小川 智弘(オガワ トモヒロ)

工学部 化学生命工学科講師

Last Updated :2024/07/20

■教員コメント

コメント

肝臓の病気に関心を持ち、その病気の機構や治療法を動物や細胞を使って研究をしています。現在は、近年患者が増加している非アルコール性脂肪性肝炎(NASH)に関する基礎研究を行っている。

■研究者基本情報

学位

  • 修士(理学)(広島大学)
  • 博士(理学)(広島大学)

ORCID ID

0000-0002-1742-1798

研究キーワード

  • 肝臓病学   Hepatology   

現在の研究分野(キーワード)

肝臓の病気に関心を持ち、その病気の機構や治療法を動物や細胞を使って研究をしています。現在は、近年患者が増加している非アルコール性脂肪性肝炎(NASH)に関する基礎研究を行っている。

研究分野

  • ライフサイエンス / 消化器内科学
  • ライフサイエンス / 分子生物学

■経歴

経歴

  • 2014年04月 - 現在  近畿大学工学部講師
  • 2016年09月 - 2017年08月  University of Southern CaliforniaDepartment of Pathology
  • 2011年04月 - 2014年03月  近畿大学工学部助教
  • 2008年10月 - 2011年03月  ウイルス肝炎研究財団リサーチ・レジデント
  • 2006年11月 - 2008年09月  大阪市立大学医学研究科博士研究員
  • 2003年09月 - 2006年10月  広島大学原爆放射線医科学研究所COE研究員

学歴

  • 2002年04月 - 2006年09月   広島大学大学院   理学研究科   生物科学専攻博士課程後期
  • 2000年04月 - 2002年03月   広島大学大学院   理学研究科   生物科学専攻博士課程前期
  •         - 2002年   広島大学   Graduate School, Division of Natural Science   Department of Biological Science
  • 1996年04月 - 2000年03月   広島大学   理学部   生物科学科
  •         - 2000年   広島大学   Faculty of Science   Department of biological Science

■研究活動情報

論文

  • Tomohiro Ogawa; Takumi Terada
    Biological and Pharmaceutical Bulletin 47 7 1265 - 1274 2024年07月 [査読有り]
  • Tomoya Nakago; Yuto Oki; Tatsuki Nousou; Tomohiro Ogawa; Kohei Shiraishi
    Materials Advances 2024年04月 [査読有り]
     
    We have developed N-α-lysine acrylamide (LysAA) with a lysine side chain that enhances the fibrinolytic system; random copolymerization of LysAA with MPC [20% molar ratio] enhanced the fibrinolytic activity of LysAA.
  • 新型コロナウイルス感染症蔓延に伴う教職科目の対応の記録
    小川 智弘; 佐々木 良勝
    近畿大学工学部教職課程年報 2022年03月
  • Tatsuki Nousou; Seiryu Hirao; Tomohiro Ogawa; Kohei Shiraishi
    Journal of Applied Polymer Science 52257 - 52257 2022年02月 [査読有り]
  • L-Lysine側鎖にもつ生体適合性polyacryamide存在下でのHepG2細胞応答性
    小川智弘; 農宗辰己; 市原祐介; 沖勇斗; 白石浩平
    近畿大学工学部研究報告 7 - 11 2021年02月
  • Steven Balog; Yuchang Li; Tomohiro Ogawa; Toshio Miki; Takeshi Saito; Samuel W. French; Kinji Asahina
    Hepatology 71 1 291 - 305 2020年01月 [査読有り]
     
    Glisson's capsule is the connective tissue present in the portal triad as well as beneath the liver surface. Little is known about how Glisson's capsule changes its structure in capsular fibrosis (CF), which is characterized by fibrogenesis beneath the liver surface. In this study, we found that the human liver surface exhibits multilayered capsular fibroblasts and that the bile duct is present beneath the mesothelium, whereas capsular fibroblasts are scarce and no bile ducts are present beneath the mouse liver surface. Patients with cirrhosis caused by alcohol abuse or hepatitis C virus infection show development of massive CF. To examine the effect of alcohol on CF in mice, we first injected chlorhexidine gluconate (CG) intraperitoneally and then fed alcohol for 1 month. The CG injection induces CF consisting of myofibroblasts beneath the mesothelium. One month after CG injection, the fibrotic area returns to the normal structure. In contrast, additional alcohol feeding sustains the presence of myofibroblasts in CF. Cell lineage tracing revealed that mesothelial cells give rise to myofibroblasts in CF, but these myofibroblasts disappear 1 month after recovery with or without alcohol feeding. Capsular fibroblasts isolated from the mouse liver spontaneously differentiated into myofibroblasts and their differentiation was induced by transforming growth factor beta 1 (TGF‐β1) or acetaldehyde in culture. In alcohol‐fed mice, infiltrating CD11b+Ly‐6CLow/– monocytes had reduced mRNA expression of matrix metalloproteinase 13 and matrix metalloproteinase 9 and increased expression of tissue inhibitor of matrix metalloproteinase 1, Tgfb1, and interleukin‐10 during resolution of CF. Conclusion: The present study revealed that the structure of Glisson's capsule is different between human and mouse livers and that alcohol impairs the resolution of CF by changing the phenotype of Ly‐6CLow/– monocytes.
  • Tomohiro Ogawa; Yuchang Li; Ingrid Lua; Andrea Hartner; Kinji Asahina
    Developmental Dynamics 247 6 867 - 881 2018年04月 [査読有り]
     
