     
    The methanol-eluted fraction of the methanolic extract from the tubers of Gymnadenia conopsea was found to show radical scavenging activities for DPPH and super oxide anion (O-center dot(2)-) radicals. Three new glucosyloxybenzyl 2-isobutylmalates, gymnosides VIII, IX, and X, were isolated from this natural medicine together with 58 known constituents. The stereostructures of gymnosides were elucidated on the basis of chemical and physicochemical evidence. In addition, the phenanthrene and dihydrostilbene constituents showed radical scavenging activities and suggested the following structural requirements on radical scavenging activities; a) phenanthrenes: 1) dihydrogenation at the 9,10-positions enhances the activities, 2) the 1 or 3-p-hydroxybenzyl group enhances the activities; b) dihydrostilbenes: 1) methylation of the 3 '-position reduces the activities, 2) the 2- and/or 6-p-hydroxybenzyl groups enhance the activities.
  • Morikawa, T.; Matsuda, H.; Li, N.; Nakamura, S.; Li, X.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 68 (6) 1139 - + 0385-5414 2006 [Refereed]
     
    New triterpene saponins, theasaponins E-10, E-11, E-12, E-13, and G(2), were isolated from the saponin fraction of the seeds of Camellia sinesis. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence.
  • Yoshikawa, M.; Morikawa, T.; Tanaka, J.; Shimoda, H.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 68 (11) 2335 - 2342 0385-5414 2006 [Refereed]
     
    Novel sesquiterpene glycoside sulfate, fukinoside A, was isolated as the potassium salt from the aerial parts of Petasites japonicus. The absolute sterostructure of fukinoside A was elucidated on the basis of chemical and physicochemical evidence. In addition, fukinoside A was found to inhibit release of beta-hexosaminidase, as a marker of antigen-induced degranulation, in RBL-2H3 cells.
  • Xie, H.; Morikawa, T.; Matsuda, H.; Nakamura, S.; Muraoka, O.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 54 (5) 669 - 675 0009-2363 2006 [Refereed]
     
    Four new iridiod glycosides, kankanosides A (1), B(2), C(3), and D(4), a chlorinated iridoid, kankanol (5), and an acyclic monoterpene glycoside, kankanoside E (6), were isolated from the methanolic extract of dried stems of Cistanche tubulosa (Schrenk) R. Wight (Orobanchaceae) together with 16 known compounds. The structures of these new compounds (1-6) were determined on the basis of the chemical and physicochemical evidence.
  • Morikawa, T.; Abdel-Halim, O.B.; Matsuda, H.; Ando, S.; Muraoka, O.; Yoshikawa, M.
    Tetrahedron PERGAMON-ELSEVIER SCIENCE LTD 62 (26) 6435 - 6442 0040-4020 2006 [Refereed]
     
    Three new pseudoguaiane-type sesquiterpenes, dichrocepholides A-C, and two new pseudoguaiane-type sesquiterpene dimers, dichrocepholides D and E, were isolated from the aerial part of Dichrocephala integrifolia. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, the extract and its principal sesquiterpene constituent, parthenin, showed an inhibitory activity on nitric oxide (NO) production and on induction of inducible NO synthase. (c) 2006 Published by Elsevier Ltd.
  • Morikawa, T.; Xu, F.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 54 (11) 1530 - 1534 0009-2363 2006 [Refereed]
     
    A new flavanol, erycibenin D, and two new flavans, erycibenins E and F, were isolated from the stems of Erycibe expansa originating in Thailand. The structures of new flavonoids were elucidated on the basis of chemical and physicochemical evidence. In addition, the inhibitory activities of the isolated constituents from E. expansa on lipopolysaccharide-activated nitric oxide production in mouse peritoneal macrophages were examined. Among the principal constituents, two isoflavones, clycosin (IC50=13 mu M) and erythrinin B (18 mu M), and two rotenoids, deguelin (26 mu M) and rotenone (27 mu M), were found to show potent inhibitory activity.
  • Morikawa, T.; Li, N.; Nagatomo, A.; Matsuda, H.; Li, X.; Yoshikawa, M.
    Journal of Natural Products 2 69 (2) 185 - 90 0163-3864 2006 [Refereed]
     
    Six new triterpene saponins, theasaponins A(1) (1), A(2) (2), A(3) (3), F(1) (4), F(2) (5), and F(3) (6), were isolated from the saponin fraction of the seeds of Camellia sinensis. The stereostructures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Theasaponin A(2) (2) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o., and its activity was more potent than that of omeplazole. Structure-activity relationships for theasaponins on ethanol-induced gastroprotective activities may be suggested as follows: (1) the 28-acetyl moiety enhances activity; (2) theasaponins having a 23-aldehyde group exhibit more potent activities than those with a 23-hydroxymethyl group or a 23-methoxycarbonyl group.
  • Yoshikawa, M.; Matsuda, H.; Morikawa, T.; Xie, H.; Nakamura, S.; Muraoka, O.
    Bioorganic and Medicinal Chemistry 22 14 (22) 7468 - 75 0968-0896 2006 [Refereed]
     
    The methanolic extract from the dried stems of Cistanche tubulosa (Schrenk) R. Wight was found to show an inhibitory effect on contractions induced by noradrenaline in isolated rat aortic strips. From the extract, new phenylethanoid oligoglycoside constituents, kankanosides F and G, and an acylated oligosugar, kankanose, were isolated together with 14 known compounds. The structures of these new compounds were determined on the basis of their chemical and physicochemical evidence. In addition, principal constituents, kankanoside F, kankanose, echinacoside, acteoside, and cistanoside F, showed vasorelaxant activity, and several structural requirements for the activity were clarified.
  • Yoshikawa, M.; Nishida, N.; Ninomiya, K.; Ohgushi, T.; Kubo, M.; Morikawa, T.; Matsuda, H.
    Bioorganic and Medicinal Chemistry 2 14 (2) 456 - 63 0968-0896 2006 [Refereed]
     
    The methanolic extract (200 mg/kg, p.o. and i.p.), principal coumarin constituents (isoepoxypteryxin, anomalin, and praeroside IV), and a polyacetylene constituent (falcarindiol) (25 mg/kg, i.p.) from the roots of Angelica furcijuga protected the liver injury induced by D-galactosamine (D-GalN)/lipopolysaccharide (LPS) in mice. In in vitro experiments, coumarin constituents (hyuganins A-D, anomalin, pteryxin, isopteryxin, and suksdorfin) and polyacetylene constituents [(-)-falcarinol and falcarindiol] substantially inhibited LPS-induced NO and/or TNF-alpha production in mouse peritoneal macrophages, and isoepoxypteryxin inhibited D-GalN-induced cytotoxicity in primary cultured rat hepatocytes. Furthermore, hyuganin A, anomalin, and isopteryxin inhibited the decrease in cell viability by TNF-alpha in L929 cells.
  • Matsuda, H.; Ando, S.; Kato, T.; Morikawa, T.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 1 14 (1) 138 - 42 0968-0896 2006 [Refereed]
     
    The 80% aqueous acetone extract from the rhizomes of Alpinia officinarum, a Chinese medicinal herb, were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Through bioassay-guided separation, two diarylheptanoids [7-(4''-hydroxy-3''-methoxyphenyl-1-phenylhept-4-en-3-one and 3,5-dihydroxy-1,7-diphenylheptane] and a flavonol constituent (galangin) substantially inhibited LPS-induced NO production with IC50 values of 33-62 microM. To clarify structure-activity relationships of diarylheptanoids, related diarylheptanoids from Curcuma zedoaria were examined. Results indicate that the double bond or enone moiety at the 1-7 positions is important for the activity.
  • Morikawa, T.; Xie, H.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Products 6 69 (6) 881 - 6 0163-3864 2006 [Refereed]
     
    Seven new glucosyloxybenzyl 2-isobutylmalates, gymnosides I-VII (1-7), were isolated from the tubers of Gymnadenia conopsea. The structures of 1-7 were determined on the basis of chemical and physicochemical evidence.
  • Shimoda, H.; Tanaka, J.; Yamada, E.; Morikawa, T.; Kasajima, N.; Yoshikawa, M.
    Journal of Agricultural and Food Chemistry 8 54 (8) 2915 - 20 0021-8561 2006 [Refereed]
     
    Pollenosis is a disease that affects 1 in 10 of the Japanese population. During the season of cedar pollen dispersal, many patients suffer from symptoms such as sniffling, sternutation, and itching of the eyes. Japanese butterbur is a popular vegetable and is one of the few domestic vegetables in Japan. The anti type I allergic effects of an aqueous ethanol extract from aerial parts of Japanese butterbur (JBE) were evaluated in rats and RBL-2H3 mast cells. In the passive cutaneous anaphylaxis reaction in rats, a single oral treatment of JBE (1000 mg/kg) was found to suppress the reaction. In IgE-sensitized RBL-2H3 cells, JBE (10-100 microg/mL) inhibited beta-hexosaminidase release, leukotriene C(4)/D(4)/E(4) synthesis, and TNF-alpha production. Moreover, a high concentration of JBE (1000 microg/mL) suppressed smooth muscle constriction induced by histamine (10 microM) and leukotriene D(4) (10 nM) in a guinea pig trachea strip. The search for components in JBE with an inhibitory activity on mast cell degranulation was guided by inhibition of beta-hexsosaminidase release. Two eremophilane-type sesquiterpenes, six polyphenolic compounds, and two triterpene glycosides were isolated. Of these compounds, fukinolic acid, a principal polyphenol constituent, showed potent inhibitory activity (IC(50) value = 2.1 microg/mL). Consequently, On the basis of its inhibition of mast cell activation and direct smooth muscle reaction induced by released mediators, JBE was found to suppress the type I allergic reaction.
  • Masayuki Yoshikawa; Toshio Morikawa; Ning Li; Akifumi Nagatomo; Xian Li; Hisashi Matsuda
    Chemical & pharmaceutical bulletin 12 53 (12) 1559 - 64 0009-2363 2005/12 [Refereed]
     
    The saponin fraction from the seeds of the tea plant [Camellia sinensis (L.) O. KUNTZE (Theaceae)] was found to exhibit potent protective effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats. Five new triterpene saponins, theasaponins E3 (1), E4 (2), E5 (3), E6 (4), and E7 (5), were isolated together with 11 known saponins from the saponin fraction. The chemical structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated saponins, theasaponins E1 (6), E2 (7), and E5 (3) and assamsaponin C (10) showed an inhibitory effect on ethanol-induced gastric mucosal lesions at a dose of 5.0 mg/kg, p.o. and their activities were stronger than that of omeplazole. With regard to the structure-activity relationships of theasaponins, the following structural requirements for a protective effect on ethanol-induced gastric lesions were suggested; 1) the 21- and/or 22-acyl groups are essential for the activity, 2) acetylation of the 16-hydroxyl group reduce the activity.
  • HH Xie; T Wang; H Matsuda; T Morikawa; M Yoshikawa; T Tani
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 53 (11) 1416 - 1422 0009-2363 2005/11 [Refereed]
     
    The 80% aqueous acetone extract from the whole plant of Saussurea medusa MAXIM. was found to inhibit rat lens aldose reductase (IC50=1.4 mu g/ml). From this extract, flavonoids, lignans, and quinic acid derivatives were isolated together with two new ionone glycosides, saussureosides A and B. Their absolute stereostructures were elucidated on the basis of chemical and physicochemical evidence including the application of modified Mosher's method. In addition, some isolates were found to show an inhibitory effect on aldose reductase.
  • Toshio Morikawa; Shin Ando; Hisashi Matsuda; Shinya Kataoka; Osamu Muraoka; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 6 53 (6) 625 - 30 0009-2363 2005/06 [Refereed]
     
    The 80% aqueous acetone extract from the rhizomes of Alpinia galanga showed nitric oxide (NO) production inhibitory activities in mouse peritoneal macrophages. From the aqueous acetone extract, three new 8-9' linked neolignans, galanganal, galanganols A and B, and a sesquineolignan, galanganol C, were isolated together with nine known phenylpropanoids and p-hydroxybenzaldehyde. The structures of new neolignans were determined on the basis of physicochemical and chemical evidence. In addition, the inhibitory effects of the constituents from the rhizomes of A. galanga on NO production induced by lipopolysaccharide in mouse peritoneal macrophages were examined. Among them, galanganal (IC50=68 microM), galanganols B (88 microM) and C (33 microM), 1'S-1'-acetoxychavicol acetate (2.3 microM), 1'S-1'-acetoxyeugenol acetate (11 microM), trans-p-hydroxycinnamaldehyde (ca. 20 microM), trans-p-coumaryl alcohol (72 microM), and trans-p-coumaryl diacetate (19 microM) were found to show inhibitory activity.
  • Hisashi Matsuda; Toshio Morikawa; Teruki Ohgushi; Tomoko Ishiwada; Norihisa Nishida; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 4 53 (4) 387 - 92 0009-2363 2005/04 [Refereed]
     
    The methanolic extract from the flowers of Angelica furcijuga KITAGAWA was found to inhibit nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages. From the methanolic extract, two new glycosides, hyuganosides IV and V, were isolated together with 28 known constituents. The structures of the new constituents were determined on the basis of chemical and physicochemical evidence. Furthermore, the inhibitory effects of 11 coumarin constituents on nitric oxide production were examined. Among them, 3'-angeloyl-cis-khellactone (IC(50)=82 microM), (S)-(-)-oxypeucedanin (57 microM), imperatorin (60 microM), isoepoxypteryxin (53 microM), and isopteryxin (8.8 microM) showed inhibitory activity.
  • Yoshikawa, M.; Morikawa, T.; Li, N.; Nagatomo, A.; Li, X.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 53 (12) 1559 - 1564 0009-2363 2005 [Refereed]
     
