和氣 秀徳（ワケ ヒデノリ）
| 医学科 | 准教授 |
Last Updated :2025/06/12
■教員コメント
コメント
ニーズはあるが治療薬がないもしくは少ない疾患、特に難治性炎症疾患に対する新規治療薬開発に関する研究を行っています。
■研究者基本情報
J-Global ID
研究キーワード
- 血液・免疫検査学 感染・免疫薬理学 腫瘍・循環器薬理学 臨床検査学 血液・血栓・血管学 Pharmacology Clinical Laboratory Science Hemostasis/Thrombosis/Vascular Sciences
現在の研究分野（キーワード）
ニーズはあるが治療薬がないもしくは少ない疾患、特に難治性炎症疾患に対する新規治療薬開発に関する研究を行っています。
■経歴
経歴
学歴
■研究活動情報
受賞
- 2019年 日本集中治療医学会 第46回日本集中治療医学会優秀論文賞
受賞者: Kuroda K, Wake H, Mori S, Hinotsu S, Nishibori M, Morimatsu H. - 2018年 岡山医学会 岡山医学会賞
受賞者: 和氣 秀徳 - 2018年 東京バイオマーカー・イノベーション技術研究組合 TOBIRA賞
受賞者: 和氣 秀徳 - 2016年 Society of Critical Care Medicine 45th Critical Care Congress Research Snapshot Award
受賞者: Kuroda K, Wake H, Mori S, Hinotsu S, Nishibori M, Morimatsu H. - 2012年 公益財団法人ホクト生物科学振興財団 研究奨励賞
JPN受賞者: 和氣 秀徳
論文
- Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Hideo Takahashi; Masahiro Nishibori; Shuji MoriBiotechnology and applied biochemistry e2760 2025年04月 [査読有り]
Methylglyoxal (MGO), a byproduct produced in the process of glycolysis, has cytotoxicity and forms advanced glycation endproducts (AGEs), which cause cell failure in several tissues. Because MGO is mainly removed by the action of glyoxalase I (GLO1), the activity of this enzyme contributes to the accumulation of MGO. We recently found that quinetazone, a diuretic pharmaceutical agent, has the potential to inhibit GLO1 activity. Therefore, we explored whether diuretics that have a similar structure to quinetazone inhibit GLO1. The inhibitory characteristics of diuretics with recombinant GLO1 were spectrophotometrically determined. Cell proliferation and accumulation of MGO-derived AGEs were evaluated by MTT assay and Western blotting. Among the thiazide, thiazide-like, and loop diuretics, metolazone and azosemide were found to inhibit GLO1 activity by 97% at 100 µM. Furthermore, we examined whether the substructures of these diuretics have inhibitory activity, quinazolinone or phenyltetrazole were determined to be the minimal structures of metolazone or azosemide required for inhibition of GLO1, respectively. In proximal renal tubule-like HK-2 and vascular endothelial cell-like EA.hy926 cells, these diuretics were shown to inhibit cell proliferation and induce accumulation of MGO-derived AGEs. In contrast, the substructures of these diuretics that did not affect GLO1 activity did not cause these changes. Metolazone and azosemide have inhibitory effects against GLO1. Considering that these diuretics are clinically employed as pharmaceutical agents, high or prolonged dosages may contribute to pathogenesis through GLO1 inhibition, followed by MGO and/or AGE accumulation. - Yohei Takahashi; Soe Soe Htwe; Dengli Wang; Hidenori Wake; Mariko Yata; Nahoko Tomonobu; Rie Kinoshita; Masakiyo Sakaguchi; Masahiro NishiboriBlood Vessels, Thrombosis & Hemostasis 2025年02月 [査読有り]
- Omer Faruk Hatipoglu; Takashi Nishinaka; Kursat Oguz Yaykasli; Shuji Mori; Masahiro Watanabe; Takao Toyomura; Masahiro Nishibori; Satoshi Hirohata; Hidenori Wake; Hideo TakahashiFrontiers in pharmacology 16 1561628 - 1561628 2025年 [査読有り]
INTRODUCTION: Tumor necrosis factor-α (TNF-α)-induced angiogenesis plays a critical role in tumor progression and metastasis, making it an important therapeutic target in cancer treatment. Suppressing angiogenesis can effectively limit tumor growth and metastasis. However, despite advancements in understanding angiogenic pathways, effective strategies to inhibit TNF-α-mediated angiogenesis remain limited. METHODS: This study investigates the antiangiogenic effects of histidine-rich glycoprotein (HRG), a multifunctional plasma protein with potent antiangiogenic properties, on TNF-α-stimulated human endothelial cells (EA.hy926). Tube formation assays were performed to assess angiogenesis, and gene/protein expression analyses were conducted to evaluate HRG's effects on integrins αV and β8. The role of nuclear factor erythroid 2-related factor 2 (NRF2) in HRG-mediated antiangiogenic activity was also examined through nuclear translocation assays and NRF2 activation studies. RESULTS: At physiological concentrations, HRG effectively suppressed TNF-α-induced tube formation in vitro and downregulated TNF-α-induced expression of integrins αV and β8 at both the mRNA and protein levels. HRG treatment promoted NRF2 nuclear translocation in a time-dependent manner. Furthermore, activation of NRF2 significantly reduced TNF-α-induced tube formation and integrin expression, suggesting that NRF2 plays a key role in HRG-mediated antiangiogenic effects. DISCUSSION AND CONCLUSION: Our findings indicate that HRG suppresses TNF-α-induced angiogenesis by promoting NRF2 nuclear translocation and transcriptional activation, which in turn inhibits integrin αV and β8 expression. Given the essential role of angiogenesis in tumor progression, HRG's ability to regulate this process presents a promising therapeutic strategy for cancer treatment. - Masahiro Nishibori; Hidenori Wake; Masakiyo SakaguchiFolia Pharmacologica Japonica 159 2 107 - 111 2024年03月 [査読有り]
- Simeng Ma; Yoki Nakamura; Takahiro Kochi; Suzuna Uemoto; Kazue Hisaoka-Nakashima; Dengli Wang; Keyue Liu; Hidenori Wake; Masahiro Nishibori; Norimitsu MoriokaBiological and Pharmaceutical Bulletin 47 1 221 - 226 2024年01月 [査読有り]
- Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Hideo Takahashi; Masahiro Nishibori; Shuji MoriBiotechnology and Applied Biochemistry 71 2 264 - 271 2023年11月 [査読有り]
Abstract We previously found that ribosomal protein L9 (RPL9) is a novel advanced glycation end product (AGE)‐binding protein that can decrease pro‐inflammatory TNF‐α expression stimulated by lipopolysaccharide (LPS) plus high‐mobility group box 1 (HMGB1), suggesting that RPL9 has a role in regulating LPS+HMGB1‐stimulated inflammatory reactions. Among the various ribosomal proteins, it was found that RPS5 reproduced the regulatory activity of RPL9 on LPS+HMGB1‐stimulated TNF‐α expression in macrophage‐like RAW264.7 cells. RPL9 and RPS5 share a common feature as cationic proteins. Polylysine, a cationic polypeptide, and a synthetic peptide of the cationic region from RPL9 also exhibited reducing activity on LPS+HMGB1‐induced TNF‐α expression. By pull‐down assay, RPL9 and RPS5 were confirmed to interact with AGEs. When AGEs coexisted with LPS, HMGB1, plus RPL9 or RPS5, the reducing effect of TNF‐α expression by these cationic ribosomal proteins was shown to be abrogated. The results suggest that cationic ribosomal proteins have a regulatory role in the pro‐inflammatory response induced by LPS+HMGB1, and in the pathophysiological condition of accumulating AGEs, this regulatory effect is abolished, which exacerbates inflammation. - Takashi Nishinaka; Omer Faruk Hatipoglu; Hidenori Wake; Masahiro Watanabe; Takao Toyomura; Shuji Mori; Masahiro Nishibori; Hideo TakahashiArchives of biochemistry and biophysics 750 109808 - 109808 2023年10月 [査読有り]
Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins. - Shiho Kitaoka; Ayaka Tomohiro; Shinya Ukeshima; Keyue Liu; Hidenori Wake; Shinya H. Kimura; Yasuhiko Yamamoto; Masahiro Nishibori; Tomoyuki FuruyashikiCells 12 13 1789 - 1789 2023年07月 [査読有り]
Inflammation has been associated with depression, and innate immune receptors, such as the Toll-like receptor (TLR) 2/4 in the medial prefrontal cortex (mPFC), are crucial for chronic stress-induced depression-related behaviors in mice. HMGB1, a putative ligand for TLR2/4, has been suggested to promote depression-related behaviors under acute stress. However, the roles of endogenous HMGB1 under chronic stress remain to be investigated. Here, we found that the cerebroventricular infusion of HMGB1 proteins blocked stress-induced social avoidance and that HMGB1-neutralizing antibodies augmented repeated social defeat stress-induced social avoidance in mice, suggesting the antidepressive-like effect of HMGB1 in the brain. By contrast, the infusion of HMGB1-neutralizing antibodies to the mPFC and HMGB1 knockout in α-CaMKII-positive forebrain neurons attenuated the social avoidance, suggesting the pro-depressive-like effect of HMGB1 released from prefrontal neurons under chronic stress. In addition, repeated social defeat stress induced HMGB1 nuclear export selectively in mPFC neurons, which was abolished in the mice lacking RAGE, one of HMGB1 receptors, suggesting the positive feedback loop of HMGB1-RAGE signaling under chronic stress. These findings pave the way for identifying multiple roles of HMGB1 in the brain for chronic stress and depression. - Handong Qiao; Yuta Morioka; Dengli Wang; Keyue Liu; Shangze Gao; Hidenori Wake; Daiki Ousaka; Kiyoshi Teshigawara; Shuji Mori; Masahiro NishiboriEuropean Journal of Pharmacology 950 175702 - 175702 2023年07月 [査読有り]
- Takao Toyomura; Masahiro Watanabe; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Hideo Takahashi; Masahiro Nishibori; Shuji MoriMolecular Biology Reports 50 7 5849 - 5858 2023年05月 [査読有り]
- Omer Faruk Hatipoglu; Takashi Nishinaka; Masahiro Nishibori; Masahiro Watanabe; Takao Toyomura; Shuji Mori; Kursat Oguz Yaykasli; Hidenori Wake; Hideo TakahashiJournal of pharmacological sciences 151 4 177 - 186 2023年04月 [査読有り]
Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R-PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways. - Naoya Kawanoue; Kosuke Kuroda; Hiroko Yasuda; Masahiko Oiwa; Satoshi Suzuki; Hidenori Wake; Hiroki Hosoi; Masahiro Nishibori; Hiroshi MorimatsuPLOS ONE 18 3 e0283426 - e0283426 2023年03月 [査読有り]
Background Few sepsis biomarkers accurately predict severity and mortality. Previously, we had reported that first-day histidine-rich glycoprotein (HRG) levels were significantly lower in patients with sepsis and were associated with mortality. Since the time trends of HRG are unknown, this study focused on the time course of HRG in patients with sepsis and evaluated the differences between survivors and non-survivors. Methods A multicenter prospective observational study was conducted involving 200 patients with sepsis in 16 Japanese hospitals. Blood samples were collected on days 1, 3, 5, and 7, and 28-day mortality was used for survival analysis. Plasma HRG levels were determined using a modified quantitative sandwich enzyme-linked immunosorbent assay. Results First-day HRG levels in non-survivors were significantly lower than those in survivors (mean, 15.7 [95% confidence interval (CI), 13.4–18.1] vs 20.7 [19.5–21.9] μg/mL; P = 0.006). Although there was no time × survivors/non-survivors interaction in the time courses of HRG (P = 0.34), the main effect of generalized linear mixed models was significant (P < 0.001). In a univariate Cox proportional hazards model with each variable as a time-dependent covariate, higher HRG levels were significantly associated with a lower risk of mortality (hazard ratio, 0.85 [95% CI, 0.78–0.92]; P < 0.001). Furthermore, presepsin levels (P = 0.02) and Sequential Organ Function Assessment scores (P < 0.001) were significantly associated with mortality. Harrell’s C-index values for the 28-day mortality effect of HRG, presepsin, procalcitonin, and C-reactive protein were 0.72, 0.70, 0.63, and 0.59, respectively. Conclusions HRG levels in non-survivors were consistently lower than those in survivors during the first seven days of sepsis. Repeatedly measured HRG levels were significantly associated with mortality. Furthermore, the predictive power of HRG for mortality may be superior to that of other singular biomarkers, including presepsin, procalcitonin, and C-reactive protein. - Takashi Nishinaka; Omer Faruk Hatipoglu; Hidenori Wake; Masahiro Watanabe; Takao Toyomura; Shuji Mori; Masahiro Nishibori; Hideo TakahashiLife sciences 310 121116 - 121116 2022年10月 [査読有り]
AIMS: We have previously reported that advanced glycation end products derived from incubation of albumin with glycolaldehyde (glycol-AGE), lead to suppression of the toll-like receptor 4 (TLR4) signaling response to lipopolysaccharide. Glycol-AGE-induced suppression of TLR4 signaling is involved in the downregulation of CD14, which is an adaptor protein necessary for transferring lipopolysaccharide to TLR4. Therefore, glycol-AGEs impair the innate immune response through suppression of the upstream process in TLR4 signaling. However, the effect of glycol-AGEs on intracellular signaling related to the innate immune response remains unclear. This study aimed to examined the effect of glycol-AGEs on stimulator of interferon gene (STING) signaling in macrophages. MAIN METHODS: In differentiated THP-1 cells, which are a human monocytic leukemia cell line, cyclic GMP-AMP (cGAMP) transfection was used to activate STING signaling. The phosphorylation levels of TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3) were evaluated by western blot analysis. Downstream cytokine levels were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays. KEY FINDINGS: Glycol-AGEs suppressed cGAMP-induced phosphorylation of TBK1 and IRF3, as well as the production of cytokines regulated by IRF3. There was no effect of glycol-AGEs on the efficacy of cGAMP transfection. Treatment of a neutralizing antibody against CD36 prevented cGAMP-induced phosphorylation of TBK1 and IRF3, and also upregulation of interferon-β and C-X-C motif chemokine ligand 10 in glycol-AGE-treated cells. SIGNIFICANCE: Glycol-AGEs negatively regulate cGAMP-induced activation of STING/TBK1/IRF3 signaling via CD36. Our findings suggest that glycol-AGEs lead to impairment of the innate immune response by suppressing intracellular signaling. - Shangze Gao; Keyue Liu; Wenhan Ku; Dengli Wang; Hidenori Wake; Handong Qiao; Kiyoshi Teshigawara; Masahiro NishiboriFRONTIERS IN IMMUNOLOGY 13 2022年10月 [査読有り]
- Masahiro Watanabe; Takao Toyomura; Ryo Ikegami; Yui Suwaki; Minami Sada; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Hideo Takahashi; Masahiro Nishibori; Shuji MoriMolecular biology reports 49 11 10499 - 10507 2022年09月 [査読有り]
BACKGROUND: Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor. METHODS: The inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells. RESULTS: NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its Ki value was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA. CONCLUSION: NDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition. - Nahoko Tomonobu; Rie Kinoshita; Hidenori Wake; Yusuke Inoue; I Made Winarsa Ruma; Ken Suzawa; Yuma Gohara; Ni Luh Gede Yoni Komalasari; Fan Jiang; Hitoshi Murata; Ken-Ichi Yamamoto; I Wayan Sumardika; Youyi Chen; Junichiro Futami; Akira Yamauchi; Futoshi Kuribayashi; Eisaku Kondo; Shinichi Toyooka; Masahiro Nishibori; Masakiyo SakaguchiInternational journal of molecular sciences 23 18 2022年09月 [査読有り]
The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis. - Kazue Hisaoka-Nakashima; Kazuto Ohata; Natsuki Yoshimoto; Shintarou Tokuda; Nanako Yoshii; Yoki Nakamura; Dengli Wang; Keyue Liu; Hidenori Wake; Takayuki Yoshida; Yukio Ago; Kouichi Hashimoto; Masahiro Nishibori; Norimitsu MoriokaExperimental Neurology 355 114146 - 114146 2022年09月 [査読有り]
- Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Hideo Takahashi; Masahiro Nishibori; Shuji MoriMolecular biology reports 49 4 2831 - 2838 2022年04月 [査読有り]
BACKGROUND: We previously reported that advanced glycation endproducts (AGEs) increase the proinflammatory activity of high mobility group box-1 (HMGB1), a representative damage-associated molecular pattern molecule (DAMP), through their direct interaction. This suggested that AGEs activate other DAMPs and led us to search for novel DAMPs capable of interacting with AGEs. METHODS AND RESULTS: The chromatographic analysis using AGE-immobilized gel revealed the ribosomal protein family to be a factor with binding activity to AGEs. Ribosomal protein L9 (RPL9), a member of the ribosomal protein family, was found in the centrifugal supernatant of ruptured cells and in the serum of lipopolysaccharide (LPS)-stimulated sepsis model mice, exhibiting similar characteristic properties to HMGB1. Although HMGB1 potentiated LPS-stimulated TNF-α expression in macrophage-like RAW264.7 cells, RPL9 hardly exhibited this activity. Of note, RPL9 significantly suppressed the potentiated mRNA expression and protein production of TNF-α by HMGB1 plus LPS stimulation, suggesting its regulatory roles in DAMP-induced proinflammatory activity. Based on the differential scanning fluorimetric analysis, the direct interaction between RPL9 and HMGB1 may play a role in the suppressive effects of RPL9. CONCLUSIONS: This study suggested that RPL9 is a novel type of DAMP with a regulatory role in the proinflammatory response and provided insight into the pathophysiology of inflammatory diseases. - Hidenori WakeFolia Pharmacologica Japonica 157 6 426 - 428 2022年 [査読有り]
- Fumiaki Sato; Yoki Nakamura; Simeng Ma; Takahiro Kochi; Kazue Hisaoka-Nakashima; Dengli Wang; Keyue Liu; Hidenori Wake; Masahiro Nishibori; Norimitsu MoriokaBiomedicine & Pharmacotherapy 145 112479 - 112479 2022年01月 [査読有り]
- Yui Yamazaki; Hidenori Wake; Takashi Nishinaka; Omer Faruk Hatipoglu; Keyue Liu; Masahiro Watanabe; Takao Toyomura; Shuji Mori; Tadashi Yoshino; Masahiro Nishibori; Hideo TakahashiExperimental cell research 408 1 112857 - 112857 2021年11月 [査読有り]
Toxic advanced glycation end products (toxic AGEs) derived from glycolaldehyde (AGE3) have been implicated in the development of diabetic vascular complications such as retinopathy characterised by excessive angiogenesis. Different receptor types, such as receptor for AGEs (RAGE), Toll like receptor-4 and scavenger receptors, are expressed in endothelial cells and contribute to AGE-elicited alteration of cell function. In the present study, we examined the involvement of AGE-related receptors on AGE-induced angiogenesis in endothelial cells. The effects of pharmacological inhibitors or receptor neutralizing antibodies on AGE3-induced tube formation were investigated using the in vitro Matrigel tube formation assay in b.End5 cells (mouse endothelial cells). AGE3-induced signalling pathways and receptor expression changes were analysed by Western blot analysis and flow cytometry, respectively. Both FPS-ZM1, a RAGE inhibitor, and fucoidan, a ligand for scavenger receptors, suppressed AGE3-induced tube formation. Cocktails of neutralizing antibodies against the scavenger receptors CD36, CD163 and LOX-1 prevented AGE3-induced tube formation. AGE3 activated mTOR signalling, resulting in facilitation of tube formation. Activation of the AGE-RAGE pathway also led to the upregulation of scavenger receptors. Taken together, our findings suggest that the scavenger receptors CD36, CD163 and LOX-1 in conjunction with the RAGE receptor work together to mediate toxic AGE-induced facilitation of angiogenesis. - Omer Faruk Hatipoglu; Eyyup Uctepe; Gabriel Opoku; Hidenori Wake; Kentaro Ikemura; Takashi Ohtsuki; Junko Inagaki; Mehmet Gunduz; Esra Gunduz; Shogo Watanabe; Takashi Nishinaka; Hideo Takahashi; Satoshi HirohataBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 139 111633 - 111633 2021年07月 [査読有り]
Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-β1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-β1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-β1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF. - Kosuke Kuroda; Kenzo Ishii; Yuko Mihara; Naoya Kawanoue; Hidenori Wake; Shuji Mori; Michihiro Yoshida; Masahiro Nishibori; Hiroshi MorimatsuScientific reports 11 1 10223 - 10223 2021年05月 [査読有り]
Various biomarkers have been proposed for sepsis; however, only a few become the standard. We previously reported that plasma histidine-rich glycoprotein (HRG) levels decreased in septic mice, and supplemental infusion of HRG improved survival in mice model of sepsis. Moreover, our previous clinical study demonstrated that HRG levels in septic patients were lower than those in noninfective systemic inflammatory response syndrome patients, and it could be a biomarker for sepsis. In this study, we focused on septic patients and assessed the differences in HRG levels between the non-survivors and survivors. We studied ICU patients newly diagnosed with sepsis. Blood samples were collected within 24 h of ICU admission, and HRG levels were determined using an enzyme-linked immunosorbent assay. Ninety-nine septic patients from 11 institutes in Japan were included. HRG levels were significantly lower in non-survivors (n = 16) than in survivors (n = 83) (median, 15.1 [interquartile ranges, 12.7-16.6] vs. 30.6 [22.1-39.6] µg/ml; p < 0.01). Survival analysis revealed that HRG levels were associated with mortality (hazard ratio 0.79, p < 0.01), and the Harrell C-index (predictive power) for HRG was 0.90. These results suggested that HRG could be a novel prognostic biomarker for sepsis. - Takahiro Kochi; Yoki Nakamura; Simeng Ma; Kazue Hisaoka-Nakashima; Dengli Wang; Keyue Liu; Hidenori Wake; Masahiro Nishibori; Masahiro Irifune; Norimitsu MoriokaMolecules 26 7 2035 - 2035 2021年04月 [査読有り]
Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries. - Yoki Nakamura; Ayako Fukuta; Keita Miyashita; Fang Fang Zhang; Dengli Wang; Keyue Liu; Hidenori Wake; Kazue Hisaoka-Nakashima; Masahiro Nishibori; Norimitsu MoriokaBiochemical Pharmacology 186 114496 - 114496 2021年04月 [査読有り]
- Yohei Takahashi; Hidenori Wake; Masakiyo Sakaguchi; Yukinori Yoshii; Kiyoshi Teshigawara; Dengli Wang; Masahiro NishiboriJournal of immunology (Baltimore, Md. : 1950) 206 4 737 - 750 2021年02月 [査読有り]
Histidine-rich glycoprotein (HRG) is a multifunctional plasma protein and maintains the homeostasis of blood cells and vascular endothelial cells. In the current study, we demonstrate that HRG and recombinant HRG concentration dependently induced the phagocytic activity of isolated human neutrophils against fluorescence-labeled Escherichia coli and Staphylococcus aureus through the stimulation of CLEC1A receptors, maintaining their spherical round shape. The phagocytosis-inducing effects of HRG were inhibited by a specific anti-HRG Ab and enhanced by opsonization of bacteria with diluted serum. HRG and C5a prolonged the survival time of isolated human neutrophils, in association with a reduction in the spontaneous production of extracellular ROS. In contrast, HRG maintained the responsiveness of neutrophils to TNF-α, zymosan, and E. coli with regard to reactive oxygen species production. The blocking Ab for CLEC1A and recombinant CLEC1A-Fc fusion protein significantly inhibited the HRG-induced neutrophil rounding, phagocytic activity, and prolongation of survival time, suggesting the involvement of the CLEC1A receptor in the action of HRG on human neutrophils. These results as a whole indicated that HRG facilitated the clearance of E. coli and S. aureus by maintaining the neutrophil morphology and phagocytosis, contributing to the antiseptic effects of HRG in vivo. - Atsuhiro Kitaura; Takashi Nishinaka; Shinichi Hamasaki; Omer Faruk Hatipoglu; Hidenori Wake; Masahiro Nishibori; Shuji Mori; Shinichi Nakao; Hideo TakahashiPLOS ONE 16 1 e0245957 - e0245957 2021年01月 [査読有り]
Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients. - Masahiro Nishibori; Dengli Wang; Daiki Ousaka; Hidenori WakeCells 9 12 2020年12月 [査読有り]
Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood-brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer's amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption. - Yukinori Yoshii; Hidenori Wake; Yoshito Nishimura; Kiyoshi Teshigawara; Dengli Wang; Masahiro NishiboriThe Journal of pharmacology and experimental therapeutics 375 3 406 - 413 2020年12月 [査読有り]
Histidine-rich glycoprotein (HRG) treatment ameliorated the survival rate of septic mice by suppressing excess immunothrombus formation. Although such findings suggested that HRG may be one of the most useful drugs for sepsis, obtaining a stable experimental system to standardize the HRG drug product is difficult to achieve using neutrophils isolated from volunteers. This is due to the short survival time and individual differences of human neutrophils. In the present study, we determined whether the differentiated neutrophil-like cell lines exhibited similar responses to HRG compared with human purified neutrophils. All-trans retinoic acid (ATRA) was employed to induce the differentiation of the human myeloid leukemia cell lines HL-60 and NB-4. Thereafter, the cells were treated with Hank's balanced salt solution, human serum albumin, or HRG. The effects of HRG on these cells were evaluated according to cell shape, microcapillary passage, reactive oxygen species (ROS) production, neutrophil extracellular traps (NETs) formation, the expression of activated CD11b, and cell viability. HRG maintained the round shape of differentiated neutrophil-like cells, decreased the time required by cells to pass through the microcapillaries, and inhibited ROS production, NETs formation, and the expression of activated CD11b on the cell surface. Moreover, the cells could survive longer in the presence of HRG than the control. The ATRA-induced differentiated cell lines could be used as alternatives to neutrophils to investigate the effects of HRG on neutrophils. This method can thus be used as an essential standardization test in pharmaceutical development. SIGNIFICANCE STATEMENT: Human neutrophils exhibit varying responses to histidine-rich glycoprotein (HRG); however, all-trans retinoic acid-induced differentiated neutrophil-like cell lines can be used as reliably proxies to investigate the effects of HRG on neutrophils. Additionally, these cell lines can be employed in the development of therapies for the treatment of sepsis. - Hidenori Wake; Yohei Takahashi; Yukinori Yoshii; Shangze Gao; Shuji Mori; Dengli Wang; Kiyoshi Teshigawara; Masahiro NishiboriFree radical research 54 8-9 1 - 13 2020年10月 [査読有り]
Sepsis is caused by infections associated with life-threatening multiple organ failure (MOF). Septic MOF appears to be closely related to circulatory failure due to immunothrombosis. This process involves the production of reactive oxygen spices (ROS) in inflammatory sites. Therefore, the detoxification of the systemic excess ROS is important for the improvement of the process in septic pathogenesis. Histidine-rich glycoprotein (HRG), a plasma glycoprotein, ameliorates a septic condition through the suppression of both excess ROS production from neutrophils and immunothrombosis. Hydroxyl radical is known as the most important species among ROS in pathogenesis; however, the direct influence of HRG on hydroxyl radical formation and ROS activity is poorly understood. In this study, we showed that HRG, in a concentration-dependent manner, efficiently inhibited the production of hydroxyl radical induced by the Fenton's reaction through chelation of the divalent iron. HRG also exhibited antioxidant activity against peroxyl radical by oxidation of HRG itself as a substrate; however, it did not show superoxide dismutase and catalase-like activities. Additionally, HRG enhanced glutathione peroxidase, a well-known antioxidant enzyme, activity. These results suggest that HRG may play a unique role in suppression of the production of hydroxyl radicals and subsequent tissue damage at inflammatory sites. Marked reduction in plasma HRG in sepsis might lose such an important protective mechanism. Thus, the present study provides evidence that inhibition of ROS and ROS-production systems by HRG may contribute to antiseptic effects in vivo and that HRG could be potential therapy for ROS-related diseases. - Shiori Tomita; Fumiko Sekiguchi; Yoshihito Kasanami; Katsuki Naoe; Maho Tsubota; Hidenori Wake; Masahiro Nishibori; Atsufumi KawabataEuropean journal of pharmacology 888 173587 - 173587 2020年09月 [査読有り]
Overexpression of Cav3.2 T-type Ca2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Cav3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Cav3.2, and ubiquitin-specific protease 5 (USP5) that protects Cav3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Cav3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Cav3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Cav3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Cav3.2 overexpression and neuropathy. - Masahiro Watanabe; Takao Toyomura; Mayuko Tomiyama; Hidenori Wake; Keyue Liu; Kiyoshi Teshigawara; Hideo Takahashi; Masahiro Nishibori; Shuji MoriMolecular biology reports 47 9 7153 - 7159 2020年09月 [査読有り]
Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis. The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS-HMGB1 mixture synergistically potentiated LPS-HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS-HMGB1-AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs. Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS-HMGB1-stimulated proinflammatory response through direct interactions. - Shiori Hiramoto; Maho Tsubota; Kaoru Yamaguchi; Kyoko Okazaki; Aya Sakaegi; Yuki Toriyama; Junichi Tanaka; Fumiko Sekiguchi; Hiroyasu Ishikura; Hidenori Wake; Masahiro Nishibori; Huy Du Nguyen; Takuya Okada; Naoki Toyooka; Atsufumi KawabataCells 9 8 2020年07月 [査読有り]
Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Cav3.2 T-type Ca2+ channel activity by H2S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca2+ channels or CSE, and genetic deletion of Cav3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X4/P2X7 receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X7/P2X4, and caused HMGB1 release via P2X7 in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent H2S-targeted Cav3.2-dependent nociceptor excitation, resulting in bladder pain. - Shangze Gao; Hidenori Wake; Masakiyo Sakaguchi; Dengli Wang; Youhei Takahashi; Kiyoshi Teshigawara; Hui Zhong; Shuji Mori; Keyue Liu; Hideo Takahashi; Masahiro NishiboriiScience 23 6 101180 - 101180 2020年06月 [査読有り]
High-mobility group box-1 (HMGB1) protein has been postulated to play a pathogenic role in severe sepsis. Histidine-rich glycoprotein (HRG), a 75 kDa plasma protein, was demonstrated to improve the survival rate of septic mice through the regulation of neutrophils and endothelium barrier function. As the relationship of HRG and HMGB1 remains poorly understood, we investigated the effects of HRG on HMGB1-mediated pathway in endothelial cells, focusing on the involvement of specific receptors for HRG. HRG potently inhibited the HMGB1 mobilization and effectively suppressed rHMGB1-induced inflammatory responses and expression of all three HMGB1 receptors in endothelial cells. Moreover, we first clarified that these protective effects of HRG on endothelial cells were mediated through C-type lectin domain family 1 member A (CLEC-1A) receptor. Thus, current study elucidates protective effects of HRG on vascular endothelial cells through inhibition of HMGB1-mediated pathways may contribute to the therapeutic effects of HRG on severe sepsis. - Yuhei Irie; Maho Tsubota; Mariko Maeda; Shiori Hiramoto; Fumiko Sekiguchi; Hiroyasu Ishikura; Hidenori Wake; Masahiro Nishibori; Atsufumi KawabataJournal of pharmacological sciences 143 2 112 - 116 2020年06月 [査読有り]
HMGB1, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin α capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS. - Takashi Nishinaka; Yui Yamazaki; Atsuko Niwa; Hidenori Wake; Shuji Mori; Tadashi Yoshino; Masahiro Nishibori; Hideo TakahashiBiomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 25 3 305 - 313 2020年05月 [査読有り]
Background: Cerebral small vessel disease (CSVD) is associated with future stroke. Although pathological alteration in small vessels of patients with CSVD can be detected by neuroimaging, diagnosis of CSVD is delayed because it is an asymptomatic disease. The stroke-prone spontaneously hypertensive rat (SHRSP) show similar pathological features to human CSVD and develop stroke-related symptoms with advancing age.Objective: We investigated the time course of haematological parameters in Wistar rats and SHRSP.Material and Methods: Blood cells were analysed using an automated haematological analyser.Results: SHRSP develop stroke-related symptoms including onset of neurological symptoms, decreased body weight and blood brain barrier leakage between 12 and 14 weeks of age. Lymphocyte counts were gradually decreased at 3 weeks before development of stoke-related symptoms and then were further decreased after the development of stroke-related symptoms. The both mean platelet volume and large platelet ratio gradually increased at 3 weeks before the development of stoke-related symptoms. However, although SHRSP showed more microcytic red cells than Wistar rats, the trajectories of change in erythrocyte-related parameters were similar between Wistar rats and SHRSP.Conclusion: Our pilot study suggests that alterations of lymphocyte count and platelet volume predictive indicators for asymptomatic CSVD and symptomatic stroke in SHRSP. - Kazue Hisaoka-Nakashima; Honami Azuma; Fumina Ishikawa; Yoki Nakamura; Dengli Wang; Keyue Liu; Hidenori Wake; Masahiro Nishibori; Yoshihiro Nakata; Norimitsu MoriokaCells 9 5 2020年04月 [査読有り]
A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but stress-associated glucocorticoids could be involved. To test this, rat primary cultured cortical astrocytes, the most abundant cell type in the central nervous system (CNS), were treated with corticosterone and HMGB1 release was assessed by Western blotting and ELISA. Significant HMGB1 was released with treatment with either corticosterone or dexamethasone, a synthetic glucocorticoid. HMGB1 translocated from the nucleus to the cytoplasm following corticosterone treatment. HMGB1 release was significantly attenuated with glucocorticoid receptor blocking. In addition, inhibition of pannexin-1, and P2X7 receptors led to a significant decrease in corticosterone-induced HMGB1 release. Taken together, corticosterone stimulates astrocytic glucocorticoid receptors and triggers cytoplasmic translocation and extracellular release of nuclear HMGB1 through a mechanism involving pannexin-1 and P2X7 receptors. Thus, under conditions of stress, glucocorticoids induce astrocytic HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders such as MDD. - Dengli Wang; Keyue Liu; Yusuke Fukuyasu; Kiyoshi Teshigawara; Li Fu; Hidenori Wake; Aiji Ohtsuka; Masahiro NishiboriCells 9 3 2020年03月 [査読有り]
High mobility group box-1 (HMGB1), a nonhistone chromatin DNA-binding protein, is released from neurons into the extracellular space under ischemic, hemorrhagic, and traumatic insults. However, the details of the time-dependent translocation of HMGB1 and the subcellular localization of HMGB1 through the release process in neurons remain unclear. In the present study, we examined the subcellular localization of HMGB1 during translocation of HMGB1 in the cytosolic compartment using a middle cerebral artery occlusion and reperfusion model in rats. Double immunofluorescence microscopy revealed that HMGB1 immunoreactivities were colocalized with MTCO1(mitochondrially encoded cytochrome c oxidase I), a marker of mitochondria, and catalase, a marker of peroxisomes, but not with Rab5/Rab7 (RAS-related GTP-binding protein), LC3A/B (microtubule-associated protein 1 light chain 3), KDEL (KDEL amino acid sequence), and LAMP1 (Lysosomal Associated Membrane Protein 1), which are endosome, phagosome, endoplasmic reticulum, and lysosome markers, respectively. Immunoelectron microscopy confirmed that immune-gold particles for HMGB1 were present inside the mitochondria and peroxisomes. Moreover, HMGB1 was found to be colocalized with Drp1 (Dynamin-related protein 1), which is involved in mitochondrial fission. These results revealed the specific subcellular localization of HMGB1 during its release process under ischemic conditions. - Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Keyue Liu; Kiyoshi Teshigawara; Hideo Takahashi; Masahiro Nishibori; Shuji MoriBiotechnology and applied biochemistry 67 2 265 - 272 2020年03月 [査読有り]
Advanced glycation end products (AGEs) are considered to be related to the pathogenesis of some inflammatory diseases. AGEs were reported to stimulate the receptor for AGEs (RAGE), which causes inflammatory reactions. However, recently, toll-like receptors (TLRs), in addition to RAGE, have been reported to be related to AGE-mediated cellular responses, and it remains unclear which receptor is responsible for AGE recognition. To reveal the role of pattern-recognition receptors, including TLRs and/or RAGE, in AGE-mediated cellular responses, we generated macrophage-like RAW264.7 knockout (KO) cells lacking these receptors by genome editing using the CRISPR/Cas9 system and assessed AGE-stimulated changes in these cells. Comparison of the established clones suggested that RAGE partially affects the expression of TLRs. In the KO clone lacking TLR4 and TLR2, AGE-stimulated tumor necrosis factor alpha (TNF-α) expression and phosphorylation of IκBα, p38, and extracellular signal-regulated kinase (ERK) were significantly attenuated, suggesting that AGE-mediated responses are largely dependent on TLRs. On the other hand, on comparison of the AGE-stimulated responses between the KO clone lacking TLR4 and TLR2, and the clone lacking TLR4, TLR2, and RAGE, RAGE played little role in AGE-stimulated TNF-α transcription and ERK phosphorylation. Taken together, this study suggested that AGE-stimulated inflammatory responses occur mainly through TLRs rather than RAGE. - Takashi Nishinaka; Shuji Mori; Yui Yamazaki; Atsuko Niwa; Hidenori Wake; Tadashi Yoshino; Masahiro Nishibori; Hideo TakahashiDiabetes and Vascular Disease Research 17 1 147916411989697 - 147916411989697 2020年01月 [査読有り]