    Background: Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. Results: Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α‐smooth muscle actin+ perivascular mesenchymal cells around the vein. A cell lineage–tracing study revealed that upon differentiation, MC‐derived HSCs or perivascular mesenchymal cells express ITGA8 during liver development. Using anti‐ITGA8 antibodies, we succeeded in isolating MC‐derived HSCs and perivascular mesenchymal cells from embryonic livers. In direct co‐culture, ITGA8+ mesenchymal cells promoted the expression of hepatocyte and cholangiocyte markers in hepatoblasts. In the normal adult liver, expression of ITGA8 was restricted to portal fibroblasts in the portal triad. Upon liver injury, myofibroblasts increased the expression of ITGA8. Conclusions: ITGA8 is a specific cell surface marker of MC‐derived HSCs and perivascular mesenchymal cells in the developing liver. Our data suggest that ITGA8+ mesenchymal cells maintain the phenotype of hepatoblast in liver development. Developmental Dynamics 247:867–881, 2018. © 2018 Wiley Periodicals, Inc.
  • 教育実習報告会の意義とその効果
    小川 智弘
    近畿大学工学部教職課程年報 2016年08月
  • タブレット型コンピューター(iPad)を使用した理科授業の実践とその教育効果の評価
    小川 智弘
    近畿大学工学部教職課程年報 2014年07月
  • Ritsuzo Kozuka; Masaru Enomoto; Hoang Hai; Tomohiro Ogawa; Mika Nakaya; Atsushi Hagihara; Hideki Fujii; Sawako Kobayashi; Shuji Iwai; Hiroyasu Morikawa; Akihiro Tamori; Norifumi Kawada
    HEPATOLOGY RESEARCH 42 12 1157 - 1167 2012年12月 [査読有り]
     
    Aim: Some regions associated with sensitivity to interferon-a and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 22092248 (interferon sensitivity-determining region, ISDR) and a.a. 23342379 (interferon and ribavirin resistance-determining region, IRRDR). Methods: We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-a and ribavirin for 2448 weeks and subsequently received retreatment for 4872 weeks. Results: At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (01 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (<6 mutations) in 19 patients at baseline and at the start of retreatment. Conclusion: Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.
  • Tomohiro Ogawa; Masaru Enomoto; Hideki Fujii; Yumiko Sekiya; Katsutoshi Yoshizato; Kazuo Ikeda; Norifumi Kawada
    GUT 61 11 1600 - 1609 2012年11月 [査読有り]
     
    Background MicroRNAs (miRNAs) are important in hepatic pathophysiology and the development of liver cancer. Objective To explore miRNAs that are regulated with the progression of liver fibrosis caused by chronic liver disease. Design The regulated miRNAs in human livers infected with hepatitis C virus were identified by microarray analysis. Their expression in human livers with nonalcoholic steatohepatitis, mouse livers from two fibrosis models and cultured stellate cells was validated by realtime RT-PCR. The regulation of miR-222 expression in stellate cells by nuclear factor kappa B (NF-kappa B) was assayed. Finally, the effects of an miR-222 precursor or inhibitor on the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and the growth of LX-2 cells were determined. Results It was found that miR-199a-5p/199a-3p and miR-221/222 were upregulated in the human liver in a fibrosis progressionedependent manner. Among these miRNAs, miR-221/222 were upregulated in LX-2 cells and increased during the course of culture-dependent activation of mouse primary stellate cells, in a manner similar to the expression of alpha 1(I) collagen and alpha-smooth muscle actin mRNAs. The expression of miR-221/222 increased in mouse models of liver fibrosis. In contrast, an NF-kappa B inhibitor significantly suppressed the miR-222 induction that was stimulated in culture by transforming growth factor alpha or tumour necrosis factor alpha. Although overexpression or downregulation of miR-222 failed to regulate the growth of LX-2 cells, miR-222 bound to the CDKN1B 3'UTR and regulated the expression of the corresponding protein. Conclusion miR-221/222 may be new markers for stellate cell activation and liver fibrosis progression.
  • 肝線維化とマイクロRNA
    池田一雄; 小川 智弘; 河田則文
    肝胆膵 65 2 203 - 209 2012年08月
  • Masashi Iizuka; Tomohiro Ogawa; Masaru Enomoto; Hiroyuki Motoyama; Katsutoshi Yoshizato; Kazuo Ikeda; Norifumi Kawada
    Fibrogenesis and Tissue Repair 5 1 12  2012年08月 [査読有り]
     
    Background: miRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases. The present study clarified the role of miR-214-5p in hepatic fibrogenesis using human clinical tissue samples, livers from rodent models, and cultured hepatic stellate cells.Methods: The expression of miR-214-5p and genes that are involved in liver fibrosis were analyzed in hepatitis C virus-infected human livers, rodent fibrotic livers, a human stellate cell line (LX-2), and the cells from intact mouse livers using real-time PCR. The effect of miR-214-5p overexpression in LX-2 cells on cell function was investigated. Twist-1 expression in the liver tissues of mouse models and primary-cultured stellate cells was also analyzed.Results: miR-214-5p was upregulated in human and mouse livers in a fibrosis progression-dependent manner. miR-214-5p expression increased during the culture-dependent activation of mouse primary stellate cells and was significantly higher in stellate cells than in hepatocytes. The overexpression of miR-214-5p in LX-2 cells increased the expression of fibrosis-related genes, such as matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin, and transforming growth factor (TGF)-β1. TGF-β stimulation induced miR-214-5p in LX-2 cells. Twist-1 was increased in fibrotic mouse livers and induced during mouse stellate cell activation.Conclusion: miR-214-5p may play crucial roles in the activation of stellate cells and the progression of liver fibrosis. Twist-1 may regulate miR-214-5p expression in the liver, particularly in stellate cells. © 2012 Iizuka et al. licensee BioMed Central Ltd.
  • 関谷 由美子; 小川 智弘; 河田 則文
    J Cell Physiol. 226 10 2535 - 2542 2011年10月 [査読有り]
     
    Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN-beta induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-beta down-regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3'UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-beta. In conclusion, IFN-beta inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. J. Cell. Physiol. 226: 2535-2542, 2011. (C) 2010 Wiley-Liss, Inc.
  • Mami Mori; Hideki Fujii; Tomohiro Ogawa; Sawako Kobayashi; Shuji Iwai; Hiroyasu Morikawa; Masaru Enomoto; Akihiro Tamori; Ayumi Sawada; Setsuko Takeda; Norifumi Kawada
    HEPATOLOGY RESEARCH 41 9 897 - 903 2011年09月 [査読有り]
     
    Aim: Transient elastography is known as a rapid, objective, and highly reliable technique for staging hepatic fibrosis caused by hepatitis C virus infection; however, the relationship between degree of fibrosis and the collagen deposition or the accumulation of myofibroblasts in non-alcoholic fatty liver disease (NAFLD) remains to be further elucidated. Methods: The subjects were 36 patients with NAFLD who received liver biopsy and liver stiffness measurement using transient elastography. Their clinical data and laboratory values were collected. Morphometric analyses of liver fibrosis indicated by collagen deposition and the relative numbers of myofibroblasts were performed. Results: Liver stiffness measured by transient elastography correlated with histopathological fibrosis staging of NAFLD determined by Brunt's scoring system (P = 0.000149). The fibrosis staging correlated with the ratios of the Sirius redpositive area (P = 0.000032) and alpha-smooth muscle actin-positive area (P = 0.000898). Finally, liver stiffness significantly correlated with the ratios of the Sirius red-positive area (r = 0.390, P = 0.0184) and alpha-smooth muscle actin-positive area (r = 0.333, P = 0.0471). Conclusions: Liver stiffness measurement by transient elastography is valuable for evaluating fibrotic progression in NAFLD.
  • Hirofumi Fujita; Kazuko Kurokawa; Tetsuya Ogino; Mio Ono; Masanao Yamamoto; Takashi Oka; Tohru Nakanishi; Naoya Kobayashi; Noriaki Tanaka; Tomohiro Ogawa; Etsuko Suzaki; Kozo Utsumi; Junzo Sasaki
    Basic & Clinical Pharmacology & Toxicology 109 2 78 - 84 2011年08月 [査読有り]
  • Le Thi Thanh Thuy; Takashi Morita; Kayo Yoshida; Kenichi Wakasa; Masashi Iizuka; Tomohiro Ogawa; Mami Mori; Yumiko Sekiya; Shinobu Momen; Hiroyuki Motoyama; Kazuo Ikeda; Katsutoshi Yoshizato; Norifumi Kawada
    AMERICAN JOURNAL OF PATHOLOGY 179 2 1050 - 1060 2011年08月 [査読有り]
     
    Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week-old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1 beta, IL-6, Tnf alpha, and Tgf beta 3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis. (Am J Pathol 2011, 179:1050-1060; DOI: 10.1016/j.ajpath.2011.05.006)
  • Yumiko Sekiya; Tomohiro Ogawa; Katsutoshi Yoshizato; Kazuo Ikeda; Norifumi Kawada
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 412 1 74 - 79 2011年08月 [査読有り]
     
    MicroRNAs (miRNAs) participate in the regulation of cellular functions including proliferation, apoptosis, and migration. It has been previously shown that the miR-29 family is involved in regulating type I collagen expression by interacting with the 3'UTR of its mRNA. Here, we investigated the roles of miR-29b in the activation of mouse primary-cultured hepatic stellate cells (HSCs), a principal collagen-producing cell in the liver. Expression of miR-29b was found to be down-regulated during HSC activation in primary culture. Transfection of a miR-29b precursor markedly attenuated the expression of Col1a1 and Col1a2 mRNAs and additionally blunted the increased expression of alpha-SMA, DDR2, FN1, ITGB1, and FDGFR-beta, which are key genes involved in the activation of HSCs. Further, overexpression of miR-29b led HSCs to remain in a quiescent state, as evidenced by their quiescent star-like cell morphology. Although phosphorylation of FAK, ERK, and Akt, and the mRNA expression of c-jun was unaffected, miR-29b overexpression suppressed the expression of c-fos mRNA. These results suggested that miR-29b is involved in the activation of HSCs and could be a candidate molecule for suppressing their activation and consequent liver fibrosis. (C) 2011 Elsevier Inc. All rights reserved.
  • Masaru Enomoto; Mami Mori; Tomohiro Ogawa; Hideki Fujii; Sawako Kobayashi; Shuji Iwai; Hiroyasu Morikawa; Akihiro Tamori; Hiroki Sakaguchi; Ayumi Sawada; Setsuko Takeda; Daiki Habu; Susumu Shiomi; Norifumi Kawada
    HEPATOLOGY RESEARCH 40 9 853 - 861 2010年09月 [査読有り]
     