    The saponin fraction from the seeds of the tea plant vertical bar Camellia sinensis (L.) O. Kuntze (Theaceae)vertical bar was found to exhibit potent protective effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats. Five new triterpene saponins, theasaponins E-3 (1), E-4, (2), E-5 (3), E-6 (4), and E-7 (5), were isolated together with I I known saponins from the saponin fraction. The chemical structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated saponins, theasaponins E-1 (6), E-2 (7), and E-5 (3) and assamsaponin C (10) showed an inhibitory effect on ethanol-induced gastric mucosal lesions at a dose of 5.0 mg/kg, p.o. and their activities were stronger than that of onieplazole. With regard to the structure-activity relationships of theasaponins, the following structural requirements for a protective effect on ethanol-induced gastric lesions were suggested; 1) the 21- and/or 22-acyl groups are essential for the activity, 2) acetylation of the 16-hydroxyl group reduce the activity.
  • Matsuda, H.; Morikawa, T.; Ohgushi, T.; Ishiwada, T.; Nishida, N.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 53 (4) 387 - 392 0009-2363 2005 [Refereed]
     
    The methanolic extract from the flowers of Angelica furcijuga K-ITAGAWA was found to inhibit nitric oxide production in lipopolysacc hand e-activated mouse peritoneal macrophages. From the methanolic extract, two new glycosides, hyuganosides IV and V, were isolated together with 28 known constituents. The structures of the new constituents were determined on the basis of chemical and physicochernical evidence. Furthermore, the inhibitory effects of I I coumarin constituents on nitric oxide production were examined. Among them, 3 '-angeloyl-cis-khellactone (IC50=82 mu m), (S)-(-)-oxypeucedanin (57 mu m), imperatorin (60 mu m), isoepoxypteryxin (53 mu m), and isopteryxin (8.8 mu m) showed inhibitory activity.
  • Morikawa, T.; Ando, S.; Matsuda, H.; Kataoka, S.; Muraoka, O.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 53 (6) 625 - 630 0009-2363 2005 [Refereed]
     
    The 80% aqueous acetone extract from the rhizomes of Alpinia galanga showed nitric oxide (NO) production inhibitory activities in mouse peritoneal macrophages. From the aqueous acetone extract, three new 8-9' linked neolignans, galanganal, galanganols A and B, and a sesquineolignan, galanganol C, were isolated together with nine known phenylpropanoids and p-hydroxybenzaldehyde. The structures of new neolignans were determined on the basis of physicochemical and chemical evidence. In addition, the inhibitory effects of the constituents from the rhizomes of A. galanga on NO production induced by lipopolysaccharide in mouse peritoneal macrophages were examined. Among them, galanganal (IC50=68 mu m), galanganols B (88 mu m) and C (33 mu m), 1'S-1'-acetoxychavicol acetate (2.3,mu m), 1'S-1'-acetoxyeugenol acetate (11 mu m), trans-p-hydroxycinnamaldehyde (ca. 20 mu m), trans-p-coumaryl alcohol (72 mu m), and trans-p-coumaryl diacetate (19 mu m) were found to show inhibitory activity.
  • Matsuda, H.; Ando, S.; Morikawa, T.; Kataoka, S.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 7 15 (7) 1949 - 53 0960-894X 2005 [Refereed]
     
    1'S-1'-Acetoxychavicol acetate from the rhizomes of Alpinia galanga inhibited nitric oxide (NO) production in lipopolysaccharide-activated mouse peritoneal macrophages with an IC(50) value of 2.3 microM. To clarify the structure-activity relationship of 1'S-1'-acetoxychavicol acetate, various natural and synthetic phenylpropanoids and synthetic phenylbutanoids were examined, and the following structural requirements were clarified. (1) The para or ortho substitution of the acetoxyl and 1-acetoxypropenyl groups at the benzene ring was essential. (2) The S configuration of the 1'-acetoxyl group was preferable. (3) The presence of the 3-methoxyl group and disappearance of the 2'-3' double bond by hydrogenation reduced the activity. (4) The substitution of acetyl groups with propionyl or methyl groups reduced the activity. (5) Lengthening of the carbon chain between the 1'- and 2'-positions reduced the activity.
  • Yoshikawa, M.; Morikawa, T.; Yamamoto, K.; Kato, Y.; Nagatomo, A.; Matsuda, H.
    Journal of Natural Products 9 68 (9) 1360 - 5 0163-3864 2005 [Refereed]
     
    The methanolic extract and its n-butanol-soluble fraction from the flowers of the tea plant (Camellia sinensis) were found to suppress serum triglyceride elevation in olive oil-treated mice. From the n-butanol-soluble fraction, three new acylated oleanane-type triterpene oligoglycosides, floratheasaponins A-C (1-3), were isolated together with several flavonol glycosides and catechins. The structures of 1-3 were elucidated on the basis of chemical and physicochemical evidence as 21-O-angeloyl-22-O-acetyltheasapogenol B 3-O-[beta-D-galactopyranosyl(1-->2)][beta-D-xylopyranosyl(1-->2)-alpha-L-arabinopyranosyl(1-->3)]-beta-D-glucopyranosiduronic acid, 21,22-di-O-angeloyl-R1-barrigenol 3-O-[beta-D-galactopyranosyl(1-->2)][beta-D-xylopyranosyl(1-->2)-alpha-L-arabinopyranosyl(1-->3)]-beta-D-glucopyranosiduronic acid, and 21-O-angeloyl-22-O-2-methylbutyryl-R1-barrigenol 3-O-[beta-D-galactopyranosyl(1-->2)][beta-D-xylopyranosyl(1-->2)-alpha-L-arabinopyranosyl(1-->3)]-beta-D-glucopyranosiduronic acid, respectively. Floratheasaponins (1-3) showed inhibitory effects on serum triglyceride elevation, with their activities being more potent than those of theasaponins E1 (4) and E2 (5) obtained previously from the seeds of C. sinensis.
  • Xie, H.; Wang, T.; Matsuda, H.; Morikawa, T.; Yoshikawa, M.; Tani, T.
    Chemical and Pharmaceutical Bulletin 11 53 (11) 1416 - 22 0009-2363 2005 [Refereed]
     
    The 80% aqueous acetone extract from the whole plant of Saussurea medusa MAXIM. was found to inhibit rat lens aldose reductase (IC50=1.4 microg/ml). From this extract, flavonoids, lignans, and quinic acid derivatives were isolated together with two new ionone glycosides, saussureosides A and B. Their absolute stereostructures were elucidated on the basis of chemical and physicochemical evidence including the application of modified Mosher's method. In addition, some isolates were found to show an inhibitory effect on aldose reductase.
  • Ando, S.; Matsuda, H.; Morikawa, T.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 9 13 (9) 3289 - 94 0968-0896 2005 [Refereed]
     
    1'S-1'-Acetoxychavicol acetate from the rhizomes of Alpinia galanga was known to show potent inhibitory effect on the production of nitric oxide (NO) in lipopolysaccharide-activated mouse peritoneal macrophages. To clarify its mechanism of action, the effects of 1'S-1'-acetoxychavicol acetate on the expression of interferon-beta (IFN-beta) mRNA and activation of nuclear factor-kappaB (NF-kappaB), both of which participate in the induction of inducible NO synthase, were examined in lipopolysaccharide-activated macrophages. The results were compared with those of two inhibitors of the NF-kappaB activation, costunolide and caffeic acid phenethyl ester. 1'S-1'-Acetoxychavicol acetate inhibited IFN-beta mRNA expression as well as NF-kappaB activation, and two related compounds, (+/-)-1-acetoxy-1-(2-acetoxyphenyl)-2-propene and (+/-)-1-acetoxy-1-(4-acetoxyphenol)-3-butene, also inhibited IFN-beta mRNA expression. In addition, 1'S-1'-acetoxychavicol acetate inhibited the production of NO stimulated by poly(I:C) via Toll-like receptor 3.
  • T Morikawa; BH Sun; H Matsuda; LJ Wu; S Harima; M Yoshikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 52 (10) 1194 - 1199 0009-2363 2004/10 [Refereed]
     
    A new beta-carboline-type alkaloidal glycoside, glucodichotomine B, four new neolignan glycosides, dichotomosides A, B, C, and D, and a new phenylpropanoid glycoside, dichotomoside E, were isolated from a Chinese natural medicine, the roots of Stellaria dichotoma L. var. lanceolata. The structures of the new glycosides were determined on the basis of chemical and physicochemical evidence. Among them, dichotomoside D inhibited the release of beta-hexosaminidase (IC50=64 muM) as well as tumor necrosis factor-alpha and interleukin-4 (IC50 = 16, 34 muM) in RBL-2H3 cells. These findings suggest that dichotomoside D is more effective against the late-phase reactions in type 1 allergy than in the immediate phase.
  • Bohang Sun; Toshio Morikawa; Hisashi Matsuda; Supinya Tewtrakul; Li Jun Wu; Shoichi Harima; Masayuki Yoshikawa
    Journal of natural products 9 67 (9) 1464 - 9 0163-3864 2004/09 [Refereed]
     
    The aqueous ethanolic extract from the roots of Stellaria dichotoma showed an antiallergic effect on ear passive cutaneous anaphylaxis (PCA) reaction in mice (in vivo) and inhibitory activity on the release of beta-hexosaminidase in RBL-2H3 cells (in vitro). From the aqueous ethanolic extract, new beta-carboline-type alkaloids, dichotomines A (1), B (2), C (3), and D (4) and dichotomides I (5) and II (6), were isolated. The structures of the new constituents (1-6) were determined on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method. The effects of the isolated constituents on the release of beta-hexosaminidase in RBL-2H3 cells were examined, and 3 was found to show inhibitory activity (IC(50) = 62 microM). Moreover, 3 also inhibited the releases of antigen-IgE-mediated TNF-alpha and IL-4 (19 and 15 microM, respectively) in RBL-2H3 cells, both of which participate in the late phase of type I allergic reactions.
  • Toshio Morikawa; Fengming Xu; Kiyofumi Ninomiya; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 4 52 (4) 494 - 7 0009-2363 2004/04 [Refereed]
     
    New dolabellane-type diterpene alkaloids, nigellamines A(3), A(4), A(5), and C, were isolated from the methanolic extract of an Egyptian medicinal food, black cumin (the seeds of Nigella sativa). Their absolute configurations were determined on the basis of chemical and physicochemical evidence. Nigellamines were found to lower triglyceride levels in primary cultured mouse hepatocytes, and in particular, the activity of nigellamine A(5) was equivalent to that of the hypolipidemic agent, clofibrate.
  • Chenchen Shao; Yoichi Suzuki; Fumiaki Kamada; Kiyoshi Kanno; Mayumi Tamari; Koichi Hasegawa; Yoko Aoki; Shigeo Kure; Xue Yang; Hiroko Endo; Reiko Takayanagi; Chifuyu Nakazawa; Toshio Morikawa; Miki Morikawa; Shigeaki Miyabayashi; Yasushi Chiba; Minoru Karahashi; Seichi Saito; Gen Tamura; Taro Shirakawa; Yoichi Matsubara
    Journal of human genetics 49 (3) 115 - 122 2004 
    Several studies have shown linkage of chromosome region 12q13-24 to bronchial asthma and related phenotypes in ethnically diverse populations. In the Japanese population, a genome-wide study failed to show strong evidence of linkage of this region. Chromosome 12 genes that showed association with the disease in at least one report include: the signal transducer and activator of transcription 6 gene ( STAT6), the nitrogen oxide synthetase 1 gene ( NOS1), the interferon gamma gene ( IFNG), and the activation-induced cytidine deaminase gene ( AICDA). To evaluate the linkage between chromosome 12 and childhood asthma in the Japanese population, we performed sib-pair linkage analysis on childhood asthma families using 18 microsatellite markers on chromosome 12. To investigate association between chromosome 12 candidate genes and asthma, distributions of alleles and genotypes of repeat polymorphisms of STAT6, NOS1, and IFNG were compared between controls and patients. Single nucleotide polymorphism of AICDA was also investigated. Chromosome region 12q24.23-q24.33 showed suggestive linkage to asthma. The NOS1 intron 2 GT repeat and STAT6 exon 1 GT repeat were associated with asthma. Neither the IFNG intron 1 CA repeat nor 465C/T of AICDA showed any association with asthma. Our results suggest that NOS1 and STAT6 are asthma-susceptibility genes and that chromosome region 12q24.23-q24.33 contains other susceptibility gene(s).
  • Morikawa, T.; Matsuda, H.; Ohgushi, T.; Nishida, N.; Ishiwada, T.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 63 (10) 2211 - + 0385-5414 2004 [Refereed]
     
    Two new acylated khellactone-type coumarin hyuganoside I (1) and hyuganin F (2) were isolated from the leaves of Angelica furcijuga. Their absolute stereostructures were determined on the basis of chemical and physicochemical evidence. Furthermore, the absolute stereostructures of the acyl moieties in hyuganins A (3) and C (4) and isoepoxypteryxin (5) were elucidated.
  • Morikawa, T.; Xu, F.; Ninomiya, K.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 52 (4) 494 - 497 0009-2363 2004 [Refereed]
     