Advanced glycation end-products, especially toxic advanced glycation end-products derived from glyceraldehyde (advanced glycation end-product-2) and glycolaldehyde (advanced glycation end-product-3), are biologically reactive compounds associated with diabetic complications. We previously demonstrated that toxic advanced glycation end-products were internalised into macrophage-like RAW264.7 cells through scavenger receptor-1 class A (CD204). Toxic advanced glycation end-product uptake was inhibited by fucoidan, a sulphated polysaccharide and antagonistic ligand for scavenger receptors, suggesting that sulphated polysaccharides are emerging candidates for treatment of advanced glycation end-product–related diseases. In this study, we compared the effects of six types of sulphated and non-sulphated polysaccharides on toxic advanced glycation end-product uptake in RAW264.7 cells. Fucoidan, carrageenan and dextran sulphate attenuated toxic advanced glycation end-product uptake. Fucoidan and carrageenan inhibited advanced glycation end-product-2–induced upregulation of SR-A, while advanced glycation end-product-3–induced upregulation of scavenger receptor-1 class A was only suppressed by fucoidan. Dextran sulphate did not affect scavenger receptor-1 class A levels in toxic advanced glycation end-product–treated cells. Chondroitin sulphate, heparin and hyaluronic acid failed to attenuate toxic advanced glycation end-product uptake. Heparin and hyaluronic acid had no effect on scavenger receptor-1 class A levels, while chondroitin sulphate inhibited advanced glycation end-product-3–induced upregulation of scavenger receptor-1 class A. Taken together, fucoidan and carrageenan, but not the other sulphated polysaccharides examined, had inhibitory activities on toxic advanced glycation end-product uptake and toxic advanced glycation end-product–induced upregulation of scavenger receptor-1 class A, possibly because of structural differences among sulphated polysaccharides. - Hidenori Wake; Masahiro NishiboriFolia pharmacologica Japonica 155 3 155 - 158 2020年 [査読有り]
Histidine-rich glycoprotein (HRG) is a 75 kDa plasma glycoprotein synthesized in liver mainly, which exists at approximately 60-100 μg/ml in human plasma. HRG is known to bind to several ligands and cells, leading to exert coagulation, fibrinolysis, immune and inflammation regulatory activity in septic condition. Thus, decreased plasma HRG level induces the dysregulations of coagulation, fibrinolysis and immune system, resulting in disseminated intravascular coagulation and multiple organ failure. This article focuses on the physiological activity of HRG and the potential of HRG as the biomarker and therapeutic drug for sepsis. - Keisuke Yamashiro; Hidetaka Ideguchi; Hiroaki Aoyagi; Chiaki Yoshihara-Hirata; Anna Hirai; Risa Suzuki-Kyoshima; Yao Zhang; Hidenori Wake; Masahiro Nishibori; Tadashi Yamamoto; Shogo TakashibaFrontiers in immunology 11 1461 - 1461 2020年 [査読有り]
High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein of about 30 kDa. It is released from a variety of cells into the extracellular milieu in response to inflammatory stimuli and acts on specific cell-surface receptors, such as receptors for advanced glycation end-products (RAGE), Toll-like receptor (TLR)2, TLR4, with or without forming a complex with other molecules. HMGB1 mediates various mechanisms such as inflammation, cell migration, proliferation, and differentiation. On the other hand, HMGB1 enhances chemotaxis acting through the C-X-C motif chemokine ligand (CXCL)12/C-X-C chemokine receptor (CXCR)4 axis and is involved in regeneration. In the oral cavity, high levels of HMGB1 have been detected in the gingival tissue from periodontitis and peri-implantitis patients, and it has been shown that secreted HMGB1 induces pro-inflammatory cytokine expression, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which prolong inflammation. In contrast, wound healing after tooth extraction or titanium dental implant osseointegration requires an initial acute inflammation, which is regulated by secreted HMGB1. This indicates that secreted HMGB1 regulates angiogenesis and bone remodeling by osteoclast and osteoblast activation and promotes bone healing in oral tissue repair. Therefore, HMGB1 can prolong inflammation in the periodontal tissue and, conversely, can regenerate or repair damaged tissues in the oral cavity. In this review, we highlight the role of HMGB1 in the oral cavity by comparing its function and regulation with its function in other diseases. We also discuss the necessity for further studies in this field to provide more specific scientific evidence for dentistry. - Maho Tsubota; Ryotaro Fukuda; Yusuke Hayashi; Takaya Miyazaki; Shin Ueda; Rika Yamashita; Nene Koike; Fumiko Sekiguchi; Hidenori Wake; Shuji Wakatsuki; Yuka Ujiie; Toshiyuki Araki; Masahiro Nishibori; Atsufumi KawabataJournal of neuroinflammation 16 1 199 - 199 2019年10月 [査読有り]
BACKGROUND: Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system. METHODS: CIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay. RESULTS: Intraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin. CONCLUSIONS: Our data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM. - Hidenori WakeActa medica Okayama 73 5 379 - 382 2019年10月 [査読有り]
Histidine-rich glycoprotein (HRG) is a 75 kDa glycoprotein synthesized in the liver whose plasma concentration is 100-150 μg/ml. HRG has been shown to modulate sepsis-related biological reactions by binding to several substances and cells, including heparin, factor XII, fibrinogen, thrombospondin, plasminogen, C1q, IgG, heme, LPS, dead cells, bacteria, and fungi. Therefore, reduction of plasma HRG levels in sepsis leads to dysregulation of coagulation, fibrinolysis, and immune response, resulting in disseminated intravascular coagulation and multiple organ failure. This review summarizes the binding and functional properties of HRG in sepsis. - Norimitsu Morioka; Kazuki Miyauchi; Keita Miyashita; Takahiro Kochi; Fang Fang Zhang; Yoki Nakamura; Keyue Liu; Hidenori Wake; Kazue Hisaoka-Nakashima; Masahiro Nishibori; Yoshihiro NakataJournal of neurochemistry 150 6 738 - 758 2019年09月 [査読有り]
Intrathecal treatment with recombinant high-mobility group box-1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal HMGB1 evokes abnormal pain processing. By contrast, repeated intrathecal treatment with anti-HMGB1 antibody significantly reverses hind paw mechano-hypersensitivity in mice with a partial sciatic nerve ligation (PSNL). By contrast, the cellular mechanism by which spinal HMGB1 induces neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal HMGB1 could induce mechanical hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with toll-like receptor (TLR) 4 inhibitors, but not TLR5, receptor for advanced glycation end-products and C-X-C chemokine receptor type 4 inhibitors, prevented rHMGB1-evoked mechanical hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1-induced mechanical hypersensitivity. Interleukin-1β (IL-1β) was up-regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL-1β. Interleukin-1β appears to be secreted by activated astrocytes, as IL-1β neutralizing antibody prevented rHMGB1-induced mechanical hypersensitivity. Furthermore, intrathecal pretreatment with either MK801 or gabapentin prevented the rHMGB1-induced mechanical hypersensitivity, suggesting roles for spinal glutamate and the N-methyl-d-aspartate receptor in the mediation of rHMGB1-induced mechanical hypersensitivity. Thus, the current findings suggest that spinal HMGB1 upregulates IL-1β in spinal astrocytes through a TLR4-dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain neuropathic pain. - Gao S; Wake H; Gao Y; Wang D; Mori S; Liu K; Teshigawara K; Takahashi H; Nishibori MBritish journal of pharmacology 176 15 2808 - 2824 2019年08月 [査読有り]
BACKGROUND AND PURPOSE: Microvascular barrier breakdown is a hallmark of sepsis that is associated with sepsis-induced multiorgan failure. Histidine-rich glycoprotein (HRG) is a 75-kDa plasma protein that was demonstrated to improve the survival of septic mice through regulation of cell shape, spontaneous ROS production in neutrophils, and adhesion of neutrophils to vascular endothelial cells. We investigated HRG's role in the LPS/TNF-α-induced barrier dysfunction of endothelial cells in vitro and in vivo and the possible mechanism, to clarify the definitive roles of HRG in sepsis. EXPERIMENTAL APPROACH: EA.hy 926 endothelial cells were pretreated with HRG or human serum albumin before stimulation with LPS/TNF-α. A variety of biochemical assays were applied to explore the underlying molecular mechanisms on how HRG protected the barrier function of vascular endothelium. KEY RESULTS: Immunostaining results showed that HRG maintains the endothelial monolayer integrity by inhibiting cytoskeleton reorganization, losses of VE-cadherin and β-catenin, focal adhesion kinase degradation, and cell detachment induced by LPS/TNF-α. HRG also inhibited the cytokine secretion from endothelial cells induced by LPS/TNF-α, which was associated with reduced NF-κB activation. Moreover, HRG effectively prevented the LPS/TNF-α-induced increase in capillary permeability in vitro and in vivo. Finally, Western blot results demonstrated that HRG prevented the phosphorylation of MAPK family and RhoA activation, which are involved mainly in the regulation of cytoskeleton reorganization and barrier permeability. CONCLUSIONS AND IMPLICATIONS: Taken together, our results demonstrate that HRG has protective effects on vascular barrier function in vitro and in vivo, which may be due to the inhibition of MAPK family and Rho activation. - Kazue Hisaoka-Nakashima; Yoshiaki Tomimura; Toshiki Yoshii; Kazuto Ohata; Naoki Takada; Fang Fang Zhang; Yoki Nakamura; Keyue Liu; Hidenori Wake; Masahiro Nishibori; Yoshihiro Nakata; Norimitsu MoriokaProgress in neuro-psychopharmacology & biological psychiatry 92 347 - 362 2019年06月 [査読有り]
Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain. However, the cellular basis for chronic pain-mediated major depression remains unclear. High-mobility group box 1 protein (HMGB1) has a key role in innate immune responses and appears to be have a role in mediating diverse disorders, including neuropathic pain and depression. The current study aimed to characterize neuropathic pain-induced changes in affect over time and to determine whether HMGB1 has a role in neuropathic pain-induced changes in affect. Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Anxiodepressive-like behaviors in mice were evaluated over 10 weeks, in the social interaction, forced swim, and novelty suppressed feeding tests. Mice developed anxiodepressive-like behavior 6 to 8 weeks after induction of neuropathy. Accompanying anxiodepressive-like behavior, increased HMGB1 protein and microglia activation were observed in frontal cortex at 8 weeks after PSNL. Intracerebroventricular administration of rHMGB1 in naïve mice induced anxiodepressive-like behavior and microglia activation. Blockage of HMGB1 in PSNL mice with glycyrrhizic acid (GZA) or anti-HMGB1 antibody reduced microglia activation and anxiodepressive-like behavior. These results indicate that PSNL-induced anxiodepressive-like behavior is likely mediated by HMGB1. Furthermore, the data indicate that inhibition of HMGB1-dependent microglia activation could be a strategy for the treatment of depression associated with neuropathic pain. - Yoshito Nishimura; Hidenori Wake; Kiyoshi Teshigawara; Dengli Wang; Masakiyo Sakaguchi; Fumio Otsuka; Masahiro NishiboriPharmacology research & perspectives 7 3 e00481 2019年06月 [査読有り]
Augmentation of natural killer (NK) cell cytotoxicity is one of the greatest challenges for cancer immunotherapy. Although histidine-rich glycoprotein (HRG), a 75-kDa glycoprotein with various immunomodulatory activities, reportedly elicits antitumor immunity, its effect on NK cell cytotoxicity is unclear. We assessed NK cell cytotoxicity against K562 cells. We also measured concentrations of cytokines and granzyme B in the cell supernatant. The proportion of CD56bright NK cells and NK cell surface PD-1 expression was assessed with flow cytometry. The neutralizing effects of anti-C-type lectin-like receptor (CLEC) 1B against HRG were also measured. NK cell morphological changes were analyzed via confocal microscopy. HRG significantly increased NK cell cytotoxicity against K562 cell lines. HRG also increased the release of granzyme B and the proportion of CD56bright NK cells. Further, HRG was able to decrease NK cell surface PD-1 expression. The effects of HRG on NK cells were reversed with anti-CLEC-1B antibodies. Additionally, we confirmed NK cell nuclear morphology and F-actin distribution, which are involved in the regulation of cytotoxic granule secretion. Because both PD-1 and CLEC-1B are associated with prognosis during malignancy, HRG incorporates these molecules to exert the antitumor immunity role. These facts indicate the potential of HRG to be a new target for cancer immunotherapy. - Masahide Nakajo; Naohiro Uezono; Hideyuki Nakashima; Hidenori Wake; Setsuro Komiya; Masahiro Nishibori; Kinichi NakashimaNeuroscience research 141 63 - 70 2019年04月 [査読有り]
Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI. - Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Keyue Liu; Kiyoshi Teshigawara; Hideo Takahashi; Masahiro Nishibori; Shuji MoriBiotechnology and applied biochemistry 66 2 254 - 260 2019年03月 [査読有り]
Previously, we found that endogenously produced pro-inflammatory molecules, advanced glycation end products (AGEs), interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and attenuate its immunomodulatory function. In the present study, to elucidate the mechanism by which AGEs attenuate TWEAK function, we searched for regions responsible for TWEAK-AGE interaction using TWEAK deletion mutants. Pull-down assays with the TWEAK mutants and AGEs revealed that the C-terminal half of TWEAK, which is the region essential for receptor stimulation, was required for this interaction. On the other hand, the N-terminal deletion mutants did not exhibit a significant decrease in AGE binding. Moreover, a moderate decrease in the AGE binding by double-deletion in quartered C-terminal half regions and a substantial decrease by triple-deletion in this region were observed. In addition, full-length TWEAK stimulated IL-8 gene expression in endothelial EA.hy.926 cells, whereas the triple-deletion mutant lost much of this activity, suggesting that the TWEAK-AGE interaction sites overlap with the region needed to exert normal function of TWEAK. Our present findings may help to elucidate the pathophysiological roles of the TWEAK-AGE interaction for prevention and treatment of AGE-related inflammatory diseases. - Yu Okuma; Hidenori Wake; Kiyoshi Teshigawara; Yu Takahashi; Tomohito Hishikawa; Takao Yasuhara; Shuji Mori; Hideo K Takahashi; Isao Date; Masahiro NishiboriWorld neurosurgery 122 e864-e871 - e871 2019年02月 [査読有り]
BACKGROUND: High mobility group box 1 (HMGB1) protein plays a key role in triggering inflammatory responses in many diseases. Our previous study showed that HMGB1 is found upstream of secondary damage in traumatic brain injury (TBI). We found that anti-HMGB1 monoclonal antibody (mAb) effectively decreased acute brain damage, including the disruption of the blood-brain barrier, brain edema, and neurologic dysfunction. This effect of anti-HMGB1 mAb lasts for at least 1 week. In this study, we explored subacute effects of anti-HMGB1 mAb after TBI. METHODS: TBI was induced in rats by fluid percussion. Anti-HMGB1 mAb or control mAb was given intravenously after TBI. Histochemical staining, plasma levels of HMGB1, motor activity and memory, and video electroencephalography monitoring were evaluated 2 weeks after fluid percussion injury. RESULTS: Anti-HMGB1 mAb remarkably attenuated accumulation of activated microglia in the rat cortex in the ipsilateral hemisphere after TBI. Anti-HMGB1 mAb also prevented neuronal death in the hippocampus in the ipsilateral hemisphere after TBI. Treatment of rats with anti-HMGB1 mAb inhibited HMGB1 translocation and suppressed impairment of motor function. The beneficial effects of anti-HMGB1 mAb on motor and cognitive function persisted for 14 days after injury. Treatment with anti-HMGB1 mAb also had positive effects on electroencephalography activity. CONCLUSIONS: The beneficial effects of anti-HMGB1 mAb continued during the subacute postinjury phase, suggesting that anti-HMGB1 mAb may prevent cognitive dysfunction after TBI. - Xiaodi Chen; Jiyong Zhang; Boram Kim; Siddhant Jaitpal; Steven S Meng; Kwame Adjepong; Sayumi Imamura; Hidenori Wake; Masahiro Nishibori; Edward G Stopa; Barbara S StonestreetExperimental neurology 311 1 - 14 2019年01月 [査読有り]
Inflammation contributes to neonatal brain injury. Pro-inflammatory cytokines represent key inflammatory meditators in neonatal hypoxic-ischemic (HI) brain injury. The high mobility group box-1 (HMGB1) protein is a nuclear protein with pro-inflammatory cytokine properties when it is translocated from the nucleus and released extracellularly after stroke in adult rodents. We have previously shown that HMGB1 is translocated from the nucleus to cytosolic compartment after ischemic brain injury in fetal sheep. In the current study, we utilized the Rice-Vannucci model to investigate the time course of HMGB1 translocation and release after HI injury in neonatal rats. HMGB1 was located in cellular nuclei of brains from sham control rats. Nuclear to cytoplasmic translocation of HMGB1 was detected in the ipsilateral-HI hemisphere as early as zero h after HI, and released extracellularly as early as 6 h after HI. Immunohistochemical double staining detected HMGB1 translocation mainly in neurons along with release from apoptotic cells after HI. Serum HMGB1 increased at 3 h and decreased by 24 h after HI. In addition, rat brains exposed to hypoxic injury alone also exhibited time dependent HMGB1 translocation at 3, 12 and 48 h after hypoxia. Consequently, HMGB1 responds similarly after HI injury in the brains of neonatal and adult subjects. We conclude that HMGB1 is sensitive early indicator of neonatal HI and hypoxic brain injury. - Fumiko Sekiguchi; Risa Domoto; Kana Nakashima; Daichi Yamasoba; Hiroki Yamanishi; Maho Tsubota; Hidenori Wake; Masahiro Nishibori; Atsufumi KawabataNeuropharmacology 141 201 - 213 2018年10月 [査読有り]
Given our recent evidence for the role of high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) in rats, we examined the origin of HMGB1 and the upstream and downstream mechanisms of HMGB1 release involved in paclitaxel-induced neuropathy in mice. Paclitaxel treatment developed mechanical allodynia in mice, as assessed by von Frey test, which was prevented by an anti-HMGB1-neutralizing antibody or thrombomodulin alfa capable of inactivating HMGB1. RAGE or CXCR4 antagonists, ethyl pyruvate or minocycline, known to inhibit HMGB1 release from macrophages, and liposomal clodronate, a macrophage depletor, prevented the paclitaxel-induced allodynia. Paclitaxel caused upregulation of RAGE and CXCR4 in the dorsal root ganglia and macrophage accumulation in the sciatic nerve. In macrophage-like RAW264.7 cells, paclitaxel evoked cytoplasmic translocation of nuclear HMGB1 followed by its extracellular release, and overexpression of CBP and PCAF, histone acetyltransferases (HATs), known to cause acetylation and cytoplasmic translocation of HMGB1, which were suppressed by ethyl pyruvate, N-acetyl-l-cysteine, an anti-oxidant, and SB203580 and PDTC, inhibitors of p38 MAP kinase (p38MAPK) and NF-κB, respectively. Paclitaxel increased accumulation of reactive oxygen species (ROS) and phosphorylation of p38MAPK, NF-κB p65 and I-κB in RAW264.7 cells. In mice, N-acetyl-l-cysteine or PDTC prevented the paclitaxel-induced allodynia. Co-culture of neuron-like NG108-15 cells or stimulation with their conditioned medium promoted paclitaxel-induced HMGB1 release from RAW264.7 cells. Our data indicate that HMGB1 released from macrophages through the ROS/p38MAPK/NF-κB/HAT pathway participates in the paclitaxel-induced peripheral neuropathy in mice, and unveils an emerging therapeutic avenue targeting a neuroimmune crosstalk in CIPN. - Kinya Terao; Hidenori Wake; Naoto Adachi; Keyue Liu; Kiyoshi Teshigawara; Hideo Takahashi; Shuji Mori; Masahiro NishiboriPancreas 47 9 1156 - 1164 2018年10月 [査読有り]