    Aim: The usefulness of transient elastography remains to be validated in chronic hepatitis B, particularly as a tool for monitoring the degree of liver fibrosis during treatment. Methods: The subjects were 50 patients with chronic hepatitis B virus infection. Liver biopsy was performed in 38 patients, and in 12 patients with platelet counts of 50 x 109/L or less, cirrhosis was clinically diagnosed on the basis of specific signs of portal hypertension. Liver stiffness was measured by transient elastography at baseline and after 12 months of treatment in 20 nucleos(t)ide-naive patients who started entecavir within 3 months after study entry. Results: Twenty (40%) patients were classified as F1, 10 (20%) as F2, 5 (10%) as F3, and 15 (30%) as F4 (cirrhosis). Median liver stiffness (interquartile range) was 7.0 kPa (5.6-9.4), 9.8 kPa (5.6-14.7), 9.8 kPa (7.6-12.9), and 17.3 kPa (8.2-27.6) in fibrosis stages F1 to F4, respectively. Liver stiffness significantly correlated with fibrosis stage (r = 0.46; P = 0.0014). Of the patients who started entecavir, median liver stiffness significantly decreased from 11.2 kPa (7.0-15.2) to 7.8 kPa (5.1-11.9; P = 0.0090) during 12 months of treatment. Median levels of amino-terminal peptide of type III procollagen and type IV collagen 7S domain in serum significantly decreased from 0.9 (0.6-1.3) to 0.6 (0.5-0.7) U/mL (P = 0.0010) and from 5.0 (4.4-6.7) to 3.9 (3.2-4.4) ng/mL (P = 0.015), respectively. Conclusion: Liver stiffness measurement can be useful for monitoring regression of liver fibrosis during entecavir treatment in patients with chronic hepatitis B virus infection.
  • Tomohiro Ogawa; Hideki Fujii; Katsutoshi Yoshizato; Norifumi Kawada
    AMERICAN JOURNAL OF PATHOLOGY 177 1 153 - 165 2010年07月 [査読有り]
     
    Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis, which can lead to life-threatening liver failure and the development of hepatocellular carcinoma. The aim of the present study was to create a rabbit model of NASH with advanced fibrosis (almost cirrhosis) by feeding the animals a diet supplemented with 0.75% cholesterol and 12% corn oil. After 9 months of feeding with this diet, the rabbits showed high total cholesterol levels in serum and liver tissues in the absence of insulin resistance. The livers became whitish and nodular. In addition, the number of rabbit macrophage antigen-positive cells and the expression of mRNAs for inflammatory cytokines showed a significant increase. Moreover, fibrotic septa composed of collagens and a-smooth muscle actin-positive cells were found between the central and portal veins, indicating alteration of the parenchymal architecture. There was also a marked increase of mRNAs for transforming growth factor-beta 1 and collagen 1A1. Comprehensive analysis of protein and gene expression revealed an imbalance of the antioxidant system and methionine metabolism. We also found that ezetimibe attenuated steatohepatitis in this model. In conclusion, the present rabbit model of NASH features advanced fibrosis that is dose to cirrhosis and may be useful for analyzing the molecular mechanisms of human NASH. Ezetimibe blunted the development of NASH in this model, suggesting its potential clinical usefulness for human steatohepatitis. (Am J Pathol 2010, 177:153-165; DOI: 10.2353/ajpath.2010.090895)
  • Yong-ping Mu; Tomohiro Ogawa; Norifumi Kawada
    LABORATORY INVESTIGATION 90 2 245 - 256 2010年02月 [査読有り]
     
    Fatty liver disease has become a health problem related to metabolic syndrome worldwide, although its molecular pathogenesis requires further study. It is also unclear whether advanced fibrosis of steatohepatitis will regress when diet is controlled. The aim of this study was to investigate whether the resolution of fibrosis occurs in steatohepatitis induced by a methionine-choline-deficient diet (MCDD). Manifestation of endoplasmic reticulum (ER) stress in this model was also studied. Nonalcoholic steatohepatitis with advanced fibrosis was induced in rats by feeding them an MCDD for 10 weeks. Instead of MCDD, a methionine-choline control diet (CD) was given for the last 2 weeks to the experimental group. Fibrosis and inflammation were determined by tissue staining. Protein and gene expressions were determined by immunoblotting and quantitative reverse transcription-PCR (RT-PCR), respectively. Expressions of caspase-7, caspase-12, glucose-regulated protein 78 (GRP78), and protein disulfide isomerase were evaluated to clarify the presence of ER stress. Changing the diet from MCDD to CD triggered the reduction of fat in hepatocytes, a decrease in inflammatory gene expression and oxidative stress, and regression of fibrosis accompanied by the disappearance of activated stellate cells and macrophages. Immunohistochemistry, immunoblotting, and RT-PCR analysis all indicated the occurrence of ER stress in steatohepatitis, while it recovered immediately after changing the diet from MCCD to CD. The ratio of hepatocyte proliferation/apoptotis increased significantly during the recovery stage. This simple experiment clearly shows that changing the diet from MCDD to a normal diet (CD) triggers the resolution of hepatic inflammatory and fibrotic reactions and hepatocyte apoptosis, suggesting that MCDD-induced steatohepatitis is also reversible. ER stress appears and disappears in association with the generation and regression of steatohepatitis, respectively, with fibrosis. Laboratory Investigation (2010) 90, 245-256; doi:10.1038/labinvest.2009.123; published online 30 November 2009
  • Tomohiro Ogawa; Masashi Iizuka; Yumiko Sekiya; Katsutoshi Yoshizato; Kazuo Ikeda; Norifumi Kawada
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 391 1 316 - 321 2010年01月 [査読有り]
     
    MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression through imperfect base pairing with the 3' untranslated region (3'UTR) of target mRNA. We Studied the regulation of alpha 1 (1) collagen (Col1A1) expression by miRNAs in human stellate cells. which are involved in liver fibrogenesis. Among miR-29b, -143, and -218, whose expressions were altered in response to transforming growth factor-beta 1 or interferon-alpha stimulation, miR-29b was the most effective Suppressor of type I collagen at the mRNA and protein level via its direct binding to Col1A1 3'UTR miR-29b also had an effect on SP1 expression These results suggested that miR-29b is involved in the regulation of type I collagen expression by interferon-alpha in hepatic stellate cells. It is anticipated that miR-29b will be used for the regulation of stellate cell activation and lead to antifibrotic therapy (C) 2009 Elsevier Inc All rights reserved.
  • Hirofumi Fujita; Daisuke Shiva; Toshihiko Utsumi; Tetsuya Ogino; Tomohiro Ogawa; Koichi Abe; Tatsuji Yasuda; Kozo Utsumi; Junzo Sasaki
    MOLECULAR AND CELLULAR BIOCHEMISTRY 333 1-2 137 - 149 2010年01月 [査読有り]
     
    Phosphatidylserine (PS) externalization is a key feature of apoptotic cell death and plays an important role in clearance of apoptotic cells by phagocytes. PS externalization during apoptosis is generally an irreversible event mediated by caspase activation and is accompanied by other apoptotic events. We report here that an apoptosis inducer alpha-tocopheryl succinate (TOS) can induce PS externalization that is independent of apoptosis and reversible in the absence of fetal bovine serum (FBS) in histiocytic lymphoma U937 cells. In the presence of FBS, TOS induced PS externalization via a caspase-dependent mechanism accompanied by mitochondrial depolarization, cell shrinkage, increase of caspase-3 activity, and chromatin condensation. In contrast, in the absence of FBS, TOS induced the rapid PS externalization which was not accompanied by other apoptotic events. The PS externalization was reversible by removing TOS and was not involved in Ca(2+)-dependent scramblase activation and thiol oxidation of aminophospholipid translocase. A similar PS externalization was also induced by cholesteryl hemisuccinate (CS), the other succinate ester. These results suggested that the mechanism of TOS- and CS-induced PS externalization in the absence of FBS was different from it occurring during typical apoptosis.
  • Tomohiro Ogawa; Norifumi Kawada; Kazuo Ikeda
    HEPATOLOGY INTERNATIONAL 3 3 497 - 503 2009年09月 [査読有り]
     
    Inhibition of the proliferation of hepatic stellate cells (HSC) is clinically important for the control of liver fibrosis and cirrhosis. Interferons are now frequently used for chronic viral hepatitis because of their anti-viral activity. However, patients treated with interferons exhibit a regression of liver fibrosis even if viral eradication is not achieved, indicating that interferon itself has anti-fibrotic activity. Herein, we show the anti-proliferation and pro-apoptotic activity of natural interferon alpha against HSC. We found that interferon alpha inhibited serum-stimulated [ (3)H]thymidine incorporation of HSC in a dose-dependent manner, with a significant reduction at more than 100 U/ml. Interferon alpha also attenuated PDGF-BB-stimulated DNA synthesis of HSC. Although the molecular mechanism behind these phenomena has not been defined, we found that interferon alpha triggers the apoptosis of HSC treated with low-dose tumor necrosis factor alpha, as determined by the Alamar blue assay, morphology, and DNA ladder formation. Furthermore, interferon alpha decreased inhibitor of caspase-activated DNase (ICAD) levels, which may augment tumor necrosis factor alpha-induced cell death signals. Thus, interferon alpha regulates the number of myofibroblastic hepatic stellate cells and may clinically contribute to the regression of human liver fibrosis.
  • Kohji Otogawa; Tomohiro Ogawa; Ryoko Shiga; Kazuo Ikeda; Norifumi Kawada
    HEPATOLOGY INTERNATIONAL 3 2 378 - 383 2009年06月 [査読有り]
     
    The activation of hepatic stellate cells (HSCs) is a cue to initiate liver fibrosis. Activated stellate cells acquire contractile activity similar to pericytes and myofibroblasts in other organs by inducing the contractile machinery of cytoskeletons such as smooth muscle alpha-actin (alpha-SMA), a well-known marker of activated stellate cells, and actin-binding proteins. We further show herein the expression of tropomyosin in rat HSCs in the course of their activation during primary culture and liver tissue damaged by thioacetamide intoxication. In immunoblot analysis, tropomyosin became detectable in an early stage of the primary culture of rat stellate cells in a manner similar to the expression of alpha-SMA and platelet-derived growth factor receptor-beta. Tropomyosin was found to be colocalized with alpha-SMA on fluorescent immunocytochemistry. At the liver tissue level, an increased expression of tropomyosin was observed by immunoblot analysis and immunohistochemistry along the septum of fibrosis, where alpha-SMA was enriched. These results strongly suggest that tropomyosin is a new marker of activated stellate cells and may serve as a useful diagnostic marker of liver fibrosis.
  • Tae Jun Park; Bo Ra Jeong; Chise Tateno; Hong Seok Kim; Tomohiro Ogawa; In Kyoung Lim; Katsutoshi Yoshizato
    MOLECULAR CARCINOGENESIS 47 10 784 - 796 2008年10月 [査読有り]
     
    Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. in this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor beta 1 (TGF beta 1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGF beta 1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGF beta 1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGF beta 1-reluctant cells. The TGF beta 1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGF beta 1 activity during liver fibrosis. (C) 2008 Wiley-Liss, Inc.
  • 線維化のMechanism-肝線維化と細胞間ネットワーク
    小川 智弘; 河田則文
    肝胆膵 57 2 205 - 209 2008年08月
  • Kohji Otogawa; Tomohiro Ogawa; Ryoko Shiga; Kazuki Nakatani; Kazuo Ikeda; Yuji Nakajima; Norifumi Kawada
    AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 294 2 R311 - R320 2008年02月 [査読有り]
     