    New dolabellane-type diterpene alkaloids, nigellamines A(3), A(4), A(5), and C, were isolated from the methanolic extract of an Egyptian medicinal food, black cumin (the seeds of Nigella sativa). Their absolute configurations were determined on the basis of chemical and physicochemical evidence. Nigellamines were found to lower triglyceride levels in primary cultured mouse hepatocytes, and in particular, the activity of nigellamine A, was equivalent to that of the hypolipidemic agent, clofibrate.
  • 森川敏生
    ファルマシア 公益社団法人日本薬学会 40 (9) 857 - 858 0014-8601 2004
  • Xu, F.; Morikawa, T.; Matsuda, H.; Ninomiya, K.; Yoshikawa, M.
    Journal of Natural Products 4 67 (4) 569 - 76 0163-3864 2004 [Refereed]
     
    Six new sesquiterpenes, cyperusols A(1) (1), A(2) (2), B(1) (3), B(2) (4), C (5), and D (6), together with two monoterpenes and 13 sesquiterpenes were isolated from an Egyptian herbal medicine, the whole plants of Cyperus longus. The stereostructures of the new sesquiterpenes were determined on the basis of chemical and physicochemical evidence. In addition, the principal constituents were found to exhibit inhibitory activity on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Morikawa, T.; Matsuda, H.; Nishida, N.; Ohgushi, T.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 11 52 (11) 1387 - 90 0009-2363 2004 [Refereed]
     
    Three new aromatics glycosides, hyuganosides II, IIIa, and IIIb, were isolated from a Japanese folk medicine, the roots of Angelica furcijuga KITAGAWA. The structures of the new glycosides were determined on the basis of chemical and physicochemical evidence.
  • Morikawa, T.; Xu, F.; Kashima, Y.; Matsuda, H.; Ninomiya, K.; Yoshikawa, M.
    Organic Letters 6 6 (6) 869 - 72 1523-7060 2004 [Refereed]
     
    [structure: see text] Four new dolabellane-type diterpene alkaloids, nigellamines A(1) (1), A(2) (2), B(1) (3), and B(2) (4), were isolated from the seeds of Nigella sativa. Their absolute stereostructures were determined on the basis of chemical and physicochemical evidence. Nigellamines A(1) (1), B(1) (3), and B(2) (4) were found to show potent lipid metabolism promoting activity in primary cultured mouse hepatocytes, and their activities were equivalent to that of a PPAR-alpha agonist, clofibrate.
  • Matsuda, H.; Morikawa, T.; Xu, F.; Ninomiya, K.; Yoshikawa, M.
    Planta Medica 12 70 (12) 1201 - 9 0032-0943 2004 [Refereed]
     
    The methanolic extract from the stems of Erycibe expansa was found to show a hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. By bioassay-guided separation, two new prenylisoflavones and a pterocarpane, erycibenins A (1), B (2), and C (3), were isolated from the active fraction (the EtOAc-soluble fraction) together with ten isoflavones (4-13) and seven pterocarpanes (14-20). The stereostructures of the new compounds were determined on the basis of chemical and physicochemical evidence including modified Mosher's method. In addition, the isolated constituents, erycibenin A (1, IC50 = 79 microM), genistein (6, 29 microM), orobol (7, 36 microM), and 5,7,4'-trihydroxy-3'-methoxyisoflavone (8, 55 microM) exhibited inhibitory activity on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.
  • Abdel-Halim, O.B.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Products 7 67 (7) 1119 - 24 0163-3864 2004 [Refereed]
     
    The 80% aqueous methanolic extract from the bulbs of Crinum yemense showed a potent inhibitory effect on nitric oxide production in lipopolysaccharide-activated macrophages. Three new crinine-type alkaloids, yemenines A (1), B (2), and C (3), were isolated from the herbal extract together with six known alkaloids. The absolute configurations of 1-3 were determined on the basis of chemical and physicochemical evidence. The effects of the isolated alkaloids on nitric oxide production in lipopolysaccharide-activated macrophages were examined, and several alkaloids, e.g. 1, (+)-bulbispermine (6), (+)-crinamine (7), (+)-6-hydroxycrinamine (8), and (-)-lycorine (9), showed inhibitory effects on nitric oxide production and induction of inducible nitric oxide synthase.
  • Morikawa, T.; Matsuda, H.; Yamaguchi, I.; Pongpiriyadacha, Y.; Yoshikawa, M.
    Planta Medica 2 70 (2) 152 - 9 0032-0943 2004 [Refereed]
     
    The 80 % aqueous acetone extract from the fruit of Piper chaba was found to show protective effects on ethanol- and indomethacin-induced gastric lesions in rats. From the aqueous acetone extract, four new amides named piperchabamides A ( 1), B ( 2), C ( 3), and D ( 4) were isolated, and their structures were determined on the basis of chemical and physicochemical evidence. In addition, the gastroprotective effects of the principal constituents, piperine ( 5), piperanine ( 6), pipernonaline ( 7), dehydropipernonaline ( 8), piperlonguminine ( 9), retrofractamide B ( 10), guineensine ( 11), N-isobutyl-(2 E,4 E)-octadecadienamide ( 12), N-isobutyl-(2 E,4 E,14 Z)-eicosatrienamide ( 13), and methyl piperate ( 14), were examined. As a result, compounds 5 - 10 and 12 - 14 significantly inhibited ethanol-induced gastric lesions at a dose of 25 mg/kg, p. o., while 5, 7, 8, 10, 12, and 13 also significantly inhibited indomethacin-induced gastric lesions at the same dose.
  • Ninomiya, K.; Matsuda, H.; Shimoda, H.; Nishida, N.; Kasajima, N.; Yoshino, T.; Morikawa, T.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 8 14 (8) 1943 - 6 0960-894X 2004 [Refereed]
     
    The methanolic extract from the leaves of Salvia officinalis L. (sage) showed significant inhibitory effect on serum triglyceride elevation in olive oil-loaded mice (500 and 1000 mg/kg, p.o.) and inhibitory activity (IC(50): 94 microg/mL) against pancreatic lipase, which is participated in digestion of lipids. Through bioassay-guided separation using the inhibitory activity against pancreatic lipase activity, 4 abietan-type diterpenes (carnosic acid, carnosol, royleanonic acid, 7-methoxyrosmanol) and a triterpene (oleanolic acid) were isolated from the active fraction. Among these compounds, carnosic acid and carnosol substantially inhibited pancreatic lipase activity with IC(50) values of 12 microg/mL (36 microM) and 4.4 microg/mL (13 microM), respectively. Carnosic acid significantly inhibited triglyceride elevation in olive oil-loaded mice at doses of 5-20 mg/kg (p.o.). However, other constituents (carnosol, royleanonic acid, oleanolic acid) did not show any effects at a dose of 200 mg/kg (p.o.). Furthermore, carnosic acid (20 mg/kg/day, p.o.) reduced the gain of body weight and the accumulation of epididymal fat weight in high fat diet-fed mice after 14 days.
  • Morikawa, T.; Sun, B.; Matsuda, H.; Wu, L.J.; Harima, S.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 10 52 (10) 1194 - 9 0009-2363 2004 [Refereed]
     
    A new beta-carboline-type alkaloidal glycoside, glucodichotomine B, four new neolignan glycosides, dichotomosides A, B, C, and D, and a new phenylpropanoid glycoside, dichotomoside E, were isolated from a Chinese natural medicine, the roots of Stellaria dichotoma L. var. lanceolata. The structures of the new glycosides were determined on the basis of chemical and physicochemical evidence. Among them, dichotomoside D inhibited the release of beta-hexosaminidase (IC(50)=64 microM) as well as tumor necrosis factor-alpha and interleukin-4 (IC(50)=16, 34 microM) in RBL-2H3 cells. These findings suggest that dichotomoside D is more effective against the late-phase reactions in type I allergy than in the immediate phase.
  • Matsuda, H.; Morikawa, T.; Xie, H.; Yoshikawa, M.
    Planta Medica 9 70 (9) 847 - 55 0032-0943 2004 [Refereed]
     
    The methanolic extract from the tubers of Gymnadenia conopsea showed an antiallergic effect on ear passive cutaneous anaphylaxis reactions in mice. From the methanolic extract, three new dihydrophenanthrenes, gymconopins A ( 1), B ( 2), and C ( 3), and a new dihydrostilbene, gymconopin D ( 4), were isolated together with 10 known phenanthrene and stilbene constituents. The structures of the new compounds were determined on the basis of physicochemical evidence. Next, the inhibitory effects of the principal constituents on the release of beta-hexosaminidase, as a marker of degranulation, in RBL-2H3 cells were examined and five phenanthrenes, gymconopin B ( 2), 4-methoxy-9,10-dihydrophenanthrene-2,7-diol ( 6), 1-(4-hydroxybenzyl)-4-methoxyphenanthrene-2,7-diol ( 7), 1-(4-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene-2,7-diol ( 8), and blestriarene A ( 9), and six dihydrostilbenes, gymconopin D ( 4), batatacin III ( 10), 3'- O-methylbatatacin III ( 11), 3,3'-dihydroxy-2-(4-hydroxybenzyl)-5-methoxybibenzyl ( 12), 3',5-dihydroxy-2-(4-hydroxybenzyl)-3-methoxybibenzyl ( 13), and 3,3'-dihydroxy-2,6-bis(4-hydroxybenzyl)-5-methoxybibenzyl ( 14) were found to inhibit the antigen-induced degranulation by 65.5 to 99.4 % at 100 microM in RBL-2H3 cells.
  • Matsuda, H.; Tewtrakul, S.; Morikawa, T.; Nakamura, A.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 22 12 (22) 5891 - 8 0968-0896 2004 [Refereed]
     
    The 80% aqueous acetone extract of the rhizomes of Curcuma zedoaria cultivated in Thailand (Thai zedoary) was found to inhibit release of beta-hexosaminidase, as a marker of antigen-IgE-mediated degranulation, in RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice. From the active fraction, four curcuminoids (curcumin, dihydrocurcumin, tetrahydrodemethoxycurcumin, and tetrahydrobisdemethoxycurcumin) were isolated together with two bisabolane-type sesquiterpenes, and the effects of four curcuminoids from Thai zedoary and several related compounds on the degranulation were examined. Among them, curcumin showed the highest activity against beta-hexosaminidase release with IC(50) of 5.3 microM, followed by bisdemethoxycurcumin (IC(50) = 11 microM). With regard to the structural requirements of curcuminoids for the activity, the conjugated olefins at the 1-7 positions and the 4'- or 4''-hydroxyl groups of curcuminoids were suggested to be essential for the strong activity, whereas the 3'- or 3''-methoxyl group only enhanced the activity. Furthermore, effects of curcumin and bisdemethoxycurcumin on calcium ionophores (A23187 and ionomycin)-induced degranulation and antigen-induced release of TNF-alpha and IL-4 were examined.
  • Matsuda, H.; Tewtrakul, S.; Morikawa, T.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 18 12 (18) 4871 - 6 0968-0896 2004 [Refereed]
     
    Stilbenes isolated from the rhizomes of Rheum undulatum (Korean rhubarb) and the related compounds were investigated on their anti-allergic activities. The results revealed that 3,5,4'-trimethylpiceatannol exhibited the most potent inhibition against beta-hexosaminidase release as a marker of degranulation in RBL-2H3 cells with IC(50) of 2.1 microM, followed by trimethylresveratrol (IC(50)=5.1 microM). Structural requirements of stilbenes for the activity are as follows: (1) The oxygen functions (-OCH(3), -OH), especially methoxyl groups, are essential and their positions on aromatic rings are important for the activity; (2) the alpha-beta double bond increased the activity; (3) the glycoside moiety dramatically decreased the activity; and (4) the substitution group at the 3'-position in trimethylresveratrol (3,5,4'-trimethoxystilbene) was preferably OH>H>OCH(3) for the activity. Several active stilbenes (piceatannol, 3,5,4'-trimethylpiceatannol, resveratrol, trimethylresveratrol) also inhibited ionomycin-induced beta-hexosaminidase release, suggesting that inhibition of Ca(2+) influx or degranulation mechanisms after Ca(2+) influx is important for their activities. Piceatannol, 3,5,4'-trimethylpiceatannol, resveratrol, and trimethylresveratrol also significantly inhibited antigen-induced release of TNF-alpha and IL-4 in RBL-2H3 cells.
  • Matsuda, H.; Morikawa, T.; Ando, S.; Oominami, H.; Murakami, T.; Kimura, I.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 10 52 (10) 1200 - 3 0009-2363 2004 [Refereed]
     
    Two new polypodane-type triterpenes, myrrhanol A and myrrhanone A, were isolated from the 50% aqueous methanolic extract of guggul-gum resin [the resin of Balsamodendron (=Commiphora) mukul HOOK]. The structures of the new constituents, including their absolute configurations, were determined on the basis of chemical and physicochemical evidence.
  • Matsuda, H.; Morikawa, T.; Ando, S.; Oominami, H.; Murakami, T.; Kimura, I.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 11 12 (11) 3037 - 46 0968-0896 2004 [Refereed]
     
    The methanolic extract from guggul-gum resin, the resin of Balsamodendron mukul, was found to inhibit nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages (IC(50) = 13 microg/mL). From the methanolic extract, three new polypodane-type triterpenes, myrrhanol B and myrrhanones B and A acetate, and a new octanordammarane-type triterpene, epimansumbinol, were isolated together with 17 known compounds including progesterone and the related steroids. The absolute stereostructures of new triterpenes were elucidated on the basis of chemical and physicochemical evidence. The several constituents showed inhibitory effects on nitric oxide production and induction of inducible nitric oxide synthase.
  • Hisashi Matsuda; Toshio Morikawa; Hiromi Managi; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry letters 19 13 (19) 3197 - 202 0960-894X 2003/10 [Refereed]
     