OBJECTIVES: Severe acute pancreatitis is a highly lethal disease caused by systemic inflammatory response syndrome, leading to multiple organ failure. We recently showed that histidine-rich glycoprotein (HRG) supplemental therapy ameliorated septic acute respiratory distress syndrome due to unnecessary neutrophil activation and immunothrombosis formation. Here, we evaluated the effect of HRG on lung inflammation followed by pancreatitis in a severe acute pancreatitis mouse model. METHODS: Mice received intraperitoneal injections of cerulein 7 times (100 μg/kg each) at 1-hour intervals to induce acute pancreatitis. Immediately after the first cerulein injection, phosphate-buffered saline, human serum albumin (20 mg/kg), or HRG (20 mg/kg) was intravenously injected. One hour after the last cerulein injection, phosphate-buffered saline or lipopolysaccharide (5 mg/kg) was intravenously injected into the tail vein. We evaluated lung inflammatory level after pancreatitis. RESULTS: We observed significantly decreased plasma HRG levels in an acute pancreatitis mouse model. Histidine-rich glycoprotein treatment inhibited lung edema and the accumulation of neutrophil in severe acute pancreatitis, but HRG did not directly affect pancreatitis. Moreover, HRG suppressed tumor necrosis factor α, inducible nitric oxide synthase, interleukin 6, and neutrophil elastase mRNA expression and myeloperoxidase activity in the lung. CONCLUSIONS: These data suggested that HRG ameliorated lung inflammation secondary to pancreatitis. - Masahiro Nishibori; Hidenori Wake; Hiroshi MorimatsuCritical care (London, England) 22 1 209 - 209 2018年08月 [査読有り]
Sepsis remains a critical problem with high morbidity and mortality worldwide. One of the problems we have in critical care is the need to find a good biomarker of sepsis to determine the existence of bacterial infection and the severity of patients. This would enable us to start appropriate treatment at an earlier stage of the disease course. We propose that decreases in the plasma protein histidine-rich glycoprotein (HRG) is an excellent biomarker of sepsis compared with the current markers. Based on the novel pathophysiological roles of HRG in the cascade of events during sepsis, we also discuss the potential for supplemental therapy with purified HRG. - Htwe SS; Wake H; Liu K; Teshigawara K; Stonestreet BS; Lim YP; Nishibori MBlood advances 2 15 1923 - 1934 2018年08月 [査読有り]
The plasma levels of inter-α inhibitor proteins (IAIPs) are decreased in patients with sepsis and the reduced levels correlate with increased mortality. In the present study, we examined the effects of IAIPs on human neutrophils to better understand the beneficial effects of IAIPs in the treatment of sepsis. We demonstrated that IAIPs induced a spherical shape that was smaller in size with a smooth cellular surface in a concentration-dependent manner. These changes were inhibited by a specific antibody against IAIPs. In contrast, bikunin, light chain of IAIP, had no effect on neutrophil morphology. The neutrophils treated with IAIPs could easily pass through the artificial microcapillaries and were prevented from entrapment inside the capillaries. Coincubation of human blood neutrophils with a confluent human vascular endothelial monolayer showed that adhesion of neutrophils on endothelial cells was suppressed by treatment with IAIPs. IAIPs inhibited the spontaneous release of reactive oxygen species (ROS) in a concentration-dependent fashion. ROS inhibition was associated with reductions in p47phox phosphorylation on Ser328. These results suggest that IAIP-induced morphological changes that render neutrophils quiescent, facilitate passage through the microvasculature, and reduce adhesion to vascular endothelial cells and production of ROS. Thus, IAIP plays a key role in controlling neutrophil activation. - Nobuyuki Nosaka; Kazuki Hatayama; Mutsuko Yamada; Yousuke Fujii; Masato Yashiro; Hidenori Wake; Hirokazu Tsukahara; Masahiro Nishibori; Tsuneo MorishimaJournal of medical virology 90 7 1192 - 1198 2018年07月 [査読有り]
Encephalopathy is a major cause of influenza-associated child death and severe neurological sequelae in Japan, highlighting the urgent need for new therapeutic strategies. In this study, we evaluated the effects of anti-high mobility group box-1 monoclonal antibody (α-HMGB1) treatment on brain edema induced by influenza A virus (IAV) and lipopolysaccharide in 4-week-old BALB/c female mice. The results showed that administration of 7.5 mg/kg α-HMGB1 1 h after IAV (A/Puerto Rico/8/34) inoculation significantly alleviated brain edema at 48 h after IAV inoculation, as confirmed by the suppression of Evans Blue dye leakage and matrix metallopeptidase-9 mRNA expression in the brain. Moreover, we also observed suppression of oxidative stress and different cytokines in IAV-inoculated mice. The expression of plasminogen activator inhibitor-1 was also attenuated following treatment with α-HMGB1. Notably, α-HMGB1 treatment had no effect on virus propagation in the lung. In summary, anti-HMGB1 treatment may improve the prognosis in cases with influenza-associated encephalopathy by attenuating brain edema and reducing the inflammatory responses induced by HMGB1. - Hiroaki Aoyagi; Keisuke Yamashiro; Chiaki Hirata-Yoshihara; Hidetaka Ideguchi; Mutsuyo Yamasaki; Mari Kawamura; Tadashi Yamamoto; Shinsuke Kochi; Hidenori Wake; Masahiro Nishibori; Shogo TakashibaJournal of cellular biochemistry 119 7 5481 - 5490 2018年07月 [査読有り]
- Chiaki Yoshihara-Hirata; Keisuke Yamashiro; Tadashi Yamamoto; Hiroaki Aoyagi; Hidetaka Ideguchi; Mari Kawamura; Risa Suzuki; Mitsuaki Ono; Hidenori Wake; Masahiro Nishibori; Shogo TakashibaInfection and immunity 86 5 2018年05月 [査読有り]
- Kosuke Kuroda; Hidenori Wake; Shuji Mori; Shiro Hinotsu; Masahiro Nishibori; Hiroshi MorimatsuCritical care medicine 46 4 570 - 576 2018年04月 [査読有り]
OBJECTIVES: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. DESIGN: Single-center, prospective, observational cohort study. SETTING: ICU at an university-affiliated hospital. PATIENTS: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. CONCLUSIONS: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin. - Hui Zhong; Hidenori Wake; Keyue Liu; Yuan Gao; Kiyoshi Teshigawara; Masakiyo Sakaguchi; Shuji Mori; Masahiro NishiboriJournal of pharmacological sciences 136 3 97 - 106 2018年03月 [査読有り]
The apoptotic process of erythrocytes is known as eryptosis, and is characterized by phosphatidylserine (PS) expression on the outer membrane. PS-positive erythrocytes are increased in sepsis, and PS is believed to facilitate coagulation of erythrocytes and activate macrophages. However, the relationship between eryptosis and abnormal coagulation in sepsis is still not fully understood. Histidine-rich glycoprotein (HRG) inhibits immunothrombus formation by regulating neutrophils and vascular endothelial cells. In the present study, we subjected isolated erythrocytes to Zn2+ stimulation, which activated their aggregation and PS expression. We then determined the Zn2+ contents in septic lung and kidney tissues, and found that they were elevated, suggesting that eryptosis was enhanced in these tissues. Erythrocyte adhesion to endothelial cells was also significantly increased after Zn2+ stimulation, and this effect was inhibited by HRG. Finally, we examined HRG treatment in septic model mice, and found that HRG decreased hemolysis, possibly due to its ability to bind heme. Our study demonstrated a novel Zn2+-initiated aggregation/thrombus formation pathway. We also showed the regulatory role of HRG in this pathway, together with the ability of HRG to inhibit hemolysis under septic conditions. HRG supplementation might be a novel therapeutic strategy for inflammatory disorders, especially sepsis. - Takuro Kobori; Shinichi Hamasaki; Atsuhiro Kitaura; Yui Yamazaki; Takashi Nishinaka; Atsuko Niwa; Shinichi Nakao; Hidenori Wake; Shuji Mori; Tadashi Yoshino; Masahiro Nishibori; Hideo TakahashiFrontiers in immunology 9 doi: 10.3389/fimmu 334 - 334 2018年 [査読有り]
M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell-cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell-cell interaction with endothelial cells, possibly mediated by CD163. - Li Fu; Keyue Liu; Hidenori Wake; Kiyoshi Teshigawara; Tadashi Yoshino; Hideo Takahashi; Shuji Mori; Masahiro NishiboriScientific Reports 7 1 2017年12月 [査読有り]
- Masahiro Watanabe; Takao Toyomura; Hidenori Wake; Keyue Liu; Kiyoshi Teshigawara; Hideo Takahashi; Masahiro Nishibori; Shuji MoriMolecular and Cellular Biochemistry 434 1-2 153 - 162 2017年10月 [査読有り]
- Yuta Morioka; Kiyoshi Teshigawara; Yasuko Tomono; Dengli Wang; Yasuhisa Izushi; Hidenori Wake; Keyue Liu; Hideo Kohka Takahashi; Shuji Mori; Masahiro NishiboriJournal of Pharmacological Sciences 134 4 218 - 224 2017年08月 [査読有り]
- Dengli Wang; Keyue Liu; Hidenori Wake; Kiyoshi Teshigawara; Shuji Mori; Masahiro NishiboriScientific Reports 7 1 2017年05月 [査読有り]
Abstract As one of the most lethal stroke subtypes, intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatment. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. High mobility group box-1 (HMGB1) is a ubiquitous and abundant nonhistone DNA-binding protein, and is also an important proinflammatory molecule once released into the extracellular space from the nuclei. Here, we show that treatment with neutralizing anti-HMGB1 mAb (1 mg/kg, i.v. twice) remarkably ameliorated ICH-injury induced by local injection of collagenase IV in the striatum of rats. Administration of anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri-hematomal region, reduced serum HMGB1 levels and decreased brain edema by protecting blood-brain barrier integrity, in association with decreased activated microglia and the expression of inflammation-related factors at 24 h after ICH. Consequently, anti-HMGB1 mAb reduced the oxidative stress and improved the behavioral performance of rats. These results strongly indicate that HMGB1 plays a critical role in the development of ICH-induced secondary injury through the amplification of plural inflammatory responses. Intravenous injection of neutralizing anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH. - Yuan Gao; Hidenori Wake; Yuta Morioka; Keyue Liu; Kiyoshi Teshigawara; Megumi Shibuya; Jingxiu Zhou; Shuji Mori; Hideo Takahashi; Masahiro NishiboriOxidative Medicine and Cellular Longevity 2017 1 - 10 2017年 [査読有り]
Advanced glycation end products (AGEs) are the products of a series of nonenzymatic modifications of proteins by reducing sugars. AGEs play a pivotal role in development of diabetic complications and atherosclerosis. Accumulation of AGEs in a vessel wall may contribute to the development of vascular lesions. Although AGEs have a diverse range of bioactivities, the clearance process of AGEs from the extracellular space, including the incorporation of AGEs into specific cells, subcellular localization, and the fate of AGEs, remains unclear. In the present study, we examined the kinetics of the uptake of AGEs by mouse macrophage J774.1 cells in vitro and characterized the process. We demonstrated that AGEs bound to the surface of the cells and were also incorporated into the cytoplasm. The temperature- and time-dependent uptake of AGEs was saturable with AGE concentration and was inhibited by cytochalasin D but not chlorpromazine. We also observed the granule-like appearance of AGE immunoreactivity in subcellular localizations in macrophages. Higher concentrations of AGEs induced intracellular ROS and 4-HNE, which were associated with activation of the NF-κB pathway and caspase-3. These results suggest that incorporation of AGEs occurred actively by endocytosis in macrophages, leading to apoptosis of these cells through NF-κB activation. - Jun Haruma; Kiyoshi Teshigawara; Tomohito Hishikawa; Dengli Wang; Keyue Liu; Hidenori Wake; Shuji Mori; Hideo Kohka Takahashi; Kenji Sugiu; Isao Date; Masahiro NishiboriScientific Reports 6 1 2016年12月 [査読有り]
- Hidenori Wake; Shuji Mori; Keyue Liu; Yuta Morioka; Kiyoshi Teshigawara; Masakiyo Sakaguchi; Kosuke Kuroda; Yuan Gao; Hideo Takahashi; Aiji Ohtsuka; Tadashi Yoshino; Hiroshi Morimatsu; Masahiro NishiboriEBioMedicine 9 180 - 194 2016年07月 [査読有り]
- Atsuko Niwa; Masahiro Nishibori; Shinichi Hamasaki; Takuro Kobori; Keyue Liu; Hidenori Wake; Shuji Mori; Tadashi Yoshino; Hideo TakahashiBrain Structure and Function 221 3 1653 - 1666 2016年04月 [査読有り]
- Yasuhisa Izushi; Kiyoshi Teshigawara; Keyue Liu; Dengli Wang; Hidenori Wake; Katsuyoshi Takata; Tadashi Yoshino; Hideo Kohka Takahashi; Shuji Mori; Masahiro NishiboriJournal of Pharmacological Sciences 130 4 226 - 234 2016年04月 [査読有り]
- Yu Okuma; Keyue Liu; Hidenori Wake; Rui Liu; Yoshito Nishimura; Zhong Hui; Kiyoshi Teshigawara; Jun Haruma; Yasuhiko Yamamoto; Hiroshi Yamamoto; Isao Date; Hideo K. Takahashi; Shuji Mori; Masahiro NishiboriNeuropharmacology 85 18 - 26 2014年10月 [査読有り]
- Histamine inhibits high mobility group box 1-induced adhesion molecule expression on human monocytesHideo Takahashi; Hiroshi Sadamori; Kiyoshi Teshigawara; Atsuko Niwa; Keyue Liu; Hidenori Wake; Shuji Mori; Tadashi Yoshino; Masahiro NishiboriEuropean Journal of Pharmacology 718 1-3 305 - 313 2013年10月 [査読有り]
- Hideo Kohka Takahashi; Hiroshi Sadamori; Keyue Liu; Hidenori Wake; Shuji Mori; Tadashi Yoshino; Yasuhiko Yamamoto; Hiroshi Yamamoto; Masahiro NishiboriEuropean Journal of Pharmacology 701 1-3 194 - 202 2013年02月 [査読有り]
- Yu Okuma; Keyue Liu; Hidenori Wake; Jiyong Zhang; Tomoko Maruo; Isao Date; Tadashi Yoshino; Aiji Ohtsuka; Naoki Otani; Satoshi Tomura; Katsuji Shima; Yasuhiko Yamamoto; Hiroshi Yamamoto; Hideo K. Takahashi; Shuji Mori; Masahiro NishiboriAnnals of Neurology 72 3 373 - 384 2012年09月 [査読有り]
- Jiyong Zhang; Hideo K. Takahashi; Keyue Liu; Hidenori Wake; Rui Liu; Tomoko Maruo; Isao Date; Tadashi Yoshino; Aiji Ohtsuka; Shuji Mori; Masahiro NishiboriStroke 42 5 1420 - 1428 2011年05月 [査読有り]
Background and Purpose— High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity in the extracellular space. We previously demonstrated that intravenous injection of anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by middle cerebral artery occlusion in rats. In the present study, we focused on the protective effects of the mAb on the marked translocation of HMGB1 in the brain, the disruption of the blood–brain barrier (BBB), and the resultant brain edema. Methods— Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with anti-HMGB1 mAb or control IgG intravenously. BBB permeability was measured by MRI. Ultrastructure of the BBB unit was observed by transmission electron microscope. The in vitro BBB system was used to study the direct effects of HMGB1 in BBB components. Results— HMGB1 was time-dependently translocated and released from neurons in the ischemic rat brain. The mAb reduced the edematous area on T2-weighted MRI. Transmission electron microscope observation revealed that the mAb strongly inhibited astrocyte end feet swelling, the end feet detachment from the basement membrane, and the opening of the tight junction between endothelial cells. In the in vitro reconstituted BBB system, recombinant HMGB1 increased the permeability of the BBB with morphological changes in endothelial cells and pericytes, which were inhibited by the mAb. Moreover, the anti-HMGB1 mAb facilitated the clearance of serum HMGB1. Conclusions— These results indicated that the anti-HMGB1 mAb could be an effective therapy for brain ischemia by inhibiting the development of brain edema through the protection of the BBB and the efficient clearance of circulating HMGB1. - S Mori; HK Takahashi; K Liu; H Wake; J Zhang; R Liu; T Yoshino; M NishiboriBritish Journal of Pharmacology 161 1 229 - 240 2010年09月
- Hideo Kohka Takahashi; Jiyong Zhang; Shuji Mori; Keyue Liu; Hidenori Wake; Rui Liu; Hiroshi Sadamori; Hiroaki Matsuda; Takahito Yagi; Tadashi Yoshino; Masahiro NishiboriJournal of Pharmacology and Experimental Therapeutics 334 3 964 - 972 2010年09月 [査読有り]
- J Zhang; HK Takahashi; K Liu; H Wake; R Liu; H Sadamori; H Matsuda; T Yagi; T Yoshino; S Mori; M NishiboriBritish Journal of Pharmacology 160 6 1378 - 1386 2010年07月
- Shuji Mori; Hidenori Wake; Keyue Liu; Hideo K Takahashi; Masahiro NishiboriNihon rinsho. Japanese journal of clinical medicine 68 Suppl 6 711 - 3 2010年06月 [査読有り]
- Katsuhisa Ohashi; Hideo Kohka Takahashi; Shuji Mori; Keyue Liu; Hidenori Wake; Hiroshi Sadamori; Hiroaki Matsuda; Takahito Yagi; Tadashi Yoshino; Masahiro Nishibori; Noriaki TanakaClinical Immunology 134 3 345 - 353 2010年03月 [査読有り]
- Hideo Kohka Takahashi; Keyue Liu; Hidenori Wake; Shuji Mori; Jiyong Zhang; Rui Liu; Tadashi Yoshino; Masahiro NishiboriJournal of Pharmacology and Experimental Therapeutics 332 3 1013 - 1021 2010年03月 [査読有り]
- Hideo Kohka Takahashi; Shuji Mori; Keyue Liu; Hidenori Wake; Jiyong Zhang; Rui Liu; Tadashi Yoshino; Masahiro NishiboriEuropean Journal of Pharmacology 627 1-3 313 - 317 2010年02月 [査読有り]
- Hideo Kohka Takahashi; Keyue Liu; Hidenori Wake; Shuji Mori; Jiyong Zhang; Rui Liu; Tadashi Yoshino; Masahiro NishiboriJournal of Pharmacology and Experimental Therapeutics 331 2 656 - 670 2009年11月 [査読有り]
- Hidenori Wake; Shuji Mori; Keyue Liu; Hideo K. Takahashi; Masahiro NishiboriEuropean Journal of Pharmacology 623 1-3 89 - 95 2009年11月 [査読有り]
- Wake Hidenori; Mori Shuji; Liu Keyue; Takahashi Hideo K.; Nishibori MasahiroActa Medica Okayama 63 5 249 - 262 Okayama University Medical School 2009年10月 [査読有り]
Angiogenesis involves complex processes mediated by several factors and is associated with inflammation and wound healing. High mobility group box 1 (HMGB1) is released from necrotic cells as well as macrophages and plays proinflammatory roles. In the present study, we examined whether HMGB1 would exhibit angiogenic activity in a matrigel plug assay in mice. HMGB1 in combination with heparin strongly induced angiogenesis, whereas neither HMGB1 nor heparin alone showed such angiogenic activity. The heparin-dependent induction of angiogenesis by HMGB1 was accompanied by increases in the expression of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor-A120 (VEGF-A120). It is likely that the dependence of the angiogenic activity of HMGB1 on heparin was due to the efficiency of the diffusion of the HMGB1-heparin complex from matrigel to the surrounding areas. VEGF-A165 possessing a heparin-binding domain showed a pattern of heparin-dependent angiogenic activity similar to that of HMGB1. The presence of heparin also inhibited the degradation of HMGB1 by plasmin in vitro. Taken together, these results suggested that HMGB1 in complex with heparin possesses remarkable angiogenic activity, probably through the induction of TNF-alpha and VEGF-A120.