    Oxidative stress due to iron deposition in hepatocytes or Kupffer cells contributes to the initiation and perpetuation of liver injury. The aim of this study was to clarify the association between dietary iron and liver injuries in rats. Liver injury was initiated by the administration of thioacetamide or ligation of the common bile duct in rats fed a control diet (CD) or iron-deficient diet (ID). In the acute liver injury model induced by thioacetamide, serum levels of aspartate aminotransferase and alanine aminotransferase, as well as hepatic levels of lipid peroxide and 4-hydroxynonenal, were significantly decreased in the ID group. The expression of 8-hydroxydeoxyguanosine and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling positivity showed a similar tendency. The expression of interleukin-1 beta and monocyte chemotactic protein-1 mRNA was suppressed in the ID group. In liver fibrosis induced by an 8-wk thioacetamide administration, ID suppressed collagen deposition and smooth muscle beta-actin expression. The expressions of collagen 1A2, transforming growth factor beta, and platelet-derived growth factor receptor beta mRNA were all significantly decreased in the ID group. Liver fibrosis was additionally suppressed in the bile-duct ligation model by ID. In culture experiments, deferoxamine attenuated the activation process of rat hepatic stellate cells, a dominant producer of collagen in the liver. In conclusion, reduced dietary iron is considered to be beneficial in improving acute and chronic liver injuries by reducing oxidative stress. The results obtained in this study support the clinical usefulness of an iron-reduced diet for the improvement of liver disorders induced by chronic hepatitis C and alcoholic/nonalcoholic steatohepatitis.
  • Tomohiro Ogawa; Chise Tateno; Kinji Asahina; Hideki Fujii; Norifumi Kawada; Masanobu Obara; Katsutoshi Yoshizato
    Histochemistry and Cell Biology 127 2 161 - 174 2007年01月 [査読有り]
  • Yuko Tateaki; Tomohiro Ogawa; Norifumi Kawada; Toshihiko Kohashi; Koji Arihiro; Chise Tateno; Masanobu Obara; Katsutoshi Yoshizato
    Histochemistry and Cell Biology 122 1 41 - 49 2004年06月 [査読有り]
     
    Fibulin-2 and cytoglobin/stellate cell activation-associated protein (Cygb/STAP) are considered to be markers of hepatic myofibroblasts (MFs) and stellate cells (HSCs), respectively. The aim of the present study was to characterize the nonparenchymal cells (NPCs) of normal rat livers and carbon tetrachloride-induced fibrotic rat livers with respect to the expression of these two proteins. NPCs in normal (Glisson's capsules) and fibrotic (fibrotic septa) connective tissues were immunohistochemically categorized into four cell types in terms of the expression of fibulin-2 and Cygb/STAP: fibulin-2 and Cygb/STAP double-positive (Fib+/STAP+) fibulin-2-positive and Cygb/STAP-negative (Fib+/STAP-) Fib -/STAP+ and Fib-/STAP-. The Glisson's capsules had Fib+/STAP+ and Fib -/STAP- cell occupancy rates of 45.5% and 54.5%, respectively, but did not contain Fib+/STAP- or Fib -/STAP+ cells. On the other hand, the fibrotic septa contained Fib+/STAP+, Fib-/STAP+, and Fib-/STAP- cells at occupancy rates of 35.0%, 50.5%, and 9.1%, respectively, but did not contain Fib+/STAP- cells. Thus, fibrosis is characterized by a dramatic increase in Fib -/STAP+ NPCs, and a dramatic decrease in Fib -/STAP- NPCs. Fib+/STAP+ NPCs are located uniformly in Glisson's capsules and peripherally in fibrotic septa. The present study strongly suggests that Fib+/STAP+ and Fib-/STAP+ NPCs correspond to MFs and activated HSCs, respectively, both of which may contribute to liver fibrogenesis. © Springer-Verlag 2004.