    The 80% aqueous acetone extract of the rhizomes of Alpinia galanga was found to inhibit release of beta-hexosaminidase, as a marker of antigen-IgE-mediated degranulation in RBL-2H3 cells. Nine known phenylpropanoids and p-hydroxybenzaldehyde were isolated from the extract. Among them, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate exhibited potent inhibitory activity with IC(50) values of 15 and 19 microM. From the effects of various related compounds, both the 1'- and 4-acetoxyl groups of 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate were essential for their strong activity, and the 2'-3' double bond enhanced the activity. In addition, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate inhibited ear passive cutaneous anaphylaxis reactions in mice and the antigen-IgE-mediated TNF-alpha and IL-4 production, both of which participate in the late phase of type I allergic reactions, in RBL-2H3 cells.
  • Toshio Morikawa; Akinobu Kishi; Yutana Pongpiriyadacha; Hisashi Matsuda; Masayuki Yoshikawa
    Journal of natural products 9 66 (9) 1191 - 6 0163-3864 2003/09 [Refereed]
     
    Three new friedelane-type triterpenes named salasones A (1), B (2), and C (3), a new norfriedelane-type triterpene, salaquinone A (4), and a new acylated eudesmane-type sesquiterpene, salasol A (5), were isolated from the 80% aqueous methanolic extract of the stems of Salacia chinensis collected in Thailand. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. In addition, six constituents, 3beta,22beta-dihydroxyolean-12-en-29-oic acid, tingenone, tingenine B, regeol A, triptocalline A, and mangiferin, were found to show an inhibitory effect on rat lens aldose reductase.
  • Jing Tao; Toshio Morikawa; Shin Ando; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 6 51 (6) 654 - 62 0009-2363 2003/06 [Refereed]
     
    Three new arborinane-type triterpene glycosides, rubianosides II, III, and IV, a new arborinane-type triterpene, rubianol-g, and a new anthraquinone, rubianthraquinone, were isolated from a Chinese natural medicine, the roots of Rubia yunnanensis. The structures of the new constituents including their absolute configurations were determined on the basis of chemical and physicochemical evidence. The inhibitory effects of the isolated constituents on nitric oxide production in lipopolysaccharide-activated macrophages were examined. Among them, a cyclic peptide constituent, RA-XII and its aglycon, RA-V (deoxybouvadin), potently inhibited overproduction of nitric oxide and induction of inducible nitric oxide synthase. In addition, an anthraquinone constituent, 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone, was found to show inhibitory effects on the release of beta-hexosaminidase in RBL-2H3 cells.
  • Yutana Pongpiriyadacha; Hisashi Matsuda; Toshio Morikawa; Yasunobu Asao; Masayuki Yoshikawa
    Biological & pharmaceutical bulletin 5 26 (5) 651 - 7 0918-6158 2003/05 [Refereed]
     
    The effects of polygodial isolated from the leaves of Tasmannia lanceolata on necrotizing agents-induced gastric lesions in rats were compared with capsaicin. Polygodial markedly inhibited the gastric mucosal lesions induced by several necrotizing agents, such as ethanol (ED(50)=0.029 mg/kg, p.o.), 0.6 M HCl (ED(50)=0.26 mg/kg, p.o.), and aspirin (ED(50)=0.38 mg/kg, p.o.), and partly inhibited the gastric mucosal lesions induced by indomethacin, but showed no significant effect on acid output in pylorus-ligated rats at doses of 0.05-0.5 mg/kg. The gastroprotection of polygodial was attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), N-ethylmaleimide (10 mg/kg, s.c.) and ruthenium red (3.5 mg/kg, s.c.). Polygodial (0.2 mg/kg, p.o.) increased the amount of reduced glutathione in gastric mucosa of ethanol-treated group. These results suggested that endogenous prostaglandins, nitric oxide, sulfhydryl compounds and vanilloid receptor-mediated effects are involved in the protective effect of polygodial.
  • Hisashi Matsuda; Toshio Morikawa; Tomoko Ishiwada; Hiromi Managi; Masatomo Kagawa; Yoshihiko Higashi; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 4 51 (4) 440 - 3 0009-2363 2003/04 [Refereed]
     
    The methanolic extract and its fractions from the fresh flowers of Prunus mume SIEB. et ZUCC. were found to show scavenging effects on 1,1-diphenylpicryl-2-hydrazyl (DPPH) radical and superoxide. The fragrance constituents of P. mume were analyzed by GC-MS and a new polyacylated sucrose, prunose III, was isolated from the ethyl acetate-soluble fraction. The structure of prunose III was determined on the basis of chemical and physicochemical evidence as 4,3',4',6'-tetra-O-acetyl-6-O-p-coumaroylsucrose. In addition, the scavenging effects of the principal constituents on DPPH radical and superoxide were examined.
  • Hisashi Matsuda; Yutana Pongpiriyadacha; Toshio Morikawa; Akinobu Kishi; Shinya Kataoka; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry letters 6 13 (6) 1101 - 6 0960-894X 2003/03 [Refereed]
     
    The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
  • Masayuki Yoshikawa; Fengming Xu; Toshio Morikawa; Kiyofumi Ninomiya; Hisashi Matsuda
    Bioorganic & medicinal chemistry letters 6 13 (6) 1045 - 9 0960-894X 2003/03 [Refereed]
     
    New skeletal flavonoids, anastatins A and B, were isolated from the methanolic extract of an Egyptian medicinal herb, the whole plants of Anastatica hierochuntica. Their flavanone structures having a benzofuran moiety were determined on the basis of chemical and physicochemical evidence. Anastatins A and B were found to show hepatoprotective effects on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes and their activities were stronger than those of related flavonoids and commercial silybin.
  • Hisashi Matsuda; Iwao Toguchida; Kiyofumi Ninomiya; Tadashi Kageura; Toshio Morikawa; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry 5 11 (5) 709 - 15 0968-0896 2003/03 [Refereed]
     
    The methanolic extract of the roots of Saussurea lappa CLARKE, a Chinese medicinal herb Saussureae Radix, was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Among the constituents from the methanolic extract, two sesquiterpene lactones (costunolide and dehydrocostus lactone) and two amino acid-sesquiterpene conjugates (saussureamines A and B) potently inhibited LPS-induced NO production (IC(50)=1.2-2.8 microM). Saussureamines A and B in addition to costunolide and dehydrocostus lactone did not inhibit iNOS enzyme activity, but they inhibited both induction of inducible NO synthase and activation of nuclear factor-kappaB in accordance with induction of heat shock protein 72.
  • Hiroshi Shimoda; Kiyofumi Ninomiya; Norihisa Nishida; Tomoe Yoshino; Toshio Morikawa; Hisashi Matsuda; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry letters 2 13 (2) 223 - 8 0960-894X 2003/01 [Refereed]
     
    The methanolic extract from the leaves of artichoke (Cynara scolymus L.) was found to suppress serum triglyceride elevation in olive oil-loaded mice. Through bioassay-guided separation, sesquiterpenes (cynaropicrin, aguerin B, and grosheimin) were isolated as the active components together with new sesquiterpene glycosides (cynarascolosides A, B, and C). The oxygen functional groups at the 3- and 8-positions and exo-methylene moiety in alpha-methylene-gamma-butyrolactone ring were found to be essential for the anti-hyperlipidemic activity of guaiane-type sesquiterpene. In addition, inhibition of gastric emptying was shown to be partly involved in anti-hyperlipidemic activity.
  • Yoshikawa, M.; Morikawa, T.; Xu, F.; Ando, S.; Matsuda, H.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 60 (8) 1787 - 1792 0385-5414 2003 [Refereed]
     
    Three new (7R,8S) and (7S,8R) 8-5' linked neolignans named hierochins A (1), B (2), and C (3) were isolated from an Egyptian herbal medicine, the whole plants of Anastatica hierochuntica. The absolute stereostructures of new compounds were elucidated on the basis of chemical and physicochemical evidence. Both enantiomers, (7R,8S) and (7S,8R)-type neolignans, were found to coexist in a state of a little differing functional structure. The effects of isolated lignans on nitric oxide production in lipopolysaccharide-activated macrophages were examined and three known neolignan constituents were found to show inhibitory effects on nitric oxide production and induction of inducible nitric oxide synthase.
  • Shimoda, H.; Ninomiya, K.; Nishida, N.; Yoshino, T.; Morikawa, T.; Matsuda, H.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters PERGAMON-ELSEVIER SCIENCE LTD 13 (2) 223 - 228 0960-894X 2003 [Refereed]
     
    The methanolic extract from the leaves of artichoke (Cynara scolymus L.) was found to suppress serum triglyceride elevation in olive oil-loaded mice. Through bioassay-guided separation, sesquiterpenes (cynaropicrin, aguerin B, and grosheimin) were isolated as the active components together with new sesquiterpene glycosides (cynarascolosides A, B, and C). The oxygen functional groups at the 3- and 8-positions and exo-methylene moiety in alpha-methylene-gamma-butyrolactone ring were found to be essential for the anti-hyperlipidemic activity of guaiane-type sesquiterpene. In addition, inhibition of gastric emptying was shown to be partly involved in anti-hyperlipidemic activity. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Matsuda, H.; Morikawa, T.; Managi, H.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters PERGAMON-ELSEVIER SCIENCE LTD 13 (19) 3197 - 3202 0960-894X 2003 [Refereed]
     
    The 80% aqueous acetone extract of the rhizomes of Alpinia galanga was found to inhibit release of beta-hexosaminidase, as a marker of antigen-IgE-mediated degranulation in RBL-2H3 cells. Nine known phenylpropanoids and p-hydroxybenzaldehyde were isolated from the extract. Among them, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate exhibited potent inhibitory activity with IC50 values of 15 and 19 muM. From the effects of various related compounds, both the 1'- and 4-acetoxyl groups of 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate were essential for their strong activity, and the 2'-3' double bond enhanced the activity. In addition, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate inhibited car passive cutaneous anaphylaxis reactions in mice and the antigen-IgE-mediated TNF-alpha and IL-4 production, both of which participate in the late phase of type I allergic reactions, in RBL-2H3 cells. (C) 2003 Elsevier Ltd. All rights reserved.
  • Tao, J.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 51 (6) 654 - 662 0009-2363 2003 [Refereed]
     
    Three new arborinane-type triterpene glycosides, rubianosides 11, 111, and IV, a new arborinane-type triterpene, rubianol-g, and a new anthraquinone, rubianthraquinone, were isolated from a Chinese natural medicine, the roots of Rubia yunnanensis. The structures of the new constituents including their absolute configurations were determined on the basis of chemical and physicochemical evidence. The inhibitory effects of the isolated constituents on nitric oxide production in lipopolysaccharide-activated macrophages were examined. Among them, a cyclic peptide constituent, RA-XII and its aglycon, RA-V (deoxybouvadin), potently inhibited overproduction of nitric oxide and induction of inducible nitric oxide synthase. In addition, an anthraquinone constituent, 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone, was found to show inhibitory effects on the release of hexosaminidase in RBL-2H3 cells.
  • Matsuda, H.; Toguchida, I.; Ninomiya, K.; Kageura, T.; Morikawa, T.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry PERGAMON-ELSEVIER SCIENCE LTD 11 (5) 709 - 715 0968-0896 2003 [Refereed]
     
    The methanolic extract of the roots of Saussurea lappa CLARKE, a Chinese medicinal herb Saussureae Radix, was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Among the constituents from the methanolic extract, two sesquiterpene lactones (costunolide and dehydrocostus lactone) and two amino acid-sesquiterpene conjugates (saussureamines A and B) potently inhibited LPS-induced NO production (IC50 = 1.2-2.8 muM). Saussureamines A and B in addition to costunolide and dehydrocostus lactone did not inhibit iNOS enzyme activity, but they inhibited both induction of inducible NO synthase and activation of nuclear factor-kappaB in accordance with induction of heat shock protein 72. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • T Morikawa; J Tao; K Ueda; H Matsuda; M Yoshikawa
    CHEMICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 51 (1) 62 - 67 0009-2363 2003/01 [Refereed]
     
    Four new aromatic constituents, rhododendroketoside, (-)-sakuraresinoside, acernikol, and nikoenoside, were isolated from a Japanese folk medicine, the stem bark of Acer nikoense MAXIM. The structures of the new constituents were determined on the basis of chemical and physicochemical evidence. The principle cyclic diaryl-heptanoids were found to show inhibitory effects on the release of beta-hexosaminidase in RBL-2H3 cells.
  • Matsuda, H.; Pongpiriyadacha, Y.; Morikawa, T.; Kishi, A.; Kataoka, S.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters PERGAMON-ELSEVIER SCIENCE LTD 13 (6) 1101 - 1106 0960-894X 2003 [Refereed]
     
    The methanolic extract from the rhizomes of Paris polyphylla Sm. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1 -->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1 -->4)-[alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1 -->2)[-alpha-L-arabinofuranosyl(1-->4)]-beta-D -glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1 -->4)-[alpha-L-rhamnopyranosy](1-->2)]-beta-D-glucopyranoside (4), and a hew furostanol-type steroid saponin, parisaponin 1 (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmalcimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • Morikawa, T.; Kishi, A.; Pongpiriyadacha, Y.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Products AMER CHEMICAL SOC 66 (9) 1191 - 1196 0163-3864 2003 [Refereed]
     