- Hidenori Wake; Hideo Kohka Takahashi; Shuji Mori; Keyue Liu; Tadashi Yoshino; Masahiro NishiboriJournal of Pharmacology and Experimental Therapeutics 330 3 826 - 833 2009年09月 [査読有り]
- Liu Rui; Mori Shuji; Wake Hidenori; Zhang Jiyong; Liu Keyue; Izushi Yasuhisa; Takahashi Hideo K.; Peng Bo; Nishibori MasahiroActa Medica Okayama 63 4 203 - 211 Okayama University Medical School 2009年08月 [査読有り]
Interaction between the receptor for advanced glycation end products (RAGE) and its ligands has been implicated in the pathogenesis of various inflammatory disorders. In this study, we establish an in vitro binding assay in which recombinant human high-mobility group box 1 (rhHMGB1) or recombinant human S100A12 (rhS100A12) immobilized on the microplate binds to recombinant soluble RAGE (rsRAGE). The rsRAGE binding to both rhHMGB1 and rhS100A12 was saturable and dependent on the immobilized ligands. The binding of rsRAGE to rhS100A12 depended on Ca2 and Zn2, whereas that to rhHMGB1 was not. Scatchard plot analysis showed that rsRAGE had higher affinity for rhHMGB1 than for rhS100A12. rsRAGE was demonstrated to bind to heparin, and rhS100A12, in the presence of Ca2, was also found to bind to heparin. We examined the effects of heparin preparations with different molecular sizesunfractionated native heparin (UFH), low molecular weight heparin (LMWH) 5000Da, and LMWH 3000Da on the binding of rsRAGE to rhHMGB1 and rhS100A12. All 3 preparations concentration-dependently inhibited the binding of rsRAGE to rhHMGB1 to a greater extent than did rhS100A12. These results suggested that heparin's anti-inflammatory effects can be partly explained by its blocking of the interaction between HMGB1 or S100A12 and RAGE. On the other hand, heparin would be a promising effective remedy against RAGE-related inflammatory disorders.
- Hideo Kohka Takahashi; Shuji Mori; Hidenori Wake; Keyue Liu; Tadashi Yoshino; Katsuhisa Ohashi; Noriaki Tanaka; Kenichi Shikata; Hirofumi Makino; Masahiro NishiboriJournal of Pharmacology and Experimental Therapeutics 330 1 89 - 98 2009年07月 [査読有り]
- Keyue Liu; Shuji Mori; Hideo K. Takahashi; Yasuko Tomono; Hidenori Wake; Toru Kanke; Yasuharu Sato; Norihito Hiraga; Naoto Adachi; Tadashi Yoshino; Masahiro NishiboriThe FASEB Journal 21 14 3904 - 3916 2007年12月 [査読有り]
- H K Takahashi; H Iwagaki; R Hamano; H Wake; T Kanke; K Liu; T Yoshino; N Tanaka; M NishiboriBritish Journal of Pharmacology 150 6 816 - 822 2007年03月
- Akira Yokoyama; Shuji Mori; Hideo K. Takahashi; Toru Kanke; Hidenori Wake; Masahiro NishiboriEuropean Journal of Pharmacology 558 1-3 179 - 184 2007年03月 [査読有り]
- Shuji Mori; Hidenori Wake; Hideo K Takahashi; Masahiro NishiboriNihon rinsho. Japanese journal of clinical medicine 63 Suppl 7 640 - 2 2005年07月 [査読有り]
MISC
書籍等出版物
- 総合診療：知っておくべき！モノクロな薬たち徳田安春; 和氣秀徳 (担当:分担執筆範囲:モノクローナル抗体の歴史と作成方法)医学書院 2023年06月
- 堀内, 久徳; 西堀, 正洋; 和氣, 秀徳 (担当:分担執筆範囲:第５節 NETs)エル・アイ・シー 2021年09月 ISBN: 9784900487581 591p
- 革新的医療技術創出拠点プロジェクト平成28年度成果報告AMED 2017年
- 日本医療研究開発機構 臨床研究・治験推進研究事業 平成25-27年度事後報告書日本医療研究開発機構 2016年
- 日本医療研究開発機構 臨床研究・治験推進研究事業 平成27年度総括研究報告書日本医療研究開発機構 2016年
- 革新的医療技術創出拠点プロジェクト平成27年度成果報告日本医療研究開発機構 2016年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成26年度分担研究報告書厚生労働省 2015年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成26年度総括研究報告書厚生労働省 2015年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成25年度総括・分担研究報告書42014年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成25年度総括・分担研究報告書32014年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成25年度総括・分担研究報告書22014年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成25年度総括・分担研究報告書12014年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成21～23年度総合研究報告書未設定 2012年
- 厚生労働科学研究費補助金医療技術実用化総合研究事業 平成23年度総括研究報告書未設定 2012年
講演・口頭発表等
- 終末糖化産物によるSTINGシグナル調節はカルボニル化合物の種類や濃度に依存する西中 崇; ハティポール; オメル ファルク; 和氣 秀徳; 渡邊 政博; 豊村 隆男; 森 秀治; 西堀 正洋; 高橋 英夫第97回日本薬理学会年会 2023年12月 口頭発表（一般）
- TNFαはインテグリンα3-β8を介して血管内皮細胞の管腔形成を促進するハティポール オメル ファルク; 西中 崇; 和氣 秀徳; 西堀 正洋; 渡邊 政博; 豊村 隆男; 森 秀治; 高橋 英夫第97回日本薬理学会年会 2023年12月 ポスター発表
- 高ヒスチジン糖タンパク質は好中球恒常性維持に寄与する多面的機能を有する和氣 秀徳; 森 秀治; 西堀 正洋; 西中 崇; ハティポール; オメル ファルク; 高橋 英夫第97回日本薬理学会年会 2023年12月 ポスター発表
- 終末糖化産物AGEs共存化でのサイトカインによるTNF-α分泌の誘導効果豊村 隆男; 渡邊 政博; 和氣 秀徳; 西中 崇; ハティポール オメル・ファルク; 高橋 英夫; 西堀 正洋; 森 秀治第96回日本生化学会大会 2023年11月 ポスター発表
- 新規GLO1阻害剤による細胞増殖抑制作用の分子機能解析森 秀治; 渡邊 政博; 和氣 秀徳; 西中 崇; ハティポール オメル ファルク; 高橋 英夫; 西堀 正洋; 豊村 隆男第96回日本生化学会大会 2023年11月 ポスター発表
- ヒスタミンはEA.hy926血管内皮細胞のH1受容体を介して管腔形成を促進するハティポール オメル ファルク; 西中 崇; 和氣 秀徳; 西堀 正洋; 渡邊 政博; 豊村 隆男; 森 秀治; 高橋 英夫第96回日本生化学会大会 2023年11月 ポスター発表
- 血液系恒常性維持に密接に関与する多機能タンパクHistidine-rich glycoprotein和氣 秀徳; 西中 崇; ハティポール; オメル ファルク; 渡邊 政博; 豊村 隆男; 森 秀治; 西堀 正洋; 髙橋 英夫第96回日本生化学会大会 2023年10月 ポスター発表
- 抑制性DAMPsとしてのリボソーム構成分子RPL9の同定渡邊 政博; 豊村 隆男; 和氣 秀徳; 西中 崇; ハティポール; オメル ファルク; 高橋 英夫; 西堀 正洋; 森 秀治第141回日本薬理学会近畿部会 2022年
- Histamine induced high mobility group box-1 release from vascular endothelial cells through H1 receptorGao Shangze; 劉 克約; 王 登莉; 和氣 秀徳; 西堀 正洋第141回日本薬理学会近畿部会 2022年
- 神経障害性疼痛マウスにおける認知機能障害に対するHMGB1中和抗体の効果に関する検討吉本 夏輝; 中島 一恵; 大畑 一努; 中村 庸輝; 王 登莉; 劉 克約; 和氣 秀徳; 吾郷 由希夫; 西堀 正洋; 森岡 徳光第95回日本薬理学会年会 2022年
- 終末糖化産物3(AGE3) 長期間刺激はヒト軟骨細胞のアグリカンとⅡ型コラーゲン産生を低下させる。ハティポール オメル ファルク; 西中 崇; 和氣 秀徳; 森 秀治; 渡邊 政博; 豊村 隆男; 高橋 英夫第95回日本薬理学会年会 2022年
- マクロファージにおけるSTING経路に対する終末糖化産物の影響西中 崇; ハティポール; オメル ファルク; 和氣 秀徳; 渡邊 政博; 豊村 隆男; 西堀 正洋; 高橋 英夫第95回日本薬理学会年会 2022年
- Anti-DAMPsタンパク質HRGの敗血症治療薬としての可能性とDAMPs関連病態への応用和氣 秀徳第95回日本薬理学会年会 2022年
- 血管内皮細胞におけるAGEスカベンジと血管新生西中 崇; ハティポール; オメル ファルク; 和氣 秀徳; 森 秀治; 西堀 正洋; 高橋 英夫第94回日本薬理学会年会
- 終末糖化産物によるLPS－HMGB1共刺激炎症応答の相乗的活性化作用森 秀治; 渡邊 政博; 和氣 秀徳; 西中 崇; ハティポール オメル ファルク; 高橋 英夫; 西堀 正洋; 豊村 隆男第94回日本生化学会大会 2021年
- グリコールアルデヒド由来AGEsによる細胞増殖機構豊村 隆男; 渡邊 政博; 和氣 秀徳; 西中 崇; 逢坂 大樹; 王 登莉; 高橋 英夫; 西堀 正洋; 森 秀治第94回日本生化学会大会 2021年
- 敗血症病態改善作用を有する高ヒスチジン糖タンパク質の抗酸化能和氣 秀徳; 森 秀治; 西堀 正洋; 西中 崇; ハティポール オメル ファルク; 高橋 英夫第94回日本生化学会大会 2021年
- ADAMTS5の発現はヒト軟骨肉腫細胞においてNF-κβによってアップレギュレートされるハティポール オメル ファルク; Bilgic Dilek Gun; 西中 崇; 和氣 秀徳; 廣畑 聡; 高橋 英夫第94回日本生化学会大会 2021年
- マクロファージによるLPS細胞内取り込みに対する終末糖化産物の影響西中 崇; 北浦 淳寛; ハティポール; オメル ファルク; 和氣 秀徳; 森 秀治; 西堀 正洋; 高橋 英夫第139回日本薬理学会近畿部会 2021年
- 新規AGEs結合分子AGE-BP2がDAMPsの作用に与える影響の解析渡邊 政博; 豊村 隆男; 和氣 秀徳; 西中 崇; 逢坂 大樹; 王 登莉; 高橋 英夫; 西堀 正洋; 森 秀治第139回日本薬理学会近畿部会 2021年
- マウス周産期における血漿高ヒスチジン糖タンパクの生理的動態解析勅使川原; 匡; 劉 克約; 王 登莉; 和氣 秀徳; 森 秀治; 髙橋 英夫; 西堀 正洋第94回日本薬理学会年会 2021年
- パーキンソン病における痛覚過敏へのhigh mobility group box-1中和抗体の抑制効果佐藤 史爽; 中村 庸輝; 麻 思萌; 河内 貴弘; 中島 一恵; 王 登莉; 劉 克約; 和氣 秀徳; 西堀 正洋; 森岡 徳光第94回日本薬理学会年会 2021年
- 終末糖化産物結合因子によるLPS－HMGB1誘導性炎症応答の相乗的亢進作用森 秀治; 渡邊 政博; 和氣 秀徳; 劉 克約; 勅使川原; 高橋 英夫; 西堀 正洋; 豊村 隆男第94回日本薬理学会年会 2021年
- 新規AGEs結合分子AGE-BP2の作用の検討渡邊 政博; 豊村 隆男; 和氣 秀徳; 劉 克約; 勅使川原 匡; 高橋 英夫; 西堀 正洋; 森 秀治第138回日本薬理学会近畿部会 2020年
- HMGB1中和抗体はパーキンソン病モデルマウスに付随する疼痛を緩和する佐藤 史爽; 中村 庸輝; 麻 思萌; 河内 貴弘; 中島 一恵; 王 登莉; 劉 克約; 和氣 秀徳; 西堀 正洋; 森岡 徳光第138回日本薬理学会近畿部会 2020年
- AGEs結合因子の単離とAGEs-RAGE結合抑制領域の同定森 秀治; 渡邊 政博; 和氣 秀徳; 劉 克約; 勅使川原 匡; 高橋 英夫; 西堀 正洋; 豊村 隆男第93回日本生化学会大会 2020年
- 終末糖化産物AGE2による細胞増殖効果とTLR2による制御豊村 隆男; 渡邊 政博; 和氣 秀徳; 逢坂 大樹; 王 登莉; 高橋 英夫; 西堀 正洋; 森 秀治第93回日本生化学会大会 2020年
- HMGB1 中和抗体の局所投与はマウス遠位眼窩下神経慢性絞扼により発生する顔面感覚異常の発症を予防する河内 貴弘; 中村 庸輝; 中島 一恵; 劉 克約; 和氣 秀徳; 西堀 正洋; 入舩 正浩; 森岡 徳光第137回日本薬理学会近畿部会 2020年
- AGEsの共存がDAMPsの作用に与える影響の検討渡邊 政博; 豊村 隆男; 和氣 秀徳; 劉 克約; 勅使川原; 高橋 英夫; 西堀 正洋; 森 秀治第137回日本薬理学会近畿部会 2020年
- 脳卒中易発症性高血圧ラットにおいて血小板容積とリンパ球数の変化は脳卒中発症を予測するバイオマーカーである西中 崇; ハティポール; オメル ファルク; 和氣 秀徳; 森 秀治; 西堀 正洋; 高橋 英夫第137回日本薬理学会近畿部会 2020年
- HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes王 登莉; 劉 克約; 勅使川原; 匡; 和氣 秀徳; 西堀 正洋第137回日本薬理学会近畿部会 2020年
- 終末糖化産物結合因子の探索研究とAGEs-RAGE結合遮断領域の同定森秀治; 渡邊正博; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 豊村隆男第93回日本薬理学会年会 2020年
- 高ヒスチジン糖タンパク質は敗血症病態下における好中球の状態を制御する和氣秀徳; 森秀治; 髙橋英夫; 王登莉; 勅使川原匡; 西堀正洋第93回日本薬理学会年会 2020年
- 胎盤形成と妊娠期高血圧における血漿高ヒスチジン糖タンパクの生理的役割の解析勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 森秀治; 髙橋英夫; 西堀正洋第93回日本薬理学会年会 2020年
- HRGの作用により球状化した好中球の機能評価高橋陽平; 和氣秀徳; 勅使川原匡; 王登莉; 吉井將哲; 西堀正洋第93回日本薬理学会年会 2020年
- LPS エンドトキシン血症マウスに対する抗酸化ストレス抗体の保護効果喬寒棟; 高尚澤; 和氣秀徳; 劉克約; 勅使川原匡; 森秀治; 西堀正洋第93回日本薬理学会年会 2020年
- ラットの脳内出血および硬膜下出血に対する抗HMGB1抗体の治療効果王登莉; 劉克約; 和氣秀徳; 勅使川原匡; 森秀治; 西堀正洋第93回日本薬理学会年会 2020年
- 好中球様細胞におけるHistidine-Rich Glycoprotein(HRG)の効果吉井將哲; 和氣秀徳; 勅使川原匡; 王登莉; 劉克約; 髙橋陽平; 西堀正洋第93回日本薬理学会年会 2020年
- 脳卒中易発症性高血圧ラットにおいてリンパ球数と血小板容積の変動は脳卒中症状の発現よりも先行する西中崇; 丹羽淳子; 和氣秀徳; 森秀治; 西堀正洋; 髙橋英夫第93回日本薬理学会年会 2020年
- 眼窩下神経慢性絞扼モデルマウスに対する神経傷害部位へのHMGB1中和抗体投与は三叉神経領域における疼痛様行動を抑制する河内貴弘; 中村庸輝; 中島一恵; 劉克約; 和氣秀徳; 西堀正洋; 入舩正浩; 森岡徳光第93回日本薬理学会年会 2020年
- Histamine induced high mobility group box 1 release from vascular endothelial cells.Gao S; Wake H; Liu K; Wang D; Teshigawara K; Nishibori M第22回日本ヒスタミン学会 2020年
- AGEs結合因子の分子同定と炎症性サイトカイン発現応答への影響森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 豊村隆男第42回日本分子生物学会年会 2019年
- 終末糖化産物による炎症応答と細胞増殖反応豊村隆男; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 森秀治第42回日本分子生物学会年会 2019年
- Advanced glycation end products の細胞内取り込みによる血管新生の調節機構西中崇; 山崎由衣; 丹羽淳子; 和氣秀徳; 森秀治; 西堀正洋; 髙橋英夫第136回日本薬理学会近畿部会 2019年
- AGEs と炎症関連分子の共存が炎症反応に与える変化の検討渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 森秀治第136回日本薬理学会近畿部会 2019年
- 終末糖化産物AGE2による細胞増殖効果と遺伝子発現解析豊村隆男; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 森秀治第92回日本生化学会大会 2019年
- AGEs-Lf相互作用に基づく炎症性サイトカイン応答の変化森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 豊村隆男第92回日本生化学会大会 2019年
- High mobility group box-1 は三叉神経障害に起因する痛覚異常の発症に寄与する中村庸輝; 河内貴弘; 中島一恵; 劉克約; 和氣秀徳; 西堀正洋; 入船正浩; 森岡徳光生体機能と創薬シンポジウム2019 2019年
- AGEs結合因子としてのLfの同定とマクロファージTNF-α発現応答変化森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 豊村隆男第40回日本炎症・再生医学会 2019年
- Advanced glycation end products による血管新生促進機序に対するエンドサイトーシスの関与山﨑由衣; 西中崇; 丹羽淳子; 森秀治; 和氣秀徳; 劉克約; 西堀正洋; 髙橋英夫第135回日本薬理学会近畿部会 2019年
- マウス反復社会挫折ストレスによる社会忌避行動の誘導におけるHMGB1の役割北岡志保; 友廣彩夏; 請島慎也; 劉克約; 和氣秀徳; 勅使川原匡; 西堀正洋; 古屋敷智之第135回日本薬理学会近畿部会 2019年
- 炎症誘発活性を有する新規AGEs結合分子の同定渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 高橋英夫; 西堀正洋; 森秀治第135回日本薬理学会近畿部会 2019年
- HRGの作用により球状化したヒト好中球の貪食能解析高橋陽平; 和氣秀徳; 吉井將哲; 阪口政清; 劉克約; 勅使川原匡; 高橋英夫; 森秀治; 西堀正洋第135回日本薬理学会近畿部会 2019年
- 好中球様細胞におけるHistidine-Rich Glycoprotein(HRG)の影響吉井將哲; 和氣秀徳; 高橋陽平; 王登莉; 勅使川原匡; 西堀正洋第135回日本薬理学会近畿部会 2019年
- 周産期における高ヒスチジン糖タンパク(HRG)の生理的役割の解析勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第135回日本薬理学会近畿部会 2019年
- 高ヒスチジン糖タンパク遺伝子欠損マウスにおける妊娠高血圧、及び、胎盤形成異常の解析勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第92回日本内分泌学会学術総会 2019年
- Roles and mechanisms of neuroinflammation in stress and depression.Furuyashiki T; Ukeshima S; Kitaoka S; Nie X; Liu K; Wake H; Teshigawara K; Nishibori MAmerican College of Neuropsychopharmacology 2019年
- The role of HMGB1 in oral inflammation and regeneration.Yamashiro K; Ideguchi H; Aoyagi H; Yoshihara-Hirata C; Kawamura M; Yamasaki M; Kyoshima-Suzuki R; Yao Z; Hirai A; Wake H; Nishibori M; Yamamoto T; Takashiba A9th International DAMPs and Alarmins Symposium 2019年
- Roles of innate immune molecules in repeated stress-induced neuronal and behavioral changes.Kitaoka S; Tomohiro A; Ukeshima S; Liu K; Wake H; Teshigawara K; Nishibori M; Furuyashiki T9th International DAMPs and Alarmins Symposium 2019年