MISC

講演・口頭発表等

  • 少人数教員養成課程における理科指導法の取り組みとその成果  [通常講演]
    小川 智弘
    日本生物教育学会第108回全国大会 2024年01月 口頭発表(一般)
  • スポーツ能力の優れた生徒に対する生物教材の作成と授業実践による評価
    小川智弘; 大畠虎太郎; 杉山祐介
    日本生物教育学会第107回全国大会 2023年03月 口頭発表(一般)
  • Cytokine expression and genomic damage analyses after in vitro X-irradiation of primary hepatic stellate cells isolated from 1-week-old mice  [通常講演]
    Masataka Taga; Kengo Yoshida; Seishi Kyoizumi; Naohiro Kato; Megumi Sasatani; Keiji Suzuki; Tomohiro Ogawa; Yoichiro Kusunoki
    日本放射線影響学会第64回大会 2021年09月 ポスター発表
  • Gene expression analysis of inflammatory cytokines in hepatic stellate cells isolated from X-irradiated mice
    Masataka Taga; Kengo Yoshida; Seishi Kyoizumi; Naohiro Kato; John Cologne; Yoichiro Kusunoki; Megumi Sasatani; Keiji Suzuki; Tomohiro Ogawa
    日本放射線影響学会第63回大会 2020年10月 ポスター発表
  • 医学部初年度学生に対する新たな化学授業の成果―医療に関連づけた実習の導入  [通常講演]
    岡田清孝; 白石浩平; 小川智弘; 武知薫子; 松村治雄; 梶博史
    第100回日本化学会春季年会 2020年03月 口頭発表(一般)
  • 肝星細胞の活性化及びコラーゲン産生に対するブラジル産プロポリスの効果の検討  [通常講演]
    小川 智弘
    日本農芸化学会2020年度大会 2020年03月 口頭発表(一般)
  • プロポリス成分による非アルコール性脂肪性肝疾患(NAFLD)に対する予防効果の検討  [通常講演]
    小川 智弘; 貞清 悠太; 山口 雅貴; 谷 海人; 寺田 拓実
    日本農芸化学会2019年度大会 2019年03月 口頭発表(一般)
  • Study on preventive effect against non-alcoholic fatty liver disease (NAFLD) by propolis
    小川智弘
    Asian Pacific Association for the Study of the Liver 2019 2019年02月 ポスター発表
  • Identification of integrin alpha8 as a specific surface marker for liver mesenchymal cells that negatively regulate maturation of liver progenitor cells in development  [通常講演]
    小川智弘; Ingrid Lua; Kinji Asahina
    20th Annual Pathology Conference 2017年03月 ポスター発表
  • 生物教材とICT教材を併用した理科授業実践の取り組み  [通常講演]
    青木洋賢; 鈴木厚; 白石浩平; 加島智子; 入潮賢和; 小川智弘
    日本理科教育学会第64回全国大会 2016年08月 口頭発表(一般)
  • Propolis components suppresses activated hepatic stellate cell invasion by inhibition of MMP-2 and MMP-9 expression and its activation.  [通常講演]
    小川智弘; 山田康枝; 河田則文
    18th International Symposium on Cells of the Hepatic Sinusoid(ISCHS) 2015年11月 ポスター発表
  • Propolis components suppresses collagen production and cell proliferation in activated hepatic stellate cells  [通常講演]
    小川智弘; 平尾凌; 寺田拓実; 山田康枝; 兵庫秀幸; 河田則文
    Asian Pacific Association for the Study of the Liver 2015 2015年03月 ポスター発表
  • 肝星細胞のコラーゲン産生および細胞増殖に対するブラジル産プロポリス成分の効果の検討  [通常講演]
    小川智弘; 平尾凌; 寺田拓実
    第28回肝類洞壁細胞研究会学術集会 2014年12月 口頭発表(一般)
  • 使い易さを考慮したデジタル教科書の作製と理科教育への活用  [通常講演]
    小川智弘; 川根章範; 加島智子
    日本理科教育学会第64回全国大会 2014年08月 口頭発表(一般)
  • ヒト神経芽細胞腫株SK-N-SHの6-OHDAおよび過酸化水素による細胞死に保護効果を示す物質の検討  [通常講演]
    中路昌司; 小川智弘; 藤原弘宜; 山田康枝
    日本農芸化学会2014年度大会 2014年03月 口頭発表(一般)
  • The beneficial effect of propolis on fat accumulation and lipid metabolism in NASH model  [通常講演]
    小川智弘; 山田康枝; 兵庫秀幸; 河田則文
    Asian Pacific Association for the Study of the Liver 2014 2014年03月 ポスター発表
  • プロポリスの脂肪肝や非アルコール性脂肪性肝炎(NASH)対する予防および治療効果の検討  [通常講演]
    小川智弘; 山田康枝; 兵庫秀幸; 河田則文
    第40回日本肝臓学会西部会 2013年12月 ポスター発表
  • The beneficial effect of propolis on fat accumulation and liver fibrosis in mice fed a methionine-choline diet  [通常講演]
    小川智弘; 山田康枝; 兵庫秀幸; 河田則文
    17th International Symposium on Cells of the Hepatic Sinusoid 2013年09月 ポスター発表
  • Role of macrophage scavenger receptor A in hepatic fibrogenesis of an animal NASH model  [通常講演]
    藤井英樹; 小川智弘; 元山宏行; 吉里勝利; 河田則文
    17th International Symposium on Cells of the Hepatic Sinusoid 2013年09月 ポスター発表
  • ヒト神経芽細胞腫株SK-N-SHに対する酸化ストレス保護効果  [通常講演]
    中路昌志; 小川智弘; 藤原弘宜; 山田康枝
    日本農芸化学会中四国支部第36回講演会 2013年08月 口頭発表(一般)
  • 教職課程科目におけるiPad導入による理科授業の実践とその評価  [通常講演]
    小川 智弘
    日本工学教育協会第61回年次大会 2013年08月 口頭発表(一般)
  • Induction of MicroRNA-221/222 in the Progression of Liver Fibrosis Caused by Chronic Hepatitis C Virus Infection  [通常講演]
    榎本大; 小川 智弘; 河田則文
    10th JSH Single Topic Conference, “Hepatitis C: Best Practice Based on Science” 2012年11月 東京 10th JSH Single Topic Conference, “Hepatitis C: Best Practice Based on Science”
  • Micro RNA profiling in activated stellate cells  [通常講演]
    池田一雄; 小川 智弘; 河田則文
    2012 ISBRA World Congress 2012年09月 北海道 2012 ISBRA World Congress
  • iPad2を使用した地学の模擬授業の取り組み  [通常講演]
    小川 智弘
    日本理科教育学会 第62回全国大会 2012年08月 鹿児島 日本理科教育学会 第62回全国大会
  • 慢性肝疾患における肝線維化診断マーカーとしてのマイクロRNAの有用性  [通常講演]
    河田則文; 小川 智弘
    第48回 日本肝臓学会総会 2012年06月 石川 第48回 日本肝臓学会総会
  • Role of CYGB in human HCC and in animal model of carcinogenesis  [通常講演]
    Thuy Thi Thanh Le; 小川 智弘; 河田則文
    第48回 日本肝臓学会総会 2012年06月 石川 第48回 日本肝臓学会総会
  • マイクロRNAの肝線維化診断マーカーとしての有用性とその機能  [通常講演]
    小川 智弘; 河田則文
    Kansai Liver Club 2012 2012年01月 大阪 Kansai Liver Club 2012
  • 慢性肝疾患における肝線維化バイオマーカーとしてのマイクロRNAの有用性  [通常講演]
    榎本大; 小川 智弘; 河田則文
    第39回 日本肝臓学会西部会 2011年12月 岡山 第39回 日本肝臓学会西部会
  • 慢性肝疾患における肝線維化診断マーカーとしてのマイクロRNAの有用性  [通常講演]
    飯塚昌司; 小川 智弘; 河田則文
    第25回 肝類洞壁細胞研究会学術集会 2011年12月 東京 第25回 肝類洞壁細胞研究会学術集会
  • Tumor formation and the role of Cygb in DEN-mediated carcinogenesis  [通常講演]
    Le Thi Thanh Thuy; 小川 智弘; 河田則文
    第25回 肝類洞壁細胞研究会学術集会 2011年12月 東京 第25回 肝類洞壁細胞研究会学術集会
  • Changes in sequences of core region, ISDR and IRRDR of the HCV genotype 1 during and after interferon alpha and ribavirin therapy, and efficacy of retreatment.  [通常講演]
    小塚立蔵; 小川 智弘; 河田則文
    62nd AASLD 2011年11月 アメリカ 62nd AASLD
  • Indication of the Activation of Stellate Cells and the Progression of Liver Fibrosis by MicroRNA-222  [通常講演]
    榎本大; 小川 智弘; 河田則文
    62nd AASLD 2011年11月 アメリカ 62nd AASLD
  • 肝線維化と星細胞活性化に関与するマイクロRNAの解析  [通常講演]
    飯塚昌司; 小川 智弘; 河田則文
    第15回 日本肝臓学会大会 2011年10月 福岡 第15回 日本肝臓学会大会
  • 慢性肝疾患における肝線維化診断マーカーとしてのmiR-222の有用性  [通常講演]
    飯塚昌司; 小川 智弘; 河田則文
    第15回 日本肝臓学会大会 2011年10月 福岡 第15回 日本肝臓学会大会
  • B型慢性肝疾患におけるエンテカビル投与中の耐性変異の出現とその検出法の検討  [通常講演]
    小塚立蔵; 小川 智弘; 河田則文
    第47回 日本肝臓学会総会 2011年06月 東京 第47回 日本肝臓学会総会
  • 肝線維化と星細胞活性化に関与するマイクロRNAの解析  [通常講演]
    飯塚昌司; 小川 智弘; 河田則文
    第18回肝細胞研究会 2011年06月 東京 第18回肝細胞研究会
  • miR-195の肝星細胞増殖における役割についての検討  [通常講演]
    関谷由美子; 小川 智弘; 河田則文
    第47回 日本肝臓学会総会 2011年06月 東京 第47回 日本肝臓学会総会
  • C型慢性肝炎患者における肝線維化診断マーカーとしてのマイクロRNAの有用性  [通常講演]
    小川 智弘; 河田則文
    第97回日本消化器病学会総会 2011年05月 東京 第97回日本消化器病学会総会