    Three new friedelane-type triterpenes named salasones A (1), B (2), and C (3), a new norfriedelane-type triterpene, salaquinone A (4), and a new acylated eudesmane-type sesquiterpene, salasol A (5), were isolated from the 80% aqueous methanolic extract of the stems of Salacia chinensis collected in Thailand. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. In addition, six constituents, 3beta,22beta-dihydroxyolean-12-en-29-oic acid, tingenone, tingenine B, regeol A, triptocalline A, and mangiferin, were found to show an inhibitory effect on rat lens aldose reductase.
  • 吉川雅之; PONGPIRIYADACHA Y; 来住明宣; 蔭浦禎士; WANG T; 森川敏生; 松田久司
    薬学雑誌 10 123 (10) 871 - 80 0031-6903 2003 [Refereed]
     
    In the course of our characterization studies on anti-obese and antidiabetogenic principles in medicinal foodstuffs, we found that the methanolic extract from the stems of Salacia chinensis (Hippocerateaceae) showed potent anti-hyperglycemic effects in oral sucrose or maltose-loaded rats, inhibitory effects on intestinal alpha-glucosidase, rat lens aldose reductase, formation of Amadori compounds and advanced glycation end-products, nitric oxide production from lipopolysaccharide-activated mouse peritoneal macrophage, and radical scavenging activities. Those in vivo and in vitro biological activities were compared with those of S. oblonga and S. reticulata. In addition, we isolated the principal alpha-glucosidase inhibitor, salacinol, from the stems of S. chinensis and examined alpha-glucosidase inhibitory activities of eleven samples of S. chinensis collected in Thailand.
  • Kishi, A.; Morikawa, T.; Matsuda, H.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 9 51 (9) 1051 - 5 0009-2363 2003 [Refereed]
     
    Two new friedelane-type triterpenes, salasones D and E, a new norfriedelane-type triterpene, salaquinone B, and a new polyacylated eudesmane-type sesquiterpene, salasol B, were isolated from the stems of Salacia chinensis LINN. (S. prinoides DC., Hippocrateaceae) collected in Thailand. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. Some norfriedelane-type triterpene, lignan, and catechin constituents were found to show radical scavenging activity.
  • Yoshikawa, M.; Morikawa, T.; Kashima, Y.; Ninomiya, K.; Matsuda, H.
    Journal of Natural Products 7 66 (7) 922 - 7 0163-3864 2003 [Refereed]
     
    The saponin fraction from the flower buds of Panax notoginseng exhibited protective effect on liver injury induced by d-galactosamine and lipopolysaccharide. From the saponin fraction with hepatoprotective effect, five new dammarane-type triterpene saponins, notoginsenosides-O (1), -P (2), -Q (3), -S (4), and -T (5), were isolated together with nine known protopanaxadiol oligoglycosides. The structures of the new saponins were elucidated on the basis of chemical and physicochemical evidence. The principal dammarane-type triterpene saponins from the roots and flower buds of Panax notoginseng were found to show potent hepatoprotective effects.
  • Morikawa, T.; Tao, J.; Toguchida, I.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Products 1 66 (1) 86 - 91 0163-3864 2003 [Refereed]
     
    Three new cyclic diarylheptanoids, acerosides B1 and B2 and aceroketoside, were isolated together with 20 known compounds from a Japanese folk medicine, the stem bark of Acer nikoense. The absolute stereostructures of the new compounds were determined on the basis of chemical and physicochemical evidence. In addition, the principal diarylheptanoid constituents were found to exhibit inhibitory activity on nitric oxide production in lipopolysaccharide-activated macrophages.
  • Matsuda, H.; Morikawa, T.; Ando, S.; Toguchida, I.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 9 11 (9) 1995 - 2000 0968-0896 2003 [Refereed]
     
    To clarify the structure-activity relationships of flavonoids for nitric oxide (NO) production inhibitory activity, we examined the inhibitory effects of 73 flavonoids on NO production in lipopolysaccharide-activated mouse peritoneal macrophages. Among those flavonoids, apigenin (IC(50)=7.7 microM), diosmetin (8.9 microM), and tetra-O-methylluteolin (2.4 microM), and hexa-O-methylmyricetin (7.4 microM) were found to show potent inhibitory activity, and the results suggested the following structural requirements of flavonoids: (1) the activities of flavones were stronger than those of corresponding flavonols; (2) the glycoside moiety reduced the activity; (3) the activities of flavones were stronger than those of corresponding flavanones; (4) the flavones and flavonols having the 4'-hydroxyl group showed stronger activities than those lacking the hydroxyl group at the B ring and having the 3',4'-dihydroxyl group; (5) the flavonols having the 3',4'-dihydroxyl group (catechol type) showed stronger activities than those having the 3',4',5'-trihydroxyl group (pyrogallol type); (6) the 5-hydroxyl group tended to enhance the activity; (7) methylation of the 3-, 5-, or 4'-hydroxyl group enhanced the activity; (8) the activities of isoflavones were weaker than those of corresponding flavones; (9) methylation of the 3-hydroxyl group reduced the cytotoxicity. In addition, potent NO production inhibitors were found to inhibit induction of inducible nitric oxide synthase (iNOS) without iNOS enzymatic inhibitory activity.
  • Matsuda, H.; Morikawa, T.; Oda, M.; Asao, Y.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 24 13 (24) 4445 - 9 0960-894X 2003 [Refereed]
     
    The methanolic extract and its alkaloid fraction from the rhizomes of Nuphar pumilum inhibited invasion of B16 melanoma cells across collagen-coated filters in vitro. Dimeric sesquiterpene thioalkaloids with the 6-hydroxyl group, 6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, and 6-hydroxythionuphlutine B, showed potent activity with IC(50) values of 0.029, 0.087, and 0.36 microM, respectively, but dimeric sesquiterpene thioalkaloids lacking the 6-hydroxyl group (thiobinupharidine, neothiobinupharidine, syn-thiobinupharidine sulfoxide, thionuphultine B beta-sulfoxide, and neothiobinupharidine beta-sulfoxide) and monomeric sesquiterpene alkaloids (nupharidine, deoxynupharidine, 7-epideoxynupharidine, and nupharolutine) showed weak activity. The alkaloid fraction (20 mg/kg/d, po) and the principal dimeric sesquiterpene thioalkaloid 6-hydroxythiobinupharidine (5 mg/kg/d, po) significantly inhibited lung tumor formation by more than 90% 10 days after injection of B16 melanoma cells in mice.
  • Toshio Morikawa; Jing Tao; Kazuho Ueda; Hisashi Matsuda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 1 51 (1) 62 - 7 0009-2363 2003/01 [Refereed]
     
    Four new aromatic constituents, rhododendroketoside, (-)-sakuraresinoside, acernikol, and nikoenoside, were isolated from a Japanese folk medicine, the stem bark of Acer nikoense MAXIM. The structures of the new constituents were determined on the basis of chemical and physicochemical evidence. The principle cyclic diarylheptanoids were found to show inhibitory effects on the release of beta-hexosaminidase in RBL-2H3 cells.
  • Matsuda, H.; Pongpiriyadacha, Y.; Morikawa, T.; Ochi, M.; Yoshikawa, M.
    European Journal of Pharmacology 1 471 (1) 59 - 67 0014-2999 2003 [Refereed]
     
    The effects of 1'S-1'-acetoxychavicol acetate and related phenylpropanoids isolated from the rhizomes of Alpinia galanga on ethanol-induced gastric lesions in rats were examined. Among them, 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate markedly inhibited the ethanol-induced gastric mucosal lesions (ED(50)=0.61 and ca. 0.90 mg/kg). In addition, 1'S-1'-acetoxychavicol acetate inhibited the lesions induced by 0.6 M HCl (ED(50)=0.73 mg/kg) and aspirin (ED(50)=0.69 mg/kg) but it did not show a significant effect on indomethacin-induced gastric lesions and acid output in pylorus-ligated rats at doses of 0.5-5.0 mg/kg. From the gastroprotective effects of various related compounds, the 1'-acetoxyl group of 1'S-1'-acetoxychavicol acetate and 1'S-1'-acetoxyeugenol acetate was found to be essential for their strong activity. With regard to the mode of action, the gastroprotective effects of 1'S-1'-acetoxychavicol acetate were attenuated by pretreatment with indomethacin and N-ethylmaleimide, and 1'S-1'-acetoxychavicol acetate significantly increased the glutathione levels of gastric mucosa in rats. These findings suggest that endogenous prostaglandins and sulfhydryl compounds are involved in the protective effect of 1'S-1'-acetoxychavicol acetate.
  • Morikawa, T.; Tao, J.; Ando, S.; Matsuda, H.; Yoshikawa, M.
    Journal of Natural Products 5 66 (5) 638 - 45 0163-3864 2003 [Refereed]
     
    The aqueous acetone extract from the roots of a Chinese herbal medicine, Rubia yunnanensis, showed a potent inhibitory effect on nitric oxide production in lipopolysaccharide-activated macrophages. Five new arborinane-type triterpenes, rubianols-a (1), -b (2), -c (3), -d (4), and -e (5), and a new arborinane-type triterpene glycoside, rubianoside I (6), were isolated from the herbal crude extract together with 10 known compounds. The absolute stereostructures of 1-6 were determined on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method. The effects of the isolated constituents on nitric oxide production in lipopolysaccharide-activated macrophages were examined, and several triterpenes were found to show inhibitory activity.
  • Jing Tao; Toshio Morikawa; Iwao Toguchida; Shin Ando; Hisashi Matsuda; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry 12 10 (12) 4005 - 12 0968-0896 2002/12 [Refereed]
     
    Three new biphenyl type diarylheptanoid glycosides, myricanol 11-O-beta-D-glucopyranoside, myricanone 5-O-beta-D-glucopyranoside, and neomyricanone 5-O-beta-D-glucopyranoside, and a new taraxerane type triterpene, myricetrione, were isolated from the bark of Chinese Myrica rubra. Their structures were elucidated on the basis of chemical and physicochemical evidence. Biphenyl type diarylheptanoids, triterpene, and their polyphenols showed potent inhibitory effects on nitric oxide production in lipopolysaccharide-activated macrophages. Furthermore, diarylheptanoids, myricanol and myricanone, were found to inhibit induction of inducible nitric oxide synthase.
  • Hisashi Mastuda; Toshio Morikawa; Kazuho Ueda; Hiromi Managi; Masayuki Yoshikawa
    Bioorganic & medicinal chemistry 10 10 (10) 3123 - 8 0968-0896 2002/10 [Refereed]
     
    To clarify the structure-activity relationships of flavonoids for antiallergic activity, the inhibitory effects of various flavonoids on the release of beta-hexosaminidase, as a marker of degranulation of RBL-2H3 cells, were examined. Among them, luteolin (IC(50)=3.0 microM), diosmetin (2.1 microM), and fisetin (3.0 microM) were found to show potent inhibitory activity, and the results suggested the following structural requirements of flavonoids: (1) the 2-3 double bond of flavones and flavonols is essential for the activity; (2) the 3- or 7-glycoside moiety reduced the activity; (3) as the hydroxyl groups at the 3'-, 4'-, 5-, 6-, and 7-positions increased in number, the inhibitory activities become stronger; (4) the flavonols with a pyrogallol type moiety (the 3',4',5'-trihydroxyl groups) at the B ring exhibited less activity than those with a phenol type moiety (the 4'-hydroxyl group) or catechol type moiety (the 3',4'-dihydroxyl groups) at the B ring; (5) the activities of flavones were stronger than those of flavonols; and (6) methylation of flavonols at the 3-position reduced the activity. However, (7) several flavones and flavonols with the 4'- and/or 7-methoxyl groups did not obey rules (3), (4), and (5). In addition, several flavonoids, that is apigenin, luteolin, diosmetin, fisetin, and quercetin, inhibited the antigen-IgE-mediated TNF-alpha and IL-4 production from RBL-2H3 cells, both of which participate in the late phase of type I allergic reactions.
  • Mitsuo Hayashi; Toshio Morikawa; Tadao Hori
    Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 113 (9) 1505 - 16 1388-2457 2002/09 
    OBJECTIVES: Afternoon sleepiness is a widespread phenomenon. The present study aimed to test Broughton's hypothesis (Sleep and alertness: chronobiological, behavioral, and medical aspects of napping. New York, NY: Raven Press, 1989. p. 71-98) that afternoon sleep propensity might reflect the circasemidian 12h cycle of slow wave sleep (SWS). METHODS: Nine subjects (21-27 year) stayed alone under constant darkness (0 lux) without social contact for 72 h. They were allowed to sleep and eat freely. Their polysomnograms during 72 h of constant darkness were analyzed. RESULTS: The total sleep time (TST) accounted for 41.6h (57.9%) of the 72 h and decreased progressively as a function of time. The reduction in TST was dependent on the decrease in sleep stage 2 and rapid eye movement (REM) sleep. The amount of SWS did not significantly change among the days. The circadian (1 cycle/day) and circasemidian (2cycles/day) cycles were observed in SWS. Those accounted for 13.9 and 11.1% of the total variance, respectively. SWS during the time corresponding to daytime occurred 9-10h before and 15-16 h after the nocturnal sleep gate. In addition, weak but significant correlations were observed between the amounts of SWS and the waking time before the sleep episodes (r=0.332) and prior REM sleep (r=-0.236). CONCLUSIONS: The present findings suggest that SWS might occur not only always in a homeostatic manner as a function of prior wakefulness, but also as a circasemidian rhythmic function.
  • Toshio Morikawa; Mitsuo Hayashi; Tadao Hori
    Perceptual and motor skills 95 (1) 131 - 54 0031-5125 2002/08 
    The aim of this study is to evaluate the spatiotemporal variation of alpha and sigma band EEGs during the waking-sleeping transition or hypnagogic period. Power and coherence from 7 EEG channels (Fp1, F7, Fz, C3, Pz, T5, O1) were studied using EEG records of the period of 5 min. before the onset of Stage 1 to 24 min. after the onset of Stage 1. The EEG spectra were computed for 4 frequency bands (alpha 1: 8.0-9.0 Hz, alpha 2: 9.5-11.0 Hz, alpha 3: 11.5-12.5 Hz, and sigma: 13.0-15.0 Hz). The power of alpha 1 and 2 bands initially started to decrease before the onset of Stage 1. Principal component analysis of the coherence yielded Generalized and Localized Components in each band. The Generalized Component was widespread across scalp areas, while the Localized Component was a restricted local area. The Generalized Components of alpha 1 and 2 bands reached stable levels of NREM sleep about 1 min. after the onset of Stage 1. The component of sigma band reached a stable level of NREM sleep about 0.6 min. before the onset of Stage 2, while the component of alpha 3 band reached a stable level of NREM sleep about 3.4 min. after the onset of Stage 2. These results suggest that the alpha-sigma band EEG structures during the waking-sleeping transition period may not be uniform across EEG bands and that the hypnagogic EEG changes may start before the onset of Stage 1 and continue for several minutes after the onset of Stage 2.
  • Masayuki Yoshikawa; Toshiyuki Murakami; Tomoko Ishiwada; Toshio Morikawa; Masatomo Kagawa; Yoshihiko Higashi; Hisashi Matsuda
    Journal of natural products 8 65 (8) 1151 - 5 0163-3864 2002/08 [Refereed]
     