- Histidine-rich glycoprotein inhibits high mobility group box 1-mediated pathway in vascular endothelial cells.Gao S; Wake H; Sakaguchi M; Wang D; Mori S; Liu K; Teshigawara K; Gao Y; Takahashi H; Nishibori M9th International DAMPs and Alarmins Symposium 2019年
- Anti-HMGB1 mAb therapy for intracerebral and subdural hemorrhage in rats.Wang D; Liu K; Wake H; Teshigawara K; Mori S; Nishibori M9th International DAMPs and Alarmins Symposium 2019年
- Perineural treatment with anti-HMGB1 antibody alleviates trigeminal neuropathy in mouse with chronic constriction injury of distal infraorbital nerve.Kochi T; Nakamura Y; Hisaoka-Nakashima K; Liu K; Wake H; Nishibori M; Irifune M; Morioka N9th International DAMPs and Alarmins Symposium 2019年
- Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury.Nakajo M; Uezono N; Nakashima H; Wake H; Nishibori M; Nakashima K; Tanagushi N9th International DAMPs and Alarmins Symposium 2019年
- Enhanced M2 polarization of macrophage and angiogenesis by interleukin-18.Nishinaka T; Yamazaki Y; Niwa A; Wake H; Mori S; Yoshino T; Nishibori M; Takahashi H9th International DAMPs and Alarmins Symposium 2019年
- Advanced glycation end products interact with lactoferrin, and change the lactoferrin-stimulated proinflammatory cytokine response.Mori S; Watanabe M; Wake H; Teshigawara K; Liu K; Takahashi H; Nishibori M; Toyomura T9th International DAMPs and Alarmins Symposium 2019年
- AGEs-Lf相互作用によるマクロファージTNF-α発現応答の影響森秀治; 渡邊政博; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 豊村隆男日本薬学会第139年会 2019年
- 終末糖化産物が細胞増殖に与える影響豊村隆男; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 森秀治日本薬学会第139年会 2019年
- インターアルファインヒビタータンパクは好中球形態を制御し、活性酸素分子種産生を抑制することによって好中球の静穏状態を維持するSoe Soe Htwe; 和氣秀徳; 劉克約; 勅使川原匡; Barbara S.Stonestreet; Yaw-Pin Lim; 西堀正洋第92回日本薬理学会年会 2019年
- マクロファージにおけるscavenger receptors-1 class A を介した終末糖化産物の取り込み西中崇; 山﨑由衣; 丹羽淳子; 森秀治; 和氣秀徳; 西堀正洋; 髙橋英夫第92回日本薬理学会年会 2019年
- 終末糖化産物はラクトフェリンに結合し，ラクトフェリン誘導性TNF-α発現応答を抑制する森秀治; 渡邊政博; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 豊村隆男第92回日本薬理学会年会 2019年
- 高ヒスチジン糖タンパク遺伝子欠損マウスにおける妊娠高血圧の病態解析勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 森秀治; 髙橋英夫; 西堀正洋第92回日本薬理学会年会 2019年
- 血管内皮細胞のHMGB1信号経路におけるHistidine-rich glycoproteinの阻止作用高尚澤; 和氣秀徳; 高遠; 王登莉; 劉克約; 勅使川原匡; 西堀正洋第92回日本薬理学会年会 2019年
- Advanced glycation end products の血管新生機序への関与の解明山﨑由衣; 西中崇; 丹羽淳子; 森秀治; 和氣秀徳; 劉克約; 西堀正洋; 髙橋英夫第92回日本薬理学会年会 2019年
- Decrease in Histidine-Rich Glycoprotein as a Novel Biomarker to Predict Sepsis Among Systemic Inflammatory Response Syndrome.Kuroda K; Wake H; Mori S; Hinotsu S; Nishibori M; Morimatsu H第46回日本集中治療医学会学術集会 2019年
- ダメージ関連分子HMGB1の糖代謝制御への関与の検討兼森玄; 勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋西日本医学生学術フォーラム2018 2018年
- 終末糖化産物AGE3によるRAW264.7細胞の増殖亢進効果の発現豊村隆男; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 森秀治第41回日本分子生物学会年会 2018年
- TWEAK-終末糖化産物相互作用による内皮細胞応答の変化森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 豊村隆男第41回日本分子生物学会年会 2018年
- AGEsがラクトフェリンの作用に与える影響の解析渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 森秀治第134回日本薬理学会近畿部会 2018年
- 高ヒスチジン糖タンパク遺伝子欠損マウスにおける妊娠高血圧症候群様表現型の解析勅使川原匡; 劉克約; 兼森玄; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第134回日本薬理学会近畿部会 2018年
- 炎症惹起因子HMGB1の糖代謝制御に対する生理的役割の検討兼森玄; 勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第134回日本薬理学会近畿部会 2018年
- マクロファージによる終末糖化産物の取り込みに対する硫酸化多糖類の影響西中崇; 山﨑由衣; 丹羽淳子; 森秀治; 和氣秀徳; 西堀正洋; 髙橋英夫第134回日本薬理学会近畿部会 2018年
- Advanced glycation end products による血管新生促進機序の解明山﨑由衣; 西中崇; 丹羽淳子; 森秀治; 和氣秀徳; 西堀正洋; 髙橋英夫第134回日本薬理学会近畿部会 2018年
- 受容体欠損細胞を用いたDAMPs分子の機能解析渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 森秀治第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会 2018年
- 新規敗血症マーカーHistidine-rich glycoproteinの開発和氣秀徳; 森秀治; 王登莉; 勅使川原匡; 西堀正洋第91回日本生化学会大会 2018年
- 高ヒスチジン糖タンパク（histidine-rich glycoprotein, HRG）と結合親和性をもつ炎症関連血漿タンパクの探索解析勅使川原匡; 丹羽淳子; 衷輝; 和氣秀徳; 劉克約; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第91回日本生化学会大会 2018年
- AGEs-TWEAK相互作用による炎症応答の制御森秀治; 渡邊政博; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 豊村隆男第91回日本生化学会大会 2018年
- 抗HMGB1抗体による脳内出血の治療王登莉; 劉克約; 和氣秀徳; 勅使川原匡; 森秀治; 西堀正洋第41回日本神経科学大会 2018年
- TWEAK誘導性内皮細胞応答と終末糖化産物による抑制森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 髙橋英夫; 西堀正洋; 豊村隆男第39回日本炎症・再生医学会 2018年
- 遺伝子改変細胞を用いたDAMPs分子の作用メカニズム解析渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 森秀治第133回日本薬理学会近畿部会 2018年
- 高ヒスチジン糖タンパク(histidine-rich glycoprotein)遺伝子欠損マウスの妊娠期表現型の解析勅使川原匡; 劉克約; 和氣秀徳; 王登莉; 髙橋英夫; 森秀治; 西堀正洋第133回日本薬理学会近畿部会 2018年
- AGEs-RAGE間結合に影響を与える因子の同定と血管内皮細胞応答への影響森秀治; 渡邊政博; 和氣秀徳; 劉克約; 勅使川原匡; 髙橋英夫; 西堀正洋; 豊村隆男日本薬学会第138年会 2018年
- Novel understanding of sepsis pathophysiology based on dynamics of plasma protein histidine-rich glycoprotein and a proposal of treatment.Nishibori M; Wake H; Wang D; Teshigawara K; Mori SBIT's 8th Annual World Congress of Molecular & Cell Biology 2018年
- HMGB1 translocation induced by histamine in vascular endothelial cells in vitro.Nishibori M; Gao S; Gao Y; Wake H; Liu K; Teshigawara K; Mori SWorld Histamine Symposium 2018年
- Effects of histidine-rich glycoprotein on erythrocyte aggregation and hemolysis: implications for a role under septic conditions.Zhong H; Wake H; Liu K; Gao Y; Teshigawara K; Sakaguchi M; Mori S; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Effects of inter-alpha inhibitor proteins (IAIP) on neutrophil functions.Htwe SS; Wake H; Liu K; Teshigawa K; Stonestreet BS; Lim YP; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Anti-HMGB1 mAb therapy for intracerebral hemorrhage-induced brain injury in rats.Wang D; Liu K; Wake H; Teshigawara K; Mori S; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- The role of histidine-rich glycoprotein on immunothrombosis in septic organ failure.Wake H; Mori S; Teshigawara K; Liu K; Wang D; Gao Y; Takahashi HK; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Protective effects of histidine-rich glycoprotein on barrier dysfunction of vascular endothelial cells.Gao S; Gao Y; Wake H; Liu K; Teshigawara K; Mori S; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Protective effect of histidine rich glycoprotein (HRG) on human vascular endothelial cells.Gao Y; Wake H; Liu K; Teshigawara K; Nishibori M8th World Congress of Basic and Clinical Pharmacology 2018年
- Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice.Nishibori M; Fu L; Wake H; Wang D; Teshigawara K; Liu K; Takahashi HK; Mori S18th World Congress of Basic and Clinical Pharmacology 2018年
- Pathophysiological role of a factor affecting AGEs-RAGE interaction on endothelial cell responses.Mori S; Watanabe M; Wake H; Liu K; Teshigawara K; Takahashi H; Nishibori M; Toyomura T18th World Congress of Basic and Clinical Pharmacology 2018年
- The effects of histidine-rich glycoprotein on neutrophil-like differentiated cell lines.Yoshii Y; Wake H; Teshigawara K; Liu K; Wang D; Takahashi Y; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Characterization of histidine-rich glycoprotein (HRG) production under the experimental pathorogical conditions.Teshigawara K; Niwa A; Wake H; Wang D; Liu K; Mori S; Takahashi H; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Anti-high mobility group box-1 antibody therapy might prevent cognitive dysfunction after traumatic brain injury.Okuma Y; Liu K; Wake H; Teshigawara K; Mori S; Takahashi HK; Hirotsune N; Nishino S; Nishibori M18th World Congress of Basic and Clinical Pharmacology 2018年
- Decrease in histidine-rich glycoprotein as a novel prognostic biomarker for sepsis: multicenter prospective observational study.Kuroda K; Morimatsu H; Kawanoue N; Wake H; Mori S; Nishibori MIARS 2018 Annual Meeting and International Science Symposium 2018年
- Histidine-rich glycoprotein as a novel biomarker for sepsis: subgroup analysis of the time-dependent change.Kawanoue N; Morimatsu H; Kuroda K; Wake H; Mori S; Nishibori MIARS 2018 Annual Meeting and International Science Symposium 2018年
- AGEs-RAGE間相互作用に影響を与える生理活性因子の同定と性状森秀治; 渡邊政博; 和氣秀徳; 劉克約; 勅使川原匡; 高橋英夫; 西堀正洋; 豊村隆男2017年度生命科学系学会合同年次大会 2017年
- 破骨細胞分化抑制因子としてのSHIL004の機能解析豊村隆男; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 高橋英夫; 西堀正洋; 森秀治2017年度生命科学系学会合同年次大会 2017年
- ゲノム編集によるAGEsの作用メカニズム解析プラットフォームの構築渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 高橋英夫; 西堀正洋; 森秀治第132回日本薬理学会近畿部会 2017年
- AGEs親和性に基づくAGEs結合因子の同定と細胞応答変化森秀治; 渡邊政博; 和氣秀徳; 勅使川原匡; 劉克約; 高橋英夫; 西堀正洋; 豊村隆男第38回日本炎症・再生医学会 2017年
- 炎症性メディエーターHMGB1が歯槽骨治癒における血管新生の遺伝子発現を促進する青柳浩明; 山城圭介; 平田千暁; 井手口英隆; 河村麻理; 山崎睦代; 和氣秀徳; 山本直史; 西堀正洋; 高柴正悟第38回日本炎症・再生医学会 2017年
- AGEsによるTNF関連サイトカインの機能阻害メカニズムの解析渡邊政博; 豊村隆男; 和氣秀徳; 劉克約; 勅使川原匡; 高橋英夫; 西堀正洋; 森秀治第131回日本薬理学会近畿部会 2017年
- Histidine-rich glycoprotein (HRG)の好中球制御による敗血症治療薬の可能性 [通常講演]第132回日本薬理学会近畿部会 2017年
- Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. [通常講演]8th International DAMPs and Alarmins Symposium 2017年
- Anti-HMGB1 monoclonal antibody therapy for broad range of CNS injuries: development of humanized antibody. [通常講演]8th International DAMPs and Alarmins Symposium 2017年
- Histidine-rich glycoprotein as a novel prognostic blomarker for sepsis: multicenter prospective observational study. [通常講演]Sepsis2017 2017年
- Histidine-rich glycoprotein protects vascular endothelial cells and red blood cells in sepsis. [通常講演]Sepsis2017 2017年
- 抗HMGB1抗体はマウスのピロカルピン誘発痙攣におけるBBB破綻と脳内炎症からマウスを保護する [通常講演]第40回日本神経科学大会 2017年
- 動脈硬化・血栓症とDAMP/anti-DAMP [通常講演]第49回日本動脈硬化学会総会・学術集会 2017年
- Protective effects of histidine-rich glycoprotein on barrier function of vascular endothelial cells. [通常講演]第131回日本薬理学会近畿部会 2017年
- The role of histidine-rich glycoprotein on NETosis and immunothrombosis in septic condition [通常講演]第90回日本薬理学会年会 2017年
- Protective effects of histidine-rich glycoprotein (HRG) on vascular endothelial cells [通常講演]第90回日本薬理学会年会 2017年
- Histidine rich-glycoprotein regulates erythrocyte PS expression adherent and aggregation [通常講演]第90回日本薬理学会年会 2017年
- Effects of inter-alpha inhibitor proteins (IAIP) on the shape and reactive oxygen species (ROS) production in purified human neutrophils [通常講演]第90回日本薬理学会年会 2017年
- Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced epilepsy in mine [通常講演]第90回日本薬理学会年会 2017年
- Anti-HMGB1 therapy for intracerebral hemorrhage [通常講演]第90回日本薬理学会年会 2017年
- Protective effects of histidine-rich glycoprotein (HRG) on human vascular endothelial cells [通常講演]第90回日本薬理学会年会 2017年
- 非炎症分子SHILsはサイトカインとともに破骨細胞分化を調節する [通常講演]第39回日本分子生物学会年会 2016年
- AGEs結合因子によるAGEsシグナリングへの影響 [通常講演]第39回日本分子生物学会年会 2016年
- AGEsによるTNF関連分子の機能変化 [通常講演]第130回日本薬理学会近畿部会 2016年
- Anti-HMGB1 mAb attenuates cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats [通常講演]第130回日本薬理学会近畿部会 2016年
- 破骨細胞分化過程に対して非炎症分子SHILsが及ぼす影響 [通常講演]第89回日本生化学会大会 2016年
- AGEs親和性因子としての60S ribosomal proteinの単離 [通常講演]第89回日本生化学会大会 2016年
- 敗血症ARDSにおけるimmunothrombus形成に対する高ヒスチジン糖タンパク質の役割 [通常講演]第89回日本生化学会大会 2016年
- Damps関連サイトカインの機能に対するAGEsの影響 [通常講演]第89回日本生化学会大会 2016年
- AGEsがDamps関連サイトカインの機能に与える影響 [通常講演]第129回日本薬理学会近畿部会 2016年