共同研究・競争的資金等の研究課題

  • 肝線維化部位に集積する筋線維芽細胞による線維形成の分子機構に関する基礎的研究
    科学研究費 若手研究(B)
    研究期間 : 2014年04月 -2016年03月 
    代表者 : 小川 智弘
  • 癌発生におけるサイトグロビン発現間葉系細胞の関与
    科学研究費 挑戦的萌芽研究
    研究期間 : 2010年04月 -2012年03月 
    代表者 : 河田 則文
  • 星細胞を標的としたマイクロRNAの強制発現による線維化治療法の開発
    科学研究費 若手研究(B)
    研究期間 : 2010年04月 -2012年03月 
    代表者 : 小川 智弘
  • サイトグロビンノックアウトマウスを用いた肝硬変・肝癌病態解析
    科学研究費 基礎研究(B)
    研究期間 : 2009年04月 -2012年03月 
    代表者 : 河田 則文
  • Study on liver fibrosis mechanism
    Basic Science Research Program
    研究期間 : 2006年

産業財産権

  • 特開2012-125215:肝線維症の存在及び/又は肝線維症の重症度の判定方法、判定マーカー、判定用キット、肝線維症の治療の効果予測方法、効果予測マーカー、並びに効果予測用キット  2012年07月
    河田則文, 小川 智弘, 榎本大  
    【課題】肝線維症の存在の判定、肝線維症の重症度の判定、及び肝線維症の治療効果の予測を正確、簡便且つ迅速に行う方法が求められていた。 【解決手段】本発明は、被験者から得られた試料に含まれるマイクロRNAを測定する工程を含む肝線維症の存在及び/又は肝線維症の重症度の判定方法、肝線維症の存在及び/又は肝線維症の重症度の判定マーカー、肝線維症の存在及び/又は肝線維症重症度の判定用キット、肝線維症の治療の効果予測方法、肝線維症の治療の効果予測マーカー、並びに肝線維症の治療の効果予測用キットである。
  • 2010-080293:脂肪組織画像表示装置  2010年03月
    堀中博道, 小川 智弘, 森川浩安

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