    The methanolic extract from the fresh flowers of Prunus mume exhibited inhibitory effects against aldose reductase and platelet aggregation. From the methanolic extract, two new flavonol oligoglycosides, 2' '-O-acetylrutin and 2' '-O-acetyl-3'-O-methylrutin, and two new polyacylated sucroses, prunoses I and II, were isolated together with 11 known constituents. The structures of 2' '-O-acetylrutin, 2' '-O-acetyl-3'-O-methylrutin, and prunoses I and II were determined on the basis of chemical and physicochemical evidence as quercetin 3-O-alpha-L-rhamnopyranosyl(1-->6)-2' '-O-acetyl-beta-D-glucopyranoside, 3'-O-methylquercetin 3-O-alpha-L-rhamnopyranosyl(1-->6)-2' '-O-acetyl-beta-D-glucopyranoside, 1,4,3',4',6'-penta-O-acetyl-6-O-p-coumaroylsucrose, and 1,3',4',6'-tetra-O-acetyl-6-O-p-coumaroylsucrose, respectively. The flavonol glycosides and prunose I were found to inhibit aldose reductase, while prunoses I and II inhibited platelet aggregation induced by thrombin.
  • Toshio Morikawa; Hisashi Matsuda; Kiyofumi Ninomiya; Masayuki Yoshikawa
    Biological & pharmaceutical bulletin 5 25 (5) 627 - 31 0918-6158 2002/05 [Refereed]
     
    The 80% aqueous acetone extract of Zedoariae Rhizoma was found to show a protective effect against D-galactosamine (D-GalN)/lipopolysaccharide-induced acute liver injury in mice. To clarify the active compounds, the principal constituents were examined and 11 sesquiterpenes (furanodiene, curdione, neocurdrione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone) and a diarylheptanoid (curcumin) were found to inhibit the increase in serum aspartate aminotransaminase and alanine aminotransaminase at a dose of 50 mg/kg p.o. in agreement with the previous in vitro studies, except for dehydrocurdione, aerugidiol, and zedoarondiol. In particular, curdione, neocurdione, curcumenol, and isocurcumenol potently inhibited the increase at a dose of 12.5 mg/kg p.o. Furthermore, the eight sesquiterpenes, furanodiene, curdione, neocurdione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, and curcumenone, also showed a protective effect against D-GalN/tumor necrosis factor-alpha-induced liver injury in mice at a dose of 50 mg/kg p.o.
  • Masayuki Yoshikawa; Toshio Morikawa; Hisashi Matsuda; Genzoh Tanabe; Osamu Muraoka
    Bioorganic & medicinal chemistry 5 10 (5) 1547 - 54 0968-0896 2002/05 [Refereed]
     
    A most potent alpha-glucosidase inhibitor named salacinol has been isolated from an antidiabetic Ayurvedic traditional medicine, Salacia reticulata WIGHT, through bioassay-guided separation. The absolute stereostructure of salacinol was determined on the basis of chemical and physicochemical evidence, which included the alkaline degradation of salacinol to 1-deoxy-4-thio-D-arabinofuranose and the X-ray crystallographic analysis, to be the unique spiro-like configuration of the inner salt comprised of 1-deoxy-4-thio-D-arabinofuranosyl sulfonium cation and 1'-deoxy-D-erythrosyl-3'-sulfate anion. Salacinol showed potent inhibitory activities on several alpha-glucosidases, such as maltase, sucrase, and isomaltase, and the inhibitory effects on serum glucose levels in maltose- and sucrose-loaded rats (in vivo) were found to be more potent than that of acarbose, a commercial alpha-glucosidase inhibitor.
  • Yoichiro Ohara; Takashi Ohrui; Toshio Morikawa; Hidetada Sasaki
    Lancet (London, England) 359 (9312) 1159 - 1159 0140-6736 2002/03
  • Hisashi Matsuda; Toshio Morikawa; Jing Tao; Kazuho Ueda; Masayuki Yoshikawa
    Chemical & pharmaceutical bulletin 2 50 (2) 208 - 15 0009-2363 2002/02 [Refereed]
     
    Three new diarylheptanoid glycosides, named (+)-S-myricanol 5-0-beta-D-glucopyranoside, myricanene A 5-O-alpha-L-arabinofuranosyl(1-->6)-beta-D-glucopyranoside, and myricanene B 5-0-alpha-L-arabinofuranosyl(1-->6)-beta-D-glucopyranoside, were isolated from the bark of Chinese Myrica rubra, together with twenty known compounds. The absolute stereostructures of the new diarylheptanoid glycosides were elucidated on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method. The inhibitory effects of isolated constituents on the release of beta-hexosaminidase from RBL-2H3 cells were examined, and several diarylheptanoids, myricanol, (+)-S-myricanol, myricanone, and myricanenes A and B, and a flavonol, myricetin, were found to show the inhibitory activity.
  • Regioselective BH3 hydride Reduction of Inosine Derivatives
    M. Yoshikawa; T. Morikawa; H. Matsuda; G. Tanabe; O. Muraoka
    Tetrahedron Lett. Elsevier Science 43 (4) 653 - 655 2002/01 [Refereed]
     
    ヌクレオシド類の部分修飾法の開発を目的として、 プリンヌクレオシドに対するヒドリド還元剤の反応性を検討した。 その結果、 ボラン （BH3） がイノシン類の 2, 3 位を位置選択的に還元することを見出した。 （英文）
  • Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka, O.
    Bioorganic and Medicinal Chemistry PERGAMON-ELSEVIER SCIENCE LTD 10 (5) 1547 - 1554 0968-0896 2002 [Refereed]
     
    A most potent alpha-glucosidase inhibitor named salacinol has been isolated from an antidiabetic Ayurvedic traditional medicine. Salacia reticulata WIGHT, through bioassay-guided separation. The absolute stereostructure of salacinol was determined on the basis of chemical and physicochemical evidence, which included the alkaline degradation of salacinol to 1-deoxy-4-thio-D-arabinofuranose and the X-ray crystallographic analysis, to be the unique spiro-like configuration of the inner salt comprised of 1-deoxy-4-thio-D-arabinofuranosyl sulfonium cation and 1'-deoxy-D-erythrosyl-3'-sulfate anion. Salacinol showed potent inhibitory activities on several alpha-glucosidases, such as maltase, sucrase, and isomaltase, and the inhibitory effects on serum glucose levels in maltose- and sucrose-loaded rats (in vivo) were found to be more potent than that of acarbose, a commercial alpha-glucosidase inhibitor. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida, I.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 56 (1-2) 45 - 50 0385-5414 2002 [Refereed]
     
    Three new labdane-type diterpenes named hedychilactones A, B, and C were isolated from the methanolic extract of the fresh rhizome of Hedychium coronarium KOENG. Their structures were elucidated on the basis of chemical and physicochemical evidence, which included the application of the allylic benzoate rule. The methanolic extract and diterpene constituents were found to inhibit the increase of vascular permeability induced by acetic acid in mice and nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages.
  • Matsuda, H.; Morikawa, T.; Tao, J.; Ueda, K.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 50 (2) 208 - 215 0009-2363 2002 [Refereed]
     
    Three new diarylheptanoid glycosides, named (+)-S-myricanol 5-O-beta-D-glucopyranoside, myricanene A 5-O-alpha-L-arabinofuranosyl(1-->6)-beta-D-glucopyranoside, and myricanene B 5-O-alpha-L-arabinofuranosyl(1-->6)-beta-D-glucopyranoside, were Isolated from the bark of Chinese Myrica rubra, together with twenty known compounds. The absolute stereostructures of the new diarylheptanoid glycosides were elucidated on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method. The inhibitory effects of isolated constituents on the release of beta-hexosaminidase from RBL-2H3 cells were examined, and several diaryl-heptanoids, myricanol, (+)-S-myricanol, myricanone, and myricanenes A and B, and a flavonol, myricetin, were found to show the inhibitory activity.
  • Tao, J.; Morikawa, T.; Toguchida, I.; Ando, S.; Matsuda, H.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry PERGAMON-ELSEVIER SCIENCE LTD 10 (12) 4005 - 4012 0968-0896 2002 [Refereed]
     
    Three neck, biphenyl type diarylheptanoid glycosides. myricanol 11-O-beta-D-glucopyranoside, myricanone 5-O-beta-D-glucopyranoside, and neomyricanone 5-O-beta-D-glucopyranoside, and a neck, taraxerane type triterpene. myricetrione. were isolated front the bark of Chinese Myrica rubra. Their structures were elucidated on the basis of chemical and physicochemical evidence. Biphenyl type diarylheptanoids. triterpene, and their polyphenols showed potent inhibitory effects on nitric oxide production in lipopolysaccharide-activated macrophages, Furthermore. diarylheptanoids, myricanol and myricanone, were found to inhibit induction of inducible nitric oxide synthase. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Morikawa, T.; Matsuda, H.; Ninomiya, K.; Yoshikawa, M.
    Biological and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 25 (5) 627 - 631 0918-6158 2002 [Refereed]
     
    The 80% aqueous acetone extract of Zedoariae Rhizoma was found to show a protective effect against D-galactosamine (D-GalN)/lipopolysaccharide-induced acute liver injury in mice. To clarify the active compounds, the principal constituents were examined and 11 sesquiterpenes (furanodiene, curdione, neocurdrione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone) and a diarylheptanoid (curcumin) were found to inhibit the increase in serum aspartate amino-transaminase and alanine aminotransaminase at a dose of 50 mg/kg p.o. in agreement with the previous in vitro studies, except for dehydrocurdione, aerugidiol, and zedoarondiol. In particular, curdione, neocurdione, curcumenol, and isocurcumenol potently inhibited the increase at a dose of 12.5 mg/kg p.o. Furthermore, the eight sesquiterpenes, furanodiene, curdione, neocurdione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, and curcumenone, also showed a protective effect against D-GalN/tumor necrosis factor-alpha-induced liver injury in mice at a dose of 50 mg/kg p.o.
  • Yoshikawa, M.; Murakami, T.; Ishiwada, T.; Morikawa, T.; Kagawa, M.; Higashi, Y.; Matsuda, H.
    Journal of Natural Products AMER CHEMICAL SOC 65 (8) 1151 - 1155 0163-3864 2002 [Refereed]
     
    The methanolic extract from the fresh flowers of Prunus mume exhibited inhibitory effects against aldose reductase and platelet aggregation From the methanolic extract, two new flavonol oligoglycosides, 2 0 acetylrutin and 2 O acetyl 3 O methylrutin, and two new polyacylated sucroses, prunoses I and II, were isolated together with II known constituents The structures of 2 O acetylrutin, 2 O acetyl 3 O methylrutin, and prunoses I and II were determined on the basis of chemical and physicochemical evidence as quercetin 3 O alpha L rhamnopyranosyl(1-->6) 2 O acetyl beta D glucopyranoside, 3 O methylquercetin 3 O alpha L rhamnopyranosyl(1-->6) 2 O acetyl beta D glucopyranoside, 1,4,3',4,6 penta O acetyl 6 O p coumaroylsucrose, and 1,3',4',6' tetra O acetyl 6 O p coumaroylsucrose, respectively The flavonol gly cosides and prunose I were found to inhibit aldose reductase, while prunoses I and II inhibited platelet aggregation induced by thrombin.
  • Mastuda, H.; Morikawa, T.; Ueda, K.; Managi, H.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry PERGAMON-ELSEVIER SCIENCE LTD 10 (10) 3123 - 3128 0968-0896 2002 [Refereed]
     