- Endotoxemia併発急性膵炎に対するHistidine-rich glycoprotein(HRG)の動態及び治療効果 [通常講演]第129回日本薬理学会近畿部会 2016年
- Protective effects of histidine rich glycoprotein(HRG)on human vascular endothelial cells [通常講演]第129回日本薬理学会近畿部会 2016年
- Histidine rich glycoproteinの敗血症時好中球性微小循環障害に対する影響 [通常講演]第129回日本薬理学会近畿部会 2016年
- ラット脳内出血モデルにおける2次性炎症反応と抗HMGB1抗体効果 [通常講演]第37回日本炎症・再生医学会 2016年
- ビロカルピン誘導性てんかんモデルマウスにおける抗HMGB1抗体の炎症抑制効果 [通常講演]第89回日本薬理学会年会 2016年
- 敗血症時好中球微小循環イメージング [通常講演]第89回日本薬理学会年会 2016年
- 抗HMGB1抗体による脳内出血の治療 [通常講演]第89回日本薬理学会年会 2016年
- ストレプトゾトシン誘発糖尿病ラットにおけるAdvanced glycation end-productsの検出 [通常講演]第89回日本薬理学会年会 2016年
- ヒト血管内皮細胞におけるHistidine rich glycoprotein (HRG) の保護効果 [通常講演]第89回日本薬理学会年会 2016年
- Histidine-Rich Glycoprotein as a new Biomarker for Sepsis: Comparison to Procalcitonin and Prresepsin. [通常講演]SCCM 45th Critical Care Congress 2016年
- 敗血症性ARDSにおけるImmunothrombosis [通常講演]第89回日本薬理学会年会 2016年
- 新規敗血症治療薬と重症度判定マーカーの開発 [通常講演]技術情報協会セミナー 2016年
- 破骨細胞分化ステージ特異的な非炎症性物質SHIL002の効果 [通常講演]第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会 2015年
- AGEs-RAGE結合増大活性を示すHMGB1結合因子の探索 [通常講演]第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会 2015年
- HMGB1と相互作用するサイトカインに対するAGEsの影響 [通常講演]第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会 2015年
- 敗血症病態における微小循環障害に対する高ヒスチジン糖タンパク質の役割 [通常講演]第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会 2015年
- 高ヒスチジン糖タンパク質(HRG)の敗血症性immunothrombosis形成に対する影響 [通常講演]第128回日本薬理学会近畿部会 2015年
- LPS誘発性肺障害の炎症病態に対する可溶性Receptor for advanced glycation end-products(sRAGE)の役割 [通常講演]第128回日本薬理学会近畿部会 2015年
- Anti-HMGB1 therap for intracerebral hemorrhage [通常講演]7th International Symposium DAMPS and HMGB1 2015年
- The effects of anti-HMGB1 antibody on pilocarpine-induced epilepsy in mice [通常講演]7th International Symposium DAMPS and HMGB1 2015年
- Tissue factor(TF)誘発DICモデルにおけるHistidine-rich glycoprotein(HRG)の動態及び治療効果について [通常講演]第127回日本薬理学会近畿部会 2015年
- 敗血症病態における高ヒスチジン糖タンパク質（HRG）の好中球形態と微小循環に対する影響 [通常講演]第127回日本薬理学会近畿部会 2015年
- Histidine-Rich Glycoprotein as a Novel Prognostic Biomarker in Critically Ill Patients. [通常講演]Euroanaesthesia 2015 2015年
- SIRSにおける新たな重症度バイオマーカーとしてのHistidine-Rich Glycoprotein：前向き観察研究 [通常講演]日本麻酔科学会第62回学術集会 2015年
- Plasma levels of Histidine-Rich Glycoprotein in Critically Ill Patients [通常講演]IARS 2015 Annual meeting and International Science Symposium 2015年
- ラットリンパ節法によるALE特異モノクローナル抗体の作製 [通常講演]第88回日本薬理学会年会 2015年
- 高ヒスチジン糖タンパク質(HRG)の敗血症時血管内好中球流動性に対する効果 [通常講演]第88回日本薬理学会年会 2015年
- マクロファージによるadvanced glycation end products (AGEs)の細胞内取り込み [通常講演]第88回日本薬理学会年会 2015年
- ピロカルピン誘発性てんかんモデルマウスにおける抗HMGB-1抗体の効果 [通常講演]第88回日本薬理学会年会 2015年
- SIRS患者におけるHistidine-Rich Glycoproteinについて [通常講演]第42回日本集中治療医学会学術大会 2015年
- Production of ALE subspecies-specific monoclonal antibodies rats. [通常講演]The 88th Annual Meeting of The Japanese Pharmacological Society 2015年
- The effect of histidine rich glycoprotein on flow and adhesion of neutrophils in microvessels in septic condition [通常講演]The 88th Annual Meeting of The Japanese Pharmacological Society 2015年
- The phagocytosis of advanced glycation end products (AGEs) in marcrophages [通常講演]The 88th Annual Meeting of The Japanese Pharmacological Society 2015年
- The effects of anti-HMGB1 antibody on pilocarpine-induced epilepsy in mice [通常講演]The 88th Annual Meeting of The Japanese Pharmacological Society 2015年
- Histidine-rich glycoprotein prevents septic lethality through neutrophil regulation. [通常講演]SEPSIS 2014 2014年
- 循環好中球制御不全による敗血症性ARDSとHRG補充効果 [通常講演]第126回日本薬理学会近畿部会 2014年
- 好中球活性化制御に着目した敗血症病態解析と治療法開発 [通常講演]第87回日本生化学会大会 2014年
- 破骨細胞様細胞の分化培養における非炎症性物質の影響 [通常講演]第87回日本生化学会大会 2014年
- HMGB1結合因子によるAGEs-RAGE結合阻害解析 [通常講演]第87回日本生化学会大会 2014年
- AGEs結合親和性に基づいたAGEs遮断ペプチドの同定 [通常講演]第125回日本薬理学会近畿部会 2014年
- Endotoxin血症併発急性膵炎に対するHistidine Rich Grycoprotein (HRG) の効果 [通常講演]第125回日本薬理学会近畿部会 2014年
- 好中球の制御による敗血症、多臓器不全の治療法開発 [通常講演]BIO tech 2014 アカデミックフォーラム 2014年
- コラゲナーゼで誘発脳内出血モデルにおける抗HMGB1単クローン抗体の効果 [通常講演]第87回日本薬理学会年会 2014年
- 高ヒスチジン糖タンパク質（HRG）による敗血症治療の可能性 [通常講演]第87回日本薬理学会年会 2014年
- 炎症誘発因子HMGB1とインスリン抵抗性の関係についての検討 [通常講演]第87回日本薬理学会年会 2014年
- Receptor for advanced glycation end products と肺障害 [通常講演]第87回日本薬理学会年会 2014年
- 血漿蛋白HRGによる好中球制御と敗血症治療薬開発 [通常講演]第87回日本薬理学会年会 2014年
- 大学発敗血症治療開発の試み [通常講演]岡山朝日大学訪問会 2014年
- 大学発敗血症治療開発の試み [通常講演]第98回 岡山県医用工学研究会 2014年
- Anti-HMGB1 Monoclonal Antibody Therapy for Traumatic Brain Injury in Rats. [通常講演]Merinoff World Congress 2013：HMGB1 2013年
- Protection of BBB disruption in ischemic and traumatic injuries by anti-HMGB1 monoclonal antibody [通常講演]Signalling in the Blood-Brain Barriers 2013年
- マウスミクログリア細胞における炎症反応の憎悪化 [通常講演]第86回日本生化学会大会 2013年
- AGEs-RAGE相互作用に基づいた遮断物質探索系への応用 [通常講演]第86回日本生化学会大会 2013年
- マクロファージによるAdvanced glycation end productsの細胞内取り込み [通常講演]第123回日本薬理学会近畿部会 2013年
- グリチルリチンはHMGB1に結合し脳外傷を抑制する [通常講演]第123回日本薬理学会近畿部会 2013年
- Glycyrrhizin therapy for traumatic brain injury. [通常講演]Shanghai BRAIN 2013 2013年
- ヒトPBMC、マウス脾臓細胞におけるHMGB1活性が及ぼす細胞間相互作用の役割 [通常講演]第86回日本薬理学会年会 2013年
- ラットランゲルハンス島におけるadvanced glycation end-products の免疫組織化学的検出 [通常講演]第86回日本薬理学会年会 2013年
- ピルカルピンで誘発癲癇モデルにおける抗HMGB1単クローン抗体の効果 [通常講演]第86回日本薬理学会年会 2013年
- 高ヒスチジン糖タンパク質の好中球走化性に対する影響 [通常講演]第86回日本薬理学会年会 2013年
- 外傷性脳傷害に対する抗high mobility group box-1 (HMGB-1)抗体治療 [通常講演]第36回日本脳神経外傷学会 2013年
- Role of cell-cell interactions in HMGB1 activity in human PBMCs and mouse splenocytes [通常講演]The 86th Annual Meeting of The Japanese Phamacological Society 2013年
- Immunohistochemical detection of advanced glycation end-products in rat islets of Langerhans [通常講演]The 86th Annual Meeting of The Japanese Phamacological Society 2013年
- The effect of anti-HMGB1 antibody on pilocarpine-induced epilepsy in mice [通常講演]The 86th Annual Meeting of The Japanese Phamacological Society 2013年
- The effect of histidine rich giycoprotein on neutrophil chemotaxis [通常講演]The 86th Annual Meeting of The Japanese Phamacological Society 2013年
- HMGB1誘導性のヒト単球の活性化に対するヒスタミンの効果 [通常講演]第16回日本ヒスタミン学会 2012年
- Anti-high mobility group box-1 antibody therapy for traumatic brain injury [通常講演]Neuroscience 2012 2012年
- 頭部外傷モデルを用いた抗High Mobiliyt Group Box-1(HMGB1)抗体の神経保護効果の検討 [通常講演]第13回日本分子脳神経外科学会 2012年
- 抗HMGB1単クローン抗体によるラット頭部外傷モデルの治療 [通常講演]第35回日本神経科学大会 2012年
- 頭部外傷モデルを用いた抗HMGB1抗体の神経保護効果の検討 [通常講演]第121回日本薬理学会近畿部会 2012年
- マクロファ－ジによるAdvanced glycation end product(AGE)の細胞内取り込み [通常講演]第85回日本薬理学会年会 2012年
- ラットリンパ節細胞を用いた抗AGEモノクローナル抗体の作製 [通常講演]第85回日本薬理学会年会 2012年
- 高ヒスチジン糖タンパク質はHMGB1-ヘパリン複合体誘導血管新生を抑制する [通常講演]第85回日本薬理学会年会 2012年
- 虚血時のBBB透過性亢進を濾出したEvans blue/Albuminの追跡検討 [通常講演]第85回日本薬理学会年会 2012年
- 虚血時に脳神経細胞内HMGB1は、核からペルオキシソーム/ミトコンドリアに移動する [通常講演]第85回日本薬理学会年会 2012年
- Anti-high mobility group box-1 antibody therapy for traumatic brain injury [通常講演]Neuroscience 2012 2012年
- Anti-HMGB1 Antibody Therapy for Traumatic Brain lnjury [通常講演]The 13th Annual Meeting of the Japan Society of Molecular Neurosurgery 2012年
- Anti-High Mobility Group Box-1 Antibody for Traumatic Brain lnjury [通常講演]The 35th Annual Meeting of the Japan Neuroscience Society 2012年
- The intake of Advanced Glycation End products(AGEs) in macrophage [通常講演]The 85th Annual Meeting of the Japanese Pharmacological Society 2012年
- Production of AEG subspecies-specific monoclonal antibodies in rats [通常講演]The 85th Annual Meeting of the Japanese Pharmacological Society 2012年
- Histidine-rich glycoprotein inhibited high mobility group box 1 in complex with heparin-induced angiogenesis in matrigel plug assay [通常講演]The 85th Annual Meeting of the Japanese Pharmacological Society 2012年
- Tracking the Leakage of Albumin in BBB-disrupted ischemia [通常講演]The 85th Annual Meeting of the Japanese Pharmacological Society 2012年
- High Mobility Group Box-1 is Translocated from Nuclei into Peroxisomes / Mitochondoria in Neurons after lschemic lnsult [通常講演]The 85th Annual Meeting of the Japanese Pharmacological Society 2012年
- HRGのHMGB1-ヘパリン複合体誘導性血管新生調節機構 [通常講演]第120回日本薬理学会近畿部会 2011年
- 高ヒスチジン糖タンパク質はHMGB1-ヘパリン複合体誘導血管新生を抑制する [通常講演]第84回日本生化学会大会 2011年
- 抗HMGB1単クローン抗体はラット脳虚血による血液－脳関門の破錠を抑制する [通常講演]第34回日本神経科学大会－こころの脳科学－ 2011年
- 抗HMGB1単クローン抗体によるラットMCAO誘発脳梗塞の治療 [通常講演]第47回高血圧関連疾患モデル学会学術総会 2011年
- 抗HMGB1抗体は脳虚血誘発性の血液－脳関門破錠を防ぐ [通常講演]第119回日本薬理学会近畿部会 2011年
- HMGB1-ヘパリン複合体はVEGE-Aの発現を介して血管新生を誘導する [通常講演]第84回日本薬理学会年会 2011年
- 脳虚血早期におけるHMGB1の動態 [通常講演]第84回日本薬理学会年会 2011年
- Anti-HMGB1 monoclonal antibody protects BBB from ischemia-induced disruption in rats [通常講演]The 34th Annual Meeting of the Japan Neuroscience Society -Neuroscience of the Mind- 2011年
- 脳虚血早期におけるHMGB1の動態 [通常講演]第118回日本薬理学会近畿部会 2010年
- 移植術後糖尿病に対するヒスタミンの効果の基礎検討 [通常講演]第14回日本ヒスタミン学会 2010年
- Heparin regulates the HMGB1-induced angiogenesis in matrigel plug assay [通常講演]第14回国際免疫学会 2010年
- Anti-high mobility group box1 monoclonal antibody protects blood-brain barrier from [通常講演]第14回国際免疫学会 2010年
- Advanced glycation end products induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells [通常講演]第14回国際免疫学会 2010年
- Histidine-rich glycoprotein inhibits the angiogenic response induced by the combination of high mobility group box 1 and heparin in matrigel plug assay [通常講演]第16回国際薬理学会 2010年
- Prostaglandin E2 inhibits advanced glycation end products-induced activation of human monocytes [通常講演]第16回国際薬理学会 2010年
- Establishment of in vitro binding assay of HMGB1 and S100A12 to RAGE:Effects of heparin and domain peptides on the binding. [通常講演]第16回国際薬理学会 2010年
- Disruption of BBB in rat MCAO and a protective effect of anti-HMGB1 antibody [通常講演]第16回国際薬理学会 2010年
- Histamine inhibits advanced glycation end product-induced adhesion molecule [通常講演]第117回日本薬理学会近畿部会 2010年
- A novel anti-HMGB1 treatment for brain infarction: protection of BBB disruption [通常講演]第4回国際HMGB1学会 2010年
- ラット中大脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の効果：脳血管透過性亢進に対する影響 [通常講演]第83回日本薬理学会年会 2010年
- RAGEと急性肺障害 [通常講演]第83回日本薬理学会年会 2010年
- AGE-2とAGE-3誘導性のヒト単球の活性化に対するプロスタグランディンE2の効果 [通常講演]第83回日本薬理学会年会 2010年
- HMGB1, S100A12とRAGEの結合モデルに対するheparinの影響 [通常講演]第83回日本薬理学会年会 2010年
- 試験管内におけるHMGB1とsRAGE結合実験系の確立とHMGB1ドメインペプチドの効果の検討 [通常講演]第83回日本薬理学会年会 2010年
- HMGB1はヘパリン存在下で血管新生を誘導する [通常講演]第83回日本薬理学会年会 2010年
- 肺におけるReceptor for advanced glycation end productsの存在様式の検討 [通常講演]第116回日本薬理学会近畿部会 2009年
- Establishment of in vitro binding assay of HMGB1 and S100A12 to RAGE: heparin’s effect on the binding [通常講演]第116回日本薬理学会近畿部会 2009年
- AGE-2とAGE-3誘導性のヒト単球の活性化に対するプロスタグランディンE2の効果 [通常講演]第116回日本薬理学会近畿部会 2009年
- HMGB1はヘパリン依存的に血管新生を誘導する [通常講演]第82回日本生化学会大会 2009年
- AGE-2とAGE-3誘導性のヒト単球の活性化に対するヒスタミンの効果 －続報－ [通常講演]第13回日本ヒスタミン学会 2009年
- 脳虚血時におけるHMGB1動態の初期変化 [通常講演]第32回日本神経科学大会 2009年
- Early translocation and release of HMGB1 in ischemic brain in rats [通常講演]第115回日本薬理学会近畿部会 2009年
- ラット中大脳動脈閉塞・再灌流モデルにおけるBBB破綻と抗HMGB1抗体の効果 [通常講演]第82回日本薬理学会年会 2009年
- AGE-2とAGE-3によるヒト単球の活性化に対するヒスタミンの効果の検討 [通常講演]第82回日本薬理学会年会 2009年
- HMGB1-ヘパリン複合体誘導血管新生に対するHRGの血管新生抑制機構 [通常講演]第82回日本薬理学会年会 2009年
- 混合リンパ球培養下でのAGEによる接着分子発現とサイトカイン産生の検討 [通常講演]第82回日本薬理学会年会 2009年
- AGE－2とAGE －3誘導性のヒト単球の活性化に対するヒスタミンの効果 [通常講演]第12回日本ヒスタミン学会 2008年