    To clarify the structure-activity relationships of flavonoids for antiallergic activity, the inhibitory effects of various flavonoids on the release of beta-hexosaminidase, as a marker of degranulation of RBL-2H3 cells, were examined. Among them, luteolin (IC50 = 3.0 muM), diosmetin (2.1 muM), and fisetin (3.0 muM) were found to show potent inhibitory activity, and the results suggested the following structural requirements of flavonoids: (1) the 2-3 double bond of flavones and flavonols is essential for the activity; (2) the 3- or 7-glycoside moiety reduced the activity; (3) as the hydroxyl groups at the 3'-, 4'-, 5-, 6-, and 7-positions increased in number, the inhibitory activities become stronger; (4) the flavonols with a pyrogallol type moiety (the 3',4',5'-trihydroxyl groups) at the B ring exhibited less activity than those with a phenol type moiety (the 4-hydroxyl group) or catechol type moiety (the 3',4'-dihydroxyl groups) at the B ring; (5) the activities of flavones were stronger than those of flavonols; and (6) methylation of flavonols at the 3-position reduced the activity. However, (7) several flavones and flavonols with the 4'- and/or 7-methoxyl groups did not obey rules (3), (4), and (5). In addition, several flavonoids, that is apigenin, luteolin, diosmetin, fisetin, and quercetin, inhibited the antigen-IgE-mediated TNF-alpha and IL-4 production from RBL-2H3 cells, both of which participate in the late phase of type I allergic reactions. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Morikawa, T.; Xu, F.; Matsuda, H.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 57 (11) 1983 - 1988 0385-5414 2002 [Refereed]
     
    The methanolic extract of the whole plant of Cyperus longus originating in Egypt was found to show scavenging activity for DPPH radical. By bioassay-guided separation, a norstilbene dimer, longusone A, with a tropilene structure and three stilbene dimers, longusols A, B, and C, were isolated as the active constituents together with 10 phenolic compounds. The structures of new compounds were elucidated on the basis of chemical and physicochemical evidence.
  • 森川 敏生
    ファルマシア 公益社団法人日本薬学会 38 (1) 60 - 61 0014-8601 2002/01
  • Matsuda, H.; Morikawa, T.; Toguchida, I.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 6 50 (6) 788 - 95 0009-2363 2002 [Refereed]
     
    The methanolic extracts of several natural medicines and medicinal foodstuffs were found to show an inhibitory effect on rat lens aldose reductase. In most cases, flavonoids were isolated as the active constituents by bioassay-guided separation, and among them, quercitrin (IC(50)=0.15 microM), guaijaverin (0.18 microM), and desmanthin-1 (0.082 microM) exhibited potent inhibitory activity. Desmanthin-1 showed the most potent activity, which was equivalent to that of a commercial synthetic aldose reductase inhibitor, epalrestat (0.072 microM). In order to clarify the structural requirements of flavonoids for aldose reductase inhibitory activity, various flavonoids and related compounds were examined. The results suggested the following structural requirements of flavonoid: 1) the flavones and flavonols having the 7-hydroxyl and/or catechol moiety at the B ring (the 3',4'-dihydroxyl moiety) exhibit the strong activity; 2) the 5-hydroxyl moiety does not affect the activity; 3) the 3-hydroxyl and 7-O-glucosyl moieties reduce the activity; 4) the 2-3 double bond enhances the activity; 5) the flavones and flavonols having the catechol moiety at the B ring exhibit stronger activity than those having the pyrogallol moiety (the 3',4',5'-trihydroxyl moiety).
  • Matsuda, H.; Pongpiriyadacha, Y.; Morikawa, T.; Kashima, Y.; Nakano, K.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry Letters 3 12 (3) 477 - 82 0960-894X 2002 [Refereed]
     
    The methanolic extract from the leaves of Tasmannia lanceolata was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, three known sesquiterpenes, polygodial, polygodial 12 alpha-acetal, and polygodial 12 beta-acetal, and a new sesquiterpene, methyl isodrimeninol, were isolated as the active constituents. Among them, polygodial showed very potent gastroprotective effects (ED(50)=0.028 mg/kg, po). From the gastroprotective effects of various reduction and oxidation derivatives of polygodial, the dialdehyde or diacetal structure was found to be essential for the strong activity. Since the gastroprotection of polygodial was attenuated by pretreatment with indomethacin, N-ethylmaleimide, N(G)-nitro-L-arginine methyl ester and ruthenium red, endogenous prostaglandins, sulfhydryl compounds, nitric oxide and vanilloid receptors may be involved in the protective activity.
  • Morikawa, T.; Matsuda, H.; Sakamoto, Y.; Ueda, K.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 8 50 (8) 1045 - 9 0009-2363 2002 [Refereed]
     
    Two new farnesane-type sesquiterpenes, hedychiols A and B 8,9-diacetate, were isolated from the methanolic extract of the fresh rhizome of Hedychium coronarium KOEN. cultivated in Japan. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of isolated constituents on the release of beta-hexosaminidase from RBL-2H3 cells were examined, and hedychilactone A and coronarin D were found to show the inhibitory activity.
  • Matsuda, H.; Morikawa, T.; Toguchida, I.; Harima, S.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin 7 50 (7) 972 - 5 0009-2363 2002 [Refereed]
     
    Two new flavanone glycosides, (2S)- and (2R)-eriodictyol 7-O-beta-D-glucopyranosiduronic acids, and a new phenylbutanoid glycoside, (2S, 3S)-1-phenyl-2,3-butanediol 3-O-beta-D-glucopyranoside, were isolated from the flowers of Chrysanthemum indicum L. cultivated in China together with eight flavonoids. The absolute stereostructures of the new compounds were determined on the basis of chemical and physicochemical evidence. Both of the new flavanone glycosides were found to show inhibitory activity for rat lens aldose reductase.
  • Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida, I.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry 8 10 (8) 2527 - 34 0968-0896 2002 [Refereed]
     
    The methanolic extract from the rhizome of Hedychium coronarium was found to inhibit the increase in vascular permeability induced by acetic acid in mice and nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages. From the methanolic extract, three new labdane-type diterpenes, hedychilactones A, B, and C, were isolated together with six known diterpenes. The structures of hedychilactones were elucidated on the basis of chemical and physicochemical evidence. The diterpene constituents showed inhibitory effects on the increase in vascular permeability, nitric oxide production, and inducible nitric oxide synthase induction.
  • Yoshikawa, M.; Morikawa, T.; Nakano, K.; Pongpiriyadacha, Y.; Murakami, T.; Matsuda, H.
    Journal of Natural Products 11 65 (11) 1638 - 42 0163-3864 2002 [Refereed]
     
    Five new oleanane-type triterpene saponins, albiziasaponins A-E (1-5), were isolated from the stems of Albizia myriophylla collected in Thailand, together with two known triterpene saponins, licorice-saponin F3 and yunganoside B(1). The structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. In addition, when sensory tests were performed on sweetness, albiziasaponin B (2), with a carbonyl group at the C-30 position, was found to show a potent sweetness intensity relative to sucrose (600 times).
  • Morikawa, T.; Matsuda, H.; Toguchida, I.; Ueda, K.; Yoshikawa, M.
    Journal of Natural Products 10 65 (10) 1468 - 74 0163-3864 2002 [Refereed]
     
    The 80% aqueous acetone extract and the ethyl acetate-soluble portion from the dried fruit of Alpinia oxyphylla MIQUEL were found to show inhibitory effects on nitric oxide production in lipopolysaccharide-activated macrophages and antigen-induced degranulation in RBL-2H3 cells. A new eudesmane-type sesquiterpene, oxyphyllol A, and two eremophilane-type sesquiterpenes, oxyphyllols B and C, were isolated from the ethyl acetate-soluble portion, together with 16 known constituents. The absolute stereostructures of oxyphyllols A, B, and C were determined on the basis of chemical and physicochemical evidence. The effects of isolated components on nitric oxide production were examined, and nine constituents including oxyphyllol A and nootkatone were found to show inhibitory activity. On the other hand, five constituents inhibited the release of beta-hexosaminidase from RBL-2H3 cells.
  • Yoshikawa, M.; Morikawa, T.; Yashiro, K.; Murakami, T.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 49 (11) 1452 - 1456 0009-2363 2001 [Refereed]
     
    New dammarane-type triterpene saponins, notoginsenosides-L, -M, and -N, were isolated from the glycosidic fraction of the dried roots of Panax notoginseng (BURK.) F. H. CHEN. Their structures were elucidated on the basis of chemical and physicochemical evidence. Immunological adjuvant activities of the principal notoginsenosides and related dammarane-type triterpene saponins were examined and notoginsenosides-D, -G, -H, and -K were found to increase the serum IgG level in mice sensitized with ovalbumin.
  • Kageura, T.; Matsuda, H.; Morikawa, T.; Toguchida, I.; Harima, S.; Oda, M.; Yoshikawa, M.
    Bioorganic and Medicinal Chemistry PERGAMON-ELSEVIER SCIENCE LTD 9 (7) 1887 - 1893 0968-0896 2001 [Refereed]
     
    By bioassay-guided separation, three stilbenes (rhapontigenin, piceatannol, and resveratrol), two stilbene glucoside gallates (rhaponticin 2''-O-gallate and rhaponticin 6"-O-gallate), and a naphthalene glucoside (torachrysone 8-O-beta -D-glucopyranoside) with inhibitory activity against nitric oxide (NO) production in lipopolysaccharide-activated macrophages were isolated (IC50 = 11-69 muM). The oxygen functions (-OH, -OCH3) of stilbenes at the benzene ring were essential for the activity. The glucoside moiety reduced the activity, while the alpha,beta -double bond had no effect. Furthermore, the active stilbenes (rhapontigenin, piceatannol, and resveratrol) did not inhibit inducible NO synthase activity, but they inhibited nuclear factor-kappaB activation following expression of inducible NO synthase. (C) 2001 Elsevier Science Ltd. All rights reserved.
  • Matsuda, H.; Morikawa, T.; Toguchida, I.; Ninomiya, K.; Yoshikawa, M.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 55 (5) 841 - 846 0385-5414 2001 [Refereed]
     
    Six new guaiane- or secoguaiane-type sesquiterpenes, 4-epi-curcumenol, neocurcumenol, gajutsulactones A and B, and zedoarolides A and B, were isolated from aqueous acetone extract of Zedoariae Rhizoma (Zingiberaceae), together with 34 sesquiterpenes and two diarylheptanoids. The stereostructures of new sesquiterpenes were elucidated on the basis of chemical and physicochemical evidence, which included nuclear Overhauser effect (NOE) and circular dichroic (CD) spectroscopic analyses. Gajutsulactones A and B, and 14 sesquiterpenes, and two diarylheptanoids were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages.
  • Matsuda, H.; Morikawa, T.; Toguchida, I.; Ninomiya, K.; Yoshikawa, M.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 49 (12) 1558 - 1566 0009-2363 2001 [Refereed]
     
    A new eudesmane-type sesquiterpene. zedoarofuran, and six new guaiane- or seco-guaiane-type sesquiterpenes. 4-epicurcumenol, neocurcumenol, gajutsulactones A and B, and zedoarolides A and B, were isolated from aqueous acetone extract of Zedoariae Rhizoma together with 36 known sesquiterpenes and two diarylheptanoids. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. The effects of isolated components on nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages were examined and 16 sesquiterpenes including gajutsulactones A and B, and bis(4-hydroxy-cinnamoyl)methane were found to show inhibitory activity.
  • Yoshikawa, M.; Morikawa, T.; Fujiwara, E.; Ohgushi, T.; Asao, Y.; Matsuda, H.
    Heterocycles PERGAMON-ELSEVIER SCIENCE LTD 55 (9) 1653 - + 0385-5414 2001 [Refereed]
     
    The methanolic extract from the flowers of Camellia japonica was found to exhibit potent gastroprotective effect on ethanol-induced gastric mucosal lesions in rats and platelet aggregation activity. Through bioassay-guided separation, three new 28-noroleanane-type triterpene saponins, camelliosides A, B, and C, and an oleanane-type triterpene saponin, camellioside D, were isolated from the methanolic extract. The absolute stereostructures of camelliosides A-D were determined on the basis of physicochemical and chemical evidence, which included the structure revision of the triterpene part, camellenodiol and camelledionol, using X-Ray crystallographic analysis and modified Mosher's method. Camelliosides A and B showed gastroprotective and platelet aggregating effects.
  • Matsuda, H.; Kageura, T.; Inoue, Y.; Morikawa, T.; Yoshikawa, M.
    Tetrahedron PERGAMON-ELSEVIER SCIENCE LTD 56 (39) 7763 - 7777 0040-4020 2000 [Refereed]
     
    From the methanolic extract of the dried roots of Saussurea lappa Clarke, Saussureae Radix, five amino acid-sesquiterpene conjugates, saussureamines A, B, C, D and E, were isolated together with a lignan glycoside, (-)-massoniresinol 4 "-O-beta-D-glucopyranoside. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, saussureamines and the related amino acid-sesquiterpene conjugates were synthesized using a Michael type addition reaction of amino acid to the alpha-methylene-gamma-lactone moiety of sesquiterpenes. Saussureamines A, B and C, costunolide and dehydrocostus lactone showed a gastroprotective effect on acidified ethanol-induced gastric mucosal lesions in rats. Saussureamines A also exhibited an inhibitory effect on gastric mucosal lesions induced by water-immersion stress in mice. (C) 2000 Elsevier Science Ltd. All rights reserved.
  • Matsuda, H.; Kagerura, T.; Toguchida, I.; Ueda, H.; Morikawa, T.; Yoshikawa, M.
    Life Sciences PERGAMON-ELSEVIER SCIENCE LTD 66 (22) 2151 - 2157 0024-3205 2000 [Refereed]
     
    The methanolic extract from the leaves of Laurus nobilis (bay leaf, laurel) was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Through bioassay-guided separation, fourteen known sesquiterpenes were isolated from the active fraction and were examined for ability to inhibit the NO production. Seven sesquiterpene lactones (costunolide, dehydrocostus lactone, eremanthine, zaluzanin C, magnolialide, santamarine and spirafolide) potently inhibited LPS-induced NO production (IC50 - 1.2 similar to 3.8 mu M). Other sesquiterpene constituents also showed the inhibitory activity (IC50 greater than or equal to 21 mu M), but their inhibitory activities were less than those of sesquiterpene lactones. alpha-Methylene-gamma-butyrolactone also showed inhibitory activity (IC50 - 9.6 mu M), while mokko lactone and watsonol A etc., reductants of the alpha-methylene-gamma-butyrolactone moiety by NaBH4 or DIBAL, and a 2-mercaptoethanol adduct of dehydrocostus lactone showed little activity (IC50 greater than or equal to 18 mu M). These results indicated that the alpha-methylene-gamma-butyrolactone moiety is important for the activity. Furthermore, costunolide and dehydrocostus lactone inhibited inducible nitric oxide synthase (iNOS) induction in accordance with induction of heat shock protein 72 (HSP 72). These results suggested that, as one of their mechanisms of action, sesquiterpene lactones induce HSP 72 thereby preventing nuclear factor-kappa B activation followed by iNOS induction.
  • Yoshikawa, M.; Morikawa, T.; Toguchida, I.; Harima, S.; Matsuda, H.
    Chemical and Pharmaceutical Bulletin PHARMACEUTICAL SOC JAPAN 48 (5) 651 - 656 0009-2363 2000 [Refereed]
     
    The methanolic extract and ethyl acetate-soluble portion from the flowers of Chrysanthemum indicum L., Chrysanthemi Indici Flos, were found to show inhibitory activity against nitric oxide (NO) production in lipopolysaccharide-activated macrophages. Five new germacrane-type sesquiterpenes, kikkanols D, D monoafetate, E, F,and F monoacetate, were isolated from the ethyl acetate-soluble portion. Their absolute stereostructures were elucidated on the basis of chemical and physicochemical evidence, which included application of the modified Mosher's method. The effects of fifteen principal components from the ethyl acetate-soluble portion of this medicinal flower against NO production were examined and, among them, acetylenic compounds and flavonoids were found to show potent inhibitory activity.

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Conference Activities & Talks

MISC

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Awards & Honors

  • 2021/12 The Pharmaceutical Society of Japan The PSJ Award for Divisional Scientific Promotion
     
    受賞者: 森川 敏生
  • 2018/09 日本生薬学会 日本生薬学会学術貢献賞
     
    受賞者: 森川 敏生
  • 2016/09 日本生薬学会 平成28年度 日本生薬学会論文賞
     
    受賞者: 森川 敏生
  • 2013/10 Best Poster Award in 9th AFMC International Medicinal Chemistry Symposium (AIMECS13)
     
    受賞者: Toshio MORIKAWA
  • 2011/11 Young Investigator Award in 2011 International Conference on Food Factors (ICoFF2011)
     
    受賞者: Toshio MORIKAWA
  • 2008 日本薬学会近畿支部 The PSJ Kinki-branch Award for Young Scientists
     JPN 
    受賞者: 森川 敏生
  • 2005 日本生薬学会 The JSP Award for Young Scientists
     JPN 
    受賞者: 森川 敏生
  • 2002 和漢医薬学会 第19回和漢医薬学会大会若手研究者奨励賞
     
    受賞者: 森川 敏生
  • 2001 Young Investigator Award in the Symposium on the Chemistry of Natural Products
     JPN 
    受賞者: 森川 敏生

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2022/04 -2025/03 
    Author : 森川 敏生; 萬瀬貴昭
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2022/03 
    Author : Morikawa Toshio
     
    To explore new functional ingredients for improve glucose and/or lipid metabolisms from natural resources used for medicinal purposdes in traditional and folk medicines as well as also used as edible resources. Thus, we searched for new bioactive constituents for preventing diabetes or dyslipidemia based on visceral fat accumulation and alleviating their early symptoms. In addition, we aim to bioactivity evaluate of the active constituents and propose and develop new functional food and phytopharmaceutical candidate ingredients based on the evidence. Furthermore, we also aim to create new candidates by synthesizing and evaluating the total synthesis and analogues of the active components as new seeds.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : MORIKAWA Toshio; NINOMIYA Kiyofumi
     
    To explore new therapeutic candidates for aimed to overcoming of inflammatory bowel diseases from traditional natural resources worldwide, we searched for active constituents that regulate several inflammation reactions caused by over productions of NO and TNF-alfa etc in iNOS-positive cells. As the results, several constituents from the natural resources were investigated as the promissing candidates and their structural requirements and the mode of action were suggested.
  • メタボリックシンドローム予防および改善効果を指標としたタイ天然薬物からの新規機能性食品素材の探索
    公益財団法人 小林国際奨学財団：第３回（平成26年度）研究助成
    Date (from‐to) : 2015/07 -2017/06 
    Author : 森川 敏生
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : MORIKAWA Toshio; NINOMIYA Kiyofumi
     
    To investigate prevention and/or treatment for metabolic syndrome therapeutic candidates from Thai natural medicines, we examined following in vivo and in vitro pharmacological assays such as (i) suppressive effects on blood glucose and triglyceride elevation in sugar or olive oil-loaded mice, (ii) inhibitory effects on rat or human small intestinal α-glucosidases, (iii) suppressive effects on nitric oxide production in lipopolysaccharide-activated macrophages, and (iv) inhibitory effects on triglyceride content in high glucose-pretreated HepG2 cells, etc. As the results, several constituents were identified as the active compounds and their structural requirements and the mode of action were suggested.
  • サラシノールをシードとする新規糖尿病薬の開発研究
    The Takano Science Foundation：平成25年度研究奨励
    Date (from‐to) : 2014/01 -2014/12 
    Author : MORIKAWA Toshio
  • 香辛料由来成分をシーズとする生活習慣病予防・改善物質の開拓
    Takeda Science Foundation：薬学系研究奨励
    Date (from‐to) : 2009/04 -2011/03 
    Author : MORIKAWA Toshio
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2010 -2011 
    Author : MORIKAWA Toshio
     
    In order to investigate hepatoprotective constituents by reductive effect of sensitivity to TNF-αfrom medicinal plants, we examined inhibitory effect on TNF-α-induced cytotoxicity in L929 cells as a first screening trial. As the results, several materials such as Thai medicinal plants, Piper chaba(fruit), Sapindus rarak(pericarps), Kaempferia parviflora(rhizomes), Shorea roxburghii(bark), and Mammea siamensis(flowers) and Cistanche tubulosa(stems) were found to inhibit the activity. From those candidate materials, several constituents were investigated as the active compounds. Furthermore, the structural requirements and the mode of action of the active compounds were also examined.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2008 -2009 
    Author : MORIKAWA Toshio
     
    In order to investigate bioactive constituents from medicinal foods, we examined following extensive screening trials : (1) inhibitory effects on serum triglyceride (TG) elevation in olive oil-treated mice (2) TG accumulation inhibitory activity in HepG2 cells and TG metabolism-promoting activity in high glucose pretreated HepG2 cells, and (3) inhibitory effects on TNF-α-induced cytotoxicity in mouse primary cultured hepatocytes and/or L929 cells. As the results, (1) antihyperlipidemic saponin constituents were obtained from flowers of Bellis perennis and pericarps of Sapindus rarak, (2) lipid accumulation inhibitors were obtained from Sedum sarmentosum, and (3) TNF-α sensitivity degradation principles were obtained from Boesenbergia rotunda, Punica granatum, Helichrysum arenarium, and Piper chaba.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2006 -2007 
    Author : 森川 敏生
     
    今や国民病ともいわれる花粉症は代表的なアレルギー性疾患で,現在では日本人の20〜30%が罹患していると推定される.また,食事や飲酒などの食生活が疾病の発症・進展に関与する胃潰瘍や肝炎などの疾患も急増しており,これらの予防や初期段階の改善に様々なサプリメントや機能性食品が開発されている.しかしながら,これらのなかには科学的根拠が乏しいものがあるのも事実で,これらによる健康被害が社会問題となっている.その為,サプリメントや機能性食品素材についての物質科学的根拠(マテリアルサイエンス)に基づいた機能解明が急務であり,またそれらの活性成分を見い出だすことで,新たな医薬シーズを提案することが可能となる.本研究は,香辛料として食用にも利用される薬用食品からアレルギーやアルコール摂取による各種臓器障害に予防的あるいはその初期段階の改善に有用な機能性食品素材の提案をおこなうとともに,生物活性を指標に分離・精製し,NMRをはじめとした各種スペクトルの解析から活性成分および新規化合物の構造解析を実施する.今年度は,昨年度に実施した予備的検討により選抜した数種の薬用食品素材(1.漢薬"補骨脂",2.碾茶,3.エジプト天然薬物コロシント)の抗アレルギー作用成分および(4.椿花)のアルコール誘発胃粘膜保護作用成分を探索し,種々の新規活性成分を単離・構造決定した.中国やエジプト地域の天然素材のほか,日本人に馴染み深い茶(碾茶)や椿(花部)などの薬用食品素材に抗アレルギーおよび胃保護作用を有することを見いだすとともに,その活性成分を明らかにするなどの成果が得られたことから,今年度の当初計画は充分に達成できたと考える.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2004 -2005 
    Author : 森川 敏生
     
    本研究課題において昨年度までに,マウス腹腔マクロファージを用いたリポ多糖刺激によるNO産生抑制活性を一次スクリーニングとし,アーユル・ヴェーダやユナニー医学において炎症性疾患の治療に用いられている没薬から,myrrhanol Aをはじめ数種の含有テルペノイド成分にNO産生抑制活性が認められた.また,これら候補化合物のiNOSに及ぼす影響を検討したところ,myrrhanol Aは,iNOSに対する酵素阻害活性は殆ど認められず,iNOSの発現を抑制することが判明した.同様にエジプト地域に自生するヒガンバナ科植物のCrinum yemenseの球根部から3種の新規ヒガンバナアルカロイドyemenin A-Cを単離・構造決定するとともに,yemenin Aをはじめ数種の含有アルカロイド成分がiNOS発現抑制活性に起因するNO産生抑制活性を有することを見いだすなど,新しいタイプの天然由来化合物(低分子リガンド)にα-methylene-γ-butyrolactone構造を有するセスキテルペノイド類であるconstunolideやdehydrocostus lactoneなどと共通する作用メカニズムを見いだした.今年度はこれまでに得られた結果をふまえ,タイ料理のトムヤンクンなどに香辛料として用いられるAlpinia galangaから得られたフェニルプロパノイド成分の1'S-1'-acetoxychavicol acetateを低分子リガンドとして,NOの過剰産生に至るシグナル伝達機構に関与するタンパクあるいは遺伝子の発現に及ぼす影響を解明した.また,日本民間薬のヒュウガトウキからクマリン類やアセチレン化合物を,さらには漢薬良姜からジアリルヘプタノド類を新たなタイプの低分子リガンドとして見いだすなど,今年度の当初計画をほぼ達成した.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2002 -2003 
    Author : 森川 敏生
     
    平成14年度に引き続き,癌転移に対し促進的に作用する過剰な活性酸素種や活性窒素種などの酸化ストレスの消去系亢進の指標として,NO産生抑制活性を一次スクリーニングとして実施したところ,新たに漢薬"小紅参"(Rubia yunnanensis,根部)およびエジプト産天然薬物Anastatica hierochuntica(全草)の抽出エキスに活性が認められたことから,活性を指標に分離,精製し,有効成分を探索した.その結果,小紅参から新規化合物としてarborinane型トリテルペンrubianol-a-g, arborinane型トリテルペン配糖体rubianoside I-IVおよびアントラキノンrubianthraquihoneを単離,構造決定するとともに,含有環状ペプチド配糖体RA-XII (IC_<50>=0.85μM)およびそのアグリコン部であるdeoxybouvadin (IC_<50>=0.015μM)に顕著なNO産生抑制活性を見出し,その活性強度はチロシンキナーゼ阻害剤であるherbimycin A (IC_<50>=0.094μM)よりも強い活性であった.また,RA-XIIおよびdcoxybouvadinの作用点のひとつにiNOSの誘導を抑制することを明らかにし,これら環状ペプチド類が本課題の候補化合物として有望であることが示唆するなどの結果を得た.次いで,我々が保有するflavonoid化合物ライブラリー73種のNO産生抑制活性スクリーニングを実施し,活性発現の必須構造や構造活性相関を明らかにするとともに,漢薬"木香"の含有セスキテルペン成分やそのアミノ酸付加体に,NF-κBの活性化や熱ショック蛋白(HSP-72)の発現抑制作用を認めるなど,NO産生抑制作用メカニズムに関する知見を得た. 上記の手法を用いピックアップした候補素材のうち,日本薬局方生薬の"川骨"(Nuphar pumilum,根茎)MeOH抽出エキスおよび含有成分について,B16メラノーマ4A5細胞を用いたコラーゲンコートメンブランにおける癌細胞浸潤抑制活性(in vitro)およびマウスを用いた癌細胞転移抑制作用(in vivo)試験を実施した.その結果,エキスのアルカロイド分画および含有成分である含硫黄セスキテルペンアルカロイド2量体6-hydroxythiobinupharidineに顕著な癌転移抑制作用を見出し新たな医薬シーズの探索に成功するなど,平成15年度の当初計画をほぼ達成した.

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