- A Novel and effective antibody therapy for brain infarction targeting alarmin/HMGB1. [通常講演]EHRLICH Ⅱ-2nd World Conference on Magic Bullets, 2008 2008年
- A Novel Antibody drug for the treatment of acute brain infarction. [通常講演]Thrombolysis and Acute Stroke Therapy 2008 2008年
- アラーミン/HMGB1を標的とする新規脳梗塞治療法 [通常講演]第31回日本神経科学大会 2008年
- AGEサブタイプのヒト単球への効果の解析 [通常講演]第113回日本薬理学会近畿部会 2008年
- ラット中大脳動脈閉塞・再還流モデルにおけるBBBの破錠と抗HMGB1単クローン抗体の治療効果 [通常講演]第113回日本薬理学会近畿部会 2008年
- HMGB1誘導性血管新生を高ヒスチジン糖タンパク質は抑制する [通常講演]第113回日本薬理学会近畿部会 2008年
- ラット中脳動脈閉塞・再還流脳梗塞モデルにおける抗HMGB1単クローン抗体の治療効果 [通常講演]第81回日本薬理学会年会 2008年
- A Novel anti-inflammatory treatment of acute brain infarction by anti-HMGB1 monoclonal antibody. [通常講演]Neuroscience 2007 2007年
- 高ヒスチジン糖タンパク質の血管新生抑制効果 [通常講演]岡山大学学内COE第４回研究会 ～血管新生を巡る最新研究Ⅱ～ 2007年
共同研究・競争的資金等の研究課題
- 日本学術振興会：科学研究費助成事業研究期間 : 2025年04月 -2028年03月代表者 : 和氣 秀徳; 西中 崇; 高橋 英夫
- 日本学術振興会：科学研究費助成事業研究期間 : 2024年04月 -2027年03月代表者 : 西中 崇; 高橋 英夫; 和氣 秀徳; ハティポール オメル・ファルク
- 日本学術振興会：科学研究費助成事業研究期間 : 2024年04月 -2027年03月代表者 : ハティポール オメル・ファルク; 西中 崇; 高橋 英夫; 和氣 秀徳; 西田 圭一郎; 廣畑 聡
- 日本学術振興会：科学研究費助成事業研究期間 : 2023年04月 -2026年03月代表者 : 高橋 英夫; 西中 崇; 和氣 秀徳; ハティポール オメル・ファルク
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2021年04月 -2024年03月代表者 : ハティポール オメル・ファルク; 西中 崇; 高橋 英夫; 和氣 秀徳; 西田 圭一郎; 廣畑 聡Damage-Associated Molecular Patterns(DAMPs)は細胞ストレスに伴い放出される内因性免疫応答調節因子である。過剰なDAMPsの生成は、炎症の遷延化や増悪を促す。慢性炎症性疾患の病変部位では、血管新生を伴うリモデリングが誘導され、病態増悪の本態として考えられている。その機序として、DAMPsと炎症性メディエーターの相互作用によるマクロファージ(MΦ)の過剰な活性化が関与することが示唆されている。本研究では、慢性炎症性病態であるアレルギー性炎症に焦点をあて、その病態形成に関与するDAMPsのInterleukin-33(IL-33)と炎症性メディエーターのヒスタミンによる血管新生に対する影響について解析を行った。 ヒト血管内皮細胞株EA.hy926細胞を用いたin vitro実験系において、ヒスタミンはIL-33の発現量を増加させることを確認した。ヒスタミンによるIL-33発現量の増加作用は、ヒスタミンH1受容体が関与することを明らかにした。 さらに、マトリゲルを用いたin vitro血管新生実験モデルにおいて、ヒスタミンはヒスタミンH1受容体を介して管腔形成を促進させることを見出した。ヒスタミンにより血管内皮増殖因子(vascular endothelial growth factor、VEGF)の発現上昇が認められたが、ヒスタミンによる管腔形成促進作用はVEGF受容体の阻害剤では抑制されなかった。したがって、ヒスタミンはVEGFとは異なる機序を介して血管新生を促進する可能性が示唆された。
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2020年04月 -2023年03月代表者 : 和氣 秀徳; 勅使川原 匡; 王 登莉前回、二価鉄が血管内皮細胞の細胞膜脂質過酸化により細胞死を誘導し、HRGはこれをほぼ完全に抑制することを明らかにしていたが、今回更に、ネクロプトーシスに関与するMLKLに対する阻害剤やアポトーシス、パイロトーシスに関与するカスパーゼに対する阻害剤を用いた研究により、二価鉄誘導細胞死はネクロプトーシス、アポトーシス、及びパイロトーシスではないということが明らかとなった。更に、二価鉄の細胞死誘導にはミトコンドリアが中心的な役割を担っていることを明らかにした。つまり、二価鉄はミトコンドリアを障害し、ミトコンドリア膜電位の低下やスーパーオキサイドの産生が引き起こされることにより細胞死が起こっていることが分かった。この結果から、二価鉄はミトコンドリアを障害することで、活性酸素の産生や、細胞エネルギー産生の低下を引き起こし、細胞死が誘導されると推察された。また、HRGはこのミトコンドリア障害をほぼ完全に防ぐことより、HRGの作用点はミトコンドリアより前の段階であることが示唆された。さらに、HRGレセプターと考えられているCLEC1A及びCLEC1Bに対する中和抗体を用いた実験において、HRGの二価鉄細胞死阻害効果は阻害されなかったため、今回のHRG作用にはCLEC1A及びCLEC1Bは関与していないことが明らかとなった。加えて、HRGの血管内皮細胞表面上のグリコカリックスの状態に対する影響に関しては、前回、インビボイメージングにより、マウスの血管内皮細胞表面グリコカリックスの状態を評価した結果、血中のHRGがLPSによるグリコカリックスの剥離を抑制する効果を有することを明らかにしていたが、LPSによるグリコカリックスの剥離が好中球や血小板の血管内皮細胞への接着を促進し、HRGがそれら接着反応を抑制することを新たに明らかとした。
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2019年04月 -2022年03月代表者 : 勅使川原 匡; 西堀 正洋; 和氣 秀徳; 王 登莉; 劉 克約近年、臨床研究において妊娠期の血漿高ヒスチジン糖タンパク（histidine-rich glycoprotein, HRG）の過剰な減少が、妊娠高血圧症候群（HDP）の進展と相関することが報告されている。本研究では、健常妊娠マウスにおける血漿HRGタンパクの減少が、子宮組織（胎盤）由来のプロテアーゼによることを明らかとした。さらに、妊娠期のHRG遺伝子欠損（HRG KO)マウスは、高血圧、胎盤の過形成、トロホブラストの血管リモデリング障害などのHDP様病態を呈していた。これらの結果から、血漿HRGは、HDPの発症原因である可能性が示唆された。
- 日本学術振興会：科学研究費助成事業 基盤研究(B)研究期間 : 2019年04月 -2022年03月代表者 : 西堀 正洋; 和氣 秀徳; 勅使川原 匡; 阪口 政清; 逢坂 大樹; 王 登莉組織傷害関連分子群（DAMPs）の代表である核内因子HMGB1の刺激依存的な動態を培養血管内皮細胞EA.hy926を用いて明らかにした。 ヒスタミンは、血管内皮細胞上のH1-受容体に働き、HMGB1のトランスロケーションと分泌を誘導した。H1-選択的アゴニストはヒスタミンの作用を模倣することができた。肥満細胞の刺激薬compound 48/80で誘導されたラットアナフィラキシーショックは、抗HMGB1抗体による治療で軽減された。LPSならびにTNF-α刺激は同様にHMGB1トランスロケーションと細胞外分泌を生じさせたが、抗HMGB1抗体の添加でサイトカイン産生とともに顕著に抑制された。
- 血液・血球-血管内皮細胞インターフェイスの恒常性維持機構と網羅的新規創薬寺岡記念育英会：医学研究活動費助成事業研究期間 : 2019年04月 -2020年03月
- 敗血症治療のためのHRG血液製剤の創出日本医療研究開発機構 (AMED)：医療分野研究成果展開事業研究期間 : 2017年10月 -2020年03月代表者 : 西堀正洋; 和氣秀徳; 阪口政清; 宝田剛志; 勅使川原匡; 王登莉; 森松博史; 吉田道弘; 伊藤浩和; 上園昭人; 村上弘次; 前野英毅; 須加智也; 小林不二夫; 福永裕樹
- 日本学術振興会：科学研究費助成事業 若手研究(B)研究期間 : 2017年04月 -2020年03月代表者 : 和氣 秀徳Cecal ligation and puncture(CLP)敗血症モデルは、非常に結果のばらつきが大きく解析が困難であると判断し、今回から、よりばらつきの少ないLipopolysaccharide(LPS)誘発敗血症モデルを採用することとした。また、RNAiによるHistidine-rich glycoprotein(HRG)ノックダウンの手法は費用対効果が低い為、HRGノックアウトマウスを使用することとした。上記のモデル及びマウスを用いて、HRGの有無による腸間膜血管内の免疫血栓形成(Immunothrombosis)や血管内皮障害に対する影響を好中球、血小板および血管内皮を染め、生きたままイメージングをすることで調べた。HRGノックアウトマウスは野生型マウスと比べて有意に腸管膜血管内免疫血栓形成が亢進し、血管内皮細胞も障害されることが明らかとなり、この結果はHRGが敗血症病態下の免疫血栓形成調節に非常に重要な役割を担っていることを示唆している。 また、敗血症病態形成において鍵となる肺における免疫血栓形成および肺障害に対するHRGの作用を明らかにする為に必要となってくる肺のin vivoイメージング手法を確立した。肺をイメージングする時、ⅰ)肺を露出すると呼吸が困難となり動物が死亡しイメージングできない。ⅱ)肺が呼吸により動くと焦点を合わせられない。という２点の問題に対して、人工呼吸器を導入し、露出した肺の一部をカバーガラスに生体接着剤で固定し、そのカバーガラスを顕微鏡のステージに固定するという手法により解決した。 さらに、敗血症における免疫血栓形成を誘導すると考えられる細菌由来ポリリン酸とHRGが結合することを見出し、このポリリン酸がHRGの好中球正球化作用や細胞外活性酸素放出抑制作用と拮抗することを明らかにした。
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2016年04月 -2019年03月代表者 : 勅使川原 匡; 西堀 正洋; 高橋 英夫; 丹羽 淳子; 劉 克約; 和氣 秀徳血漿高ヒスチジン糖タンパク（HRG）の炎症病態における肝HRG遺伝子発現、及び、血漿HRGタンパクの抗炎症作用の解析をおこなった。複数種の慢性・急性炎症モデルを用いて肝遺伝子発現を網羅的に解析したところ、HRG遺伝子の発現変動と相関・逆相関する核内タンパク遺伝子を計14種同定した。これら候補遺伝子には、HRGの遺伝子発現を制御する因子が含まれる可能性が高い。また、敗血症モデルの血漿を用いたプロテオーム解析によって、HRGと結合親和性をもつ血漿タンパクを計3種同定した。これら同定タンパクは、すべて炎症病態に関与する因子であり、その炎症応答機序はHRGによって制御される可能性が示唆された。
- 日本学術振興会：科学研究費助成事業 基盤研究(B)研究期間 : 2015年04月 -2018年03月代表者 : 西堀 正洋; 白井 敦; 勅使川原 匡; 劉 克約; 森 秀治; 高橋 英夫; 和氣 秀徳敗血症は感染症に伴う重篤な臓器障害の病態であり、世界的に死因の上位を占め続けている。敗血症の新規開発薬物は過去数十年継続されてきたが、有効な薬物は何一つ見出されることがなかった。本研究では、申請者が見出した敗血症時の血漿タンパクHistidine-rich glycoprotein (HRG) の低下を原因とする免疫血栓の形成の機序を解明し、HRGの補充療法が如何にしてその病態を改善するかを明らかにした。敗血症病態に関与する細胞として、好中球や血管内皮細胞に加え、赤血球の重要性を実験データに基づき指摘した。マウスモデルにおいてHRG補充療法は、敗血症性ARDS病態に対し有効である。
- 日本学術振興会：科学研究費助成事業 若手研究(B)研究期間 : 2016年04月 -2018年03月代表者 : 山城 圭介; 青柳 浩明; 井手口 英隆; 高知 信介; 山本 直史; 高柴 正悟; 和氣 秀徳; 西堀 正洋High mobility group box 1（HMGB1）は，DNA結合タンパク質であるが，組織の損傷や壊死によって細胞外へ分泌された場合，炎症メディエーターとして機能する。HMGB1が歯周炎の進行にどのように影響を及ぼすか，その詳細なメカニズムは未だ明らかになっていない。本研究の結果，炎症刺激により歯肉上皮細胞，マクロファージ様細胞からHMGB1が産生されることが明らかとなった。また，歯周炎モデルマウスに抗HMGB1抗体を投与することで，歯周炎による炎症は抑制される。その結果，好中球の遊走，IL-1βの産生などが抑制され，歯周炎による骨吸収が抑制されることが明らかとなった。
- 新規敗血症重症度判定マーカーと治療薬の創出岡山大学：岡山大学次世代研究コア形成事業研究期間 : 2017年11月 -2018年02月
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2013年04月 -2016年03月代表者 : 勅使川原 匡; 西堀 正洋; 寺田 整司; 劉 克約; 和氣 秀徳βアミロイドの蓄積によって発症するアルツハイマー病(AD)を慢性炎症疾患と捉え、AD病態の機序解明を目指した。加齢や高血糖で増加する終末糖化産物(AGE)の受容体(RAGE)を介した炎症反応が、AD患者の血中βアミロイドや抗RAGE自己抗体によって相乗的に亢進させられることがAD病態の主要因であるという病態仮説を新規提唱し、これについて検討した。AD患者において、血漿中の抗RAGE自己抗体価が高値を示すことを見出したが、白血球のβアミロイドによる炎症活性を示すには至らなかった。今後、AD患者の血漿検体を用いて主要な炎症関連因子群の産生量を解析し、AD患者の炎症活性病態について再検討していく。
- 日本学術振興会：科学研究費助成事業 基盤研究(B)研究期間 : 2012年04月 -2015年03月代表者 : 西堀 正洋; 伊達 勲; 髙橋 英夫; 劉 克約; 和氣 秀徳; 勅使川原 匡ラット脳硬膜上から加えた液体衝撃により作製した脳外傷では、大脳半球の広範な領域に脳血管の透過性亢進を生じ、脳浮腫が惹起された。受傷局所では神経細胞の核内に局在しているHMGB1が細胞質領域から細胞外に放出された。同領域では、血液脳関門の構造破綻とミクログリア細胞の活性化像ならびに細胞数の増加が認められ、炎症性サイトカインの発現が上昇していた。以上の外傷誘発性の炎症応答は、抗HMGB1抗体の受傷後投与により85％抑制された。HMGB1と結合する生薬甘草中活性成分グリチルリチンは、抗体と類似の作用を示した。同様に、マウスの脊髄損傷モデルで抗HMGB１抗体は運動麻痺症状を著明に改善することができた。
- 日本学術振興会：科学研究費助成事業 若手研究(B)研究期間 : 2011年 -2013年代表者 : 和氣 秀徳; 西堀 正洋; 劉 克約; 高橋 英夫; 森 秀治腫瘍細胞株をマウスの背部皮下に移植した担癌マウスに浸透圧ポンプを用いて、抗HMGB1モノクローナル抗体を持続投与したところ、コントロールと比較して抗HMGB1抗体投与群において、有意に腫瘍増殖の抑制が見られた。また、抗HMGB1抗体投与群の腫瘍組織中の新生血管密度がコントロールと比較して有意に減少していた。しかしながら、免疫不全マウスを用いた担癌マウスモデルでは、抗HMGB1抗体に抗腫瘍効果は認められなかったため、抗HMGB1抗体の抗腫瘍効果は直接的な作用ではなく、リンパ球等を介した免疫反応による効果である可能性も示唆された。
- 日本学術振興会：科学研究費助成事業 挑戦的萌芽研究研究期間 : 2011年 -2012年代表者 : 西堀 正洋; 劉 克約; 和氣 秀徳; 大熊 佑High mobility group box-1(HMGB1)は、組織障害に由来する炎症惹起物質として、今大きな注目を集めている。研究者は、これまで取り組んできた脳虚血や脳血管攣縮に対する抗 HMGB1抗体の治療効果に大きなヒントを得て、現在治療法のない交通事故や転落事故後の脳外傷に対する抗体治療の応用について検討した。 その結果、ラットの脳外傷後に局所の神経細胞の核から細胞外へと HMGB1 が放出されること、HMGB1 の活性を抗 HMGB1 抗体の投与で中和すると、血管-脳関門の破綻が抑制され、脳浮腫を著明に抑制できることを実験的に証明した。抗 HMGB1 抗体による脳外傷治療は有望である。
- 日本学術振興会：科学研究費助成事業 基盤研究(B)研究期間 : 2009年 -2011年代表者 : 西堀 正洋; 劉 克約; 和氣 秀徳; 高橋 英夫Damage-associated molecular patternであるHigh mobility groupbox-1(HMGB1)は、虚血脳神経細胞や脳外傷局所の神経細胞核から細胞質を経て細胞外へ放出された。放出されたHMGB1は、血管内皮細胞、周皮細胞に働き、収縮性反応を誘導して脳血管透過性を亢進させた。HMGB1由来ペプチドに、低血圧誘導その他の活性を見出した。抗HMGB1単クローン抗体は脳外傷時の脳血管透過性亢進と炎症反応を抑制した。
- 日本学術振興会：科学研究費助成事業 基盤研究(C)研究期間 : 2009年 -2011年代表者 : 劉 克約; 西堀 正洋; 和氣 秀徳; 高橋 英夫High mobility group box1(HMGB1)は、壊死細胞核から細胞外へ放出される新規サイトカイン分子である。申請者は、HMGB1を標的とする抗体医薬を発想し、すでにラット中大脳動脈2時間閉塞・再灌流モデルを用いて、抗HMGB1単クローン抗体の劇的な脳梗塞の改善、脳浮腫の抑制作用を明らかにしてきた。虚血再灌流の脳障害に対して、抗HMGB1抗体はBBB構造・機能の保護を中心として多数の炎症応答反応を抑制することで、脳梗塞の進行を止め、脳を保護したことを解明した。
産業財産権
- 特許7340862:好中球貪食能増強剤西堀正洋, 和氣秀徳, 高橋陽平, 森秀治, 阪口政清
- 特許7340192:抗炎症作用を有する新規単クローン抗体西堀正洋, 森秀治, 森岡祐太, 和氣秀徳, 友野靖子
- 特許6983420:赤血球保護剤西堀正洋, 和氣秀徳, 衷輝, 森秀治, 阪口政清 国立大学法人 岡山大学
- サイトカインストーム抑制剤
- 特許EP.2859898.B1:好中球活性化に起因する疾患の治療薬、治療方法及び検査方法(欧州)
- 特許US.9696321.B2:好中球活性化に起因する疾患の治療薬、治療方法及び検査方法(米国)
- 特願JP.5807937.B2:好中球活性化に起因する疾患の治療薬、治療方法及び検査方法(国内)
- 特許JP.6227601.B2:好中球活性化に起因する疾患の治療薬、治療方法及び検査方法(国内)5807937
- 特許US.9504731.B2:好中球活性化に起因する疾患の治療薬、治療方法及び検査方法(米国)
- 好中球活性化調節剤
- 特許6154135:外傷性神経障害治療剤(WIPO)
- RAGEとAGEの結合抑制剤のスクリーニング方法(WIPO)
- 外傷性神経障害治療剤
- RAGEとAGEの結合抑制剤のスクリーニング方法
- ＲＡＧＥとＡＧＥの結合抑制剤のスクリーニング方法5904945
- 好中球活性化に起因する疾患の治療薬、治療方法及び検査方法9504731
- THERAPEUTIC AGENT, TREATMENT METHOD AND TEST METHOD FOR DISEASES ASSOCIATED WITH ACTIVATION OF NEUTROPHILS9504731
その他
- 2024年04月 - 2025年03月 HRGを起点とした敗血症病態解析の新しいカッティングエッ ジと創薬ヘの応用近畿大学学内研究助成金 研究種目：一般研究助成金 課題番号：IP007 研究内容：申請者は Histidine-rich glycoprotein (HRG) が、生体恒常性の維持において極めて重要な働きをする血漿タンパクであることを証明してきた。特に敗血症病態では、血漿HRGの低下が全身性の好中球を基点とした免疫血栓形成を引き起こし、多臓器不全の惹起を通じ死につながることを解明した。しかしながら、敗血症病態の理解において重要となる血管内皮細胞障害とHRG作用の詳しいメカニズムについては明らかとなっていない。本研究では、敗血症病態における血管内皮細胞障害とHRGの血管内皮細胞保護効果の本態を解明する。特に、敗血症病態において様々な傷害細胞から放出されるDamage-associated molecular patterns (DAMPs) (HMGB1, IL-33, Heme, Fe2+) や炎症性サイトカイン(TNF-α)、さらに感染細菌由来のPathogen-associated molecular patterns (PAMPs) (LPS) による血管内皮細胞障害の本態を明らかにすると共に、HRGの血管内皮細胞保護効果の詳細なメカニズムの解明を目的として行う。また、申請者らが同定したHRGレセプターとの関係性についても明らかにする。これらの研究成果は敗血症病態のより正しい理解と新たな敗血症治療薬の開発に寄与する。また、敗血症は老若男女、先進国、途上国問わず死亡率が高く、全世界で解決すべき課題の一つである。従って、敗血症の治療法を確立することは全ての人の健康に多大な貢献するものである。
- 2021年04月 - 2024年03月 病の根源「DAMPs/PAMPs」を制御するAnti-DAMPs/PAMPsの網羅的機能解析とDAMPs/PAMPs関連病態治療法開発近畿大学学内研究助成金 研究種目：21 世紀研究開発奨励金【共同研究助成金】 課題番号：KD2102 研究内容：申請者はDamage-associated molecular patterns (DAMPs) の代表分子であるHigh mobility group box 1 (HMGB1) の各種病態における起炎性作用を解明し、抗HMGB1 単クローン抗体による新規治療法開発を行った。これら一連の研究において、HMGB1と結合性を有し拮抗作用を発揮する因子として世界で初めてHistidine-rich glycoprotein (HRG) を同定し、HRGが生体恒常性の維持において極めて重要な働きをする血漿タンパクであることを証明してきた。特に敗血症病態では、血漿HRGの低下が全身性の好中球を基点とした免疫血栓形成を引き起こし、多臓器不全の惹起を通じ死につながることを解明した。また、申請者はHRGがHMGB1以外の複数のDAMP分子 (Reactive oxygen spices (ROS), Heme, Fe2+) やPathogen-associated molecular pattern (PAMP) 分子 (Lipopolysaccharide (LPS), Polyphosphate (PolyP)) に対して阻害作用を有することも明らかにしており、この阻害活性より、HRGをanti-DAMPs/PAMPs分子であると定義付けた。さらに、申請者はHRGと類似の活性を持つ内因性因子群 (Inter-alpha inhibitor protein (IAIP), Antithrombin III (ATIII), Lactoferrin) も見出しており、これらの anti-DAMPs/PAMPs分子以外にも、新たなanti-DAMPs/PAMPs分子が生体内に存在している可能性がある。そこで、本研究では、HRGのDAMPs/PAMPs関連病態への作用メカニズムを解明するとともに、DAMPs/PAMPs関連病態モデル動物サンプルを用いて、新たなanti-DAMPs/PAMPs分子を探索し、その分子の生体に対する作用に関しても解析する。DAMPs/PAMPsは多くの炎症病態と関連があり、 anti-DAMPs/PAMPs分子はこれら病態の治療薬となる可能性を秘めている。
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