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| 1 | Dual therapy with zinc acetate and rifaximin prevents from ethanolinduced liver fibrosis by maintaining intestinal barrier integrity显示文摘BACKGROUND Hepatic overload of gut-derived lipopolysaccharide dictates the progression of alcoholic liver disease(ALD)by inducing oxidative stress and activating Kupffer cells and hepatic stellate cells through toll-like receptor 4 signaling.Therefore,targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of ALD.Zinc acetate and rifaximin,which is a nonabsorbable antibiotic,had been clinically used for patients with cirrhosis,particularly those with hepatic encephalopathy,and had been known to improve intestinal barrier dysfunction.However,only few studies focused on their efficacies in preventing the ALD-related fibrosis development.AIM To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD model.METHODS To induce ALD-related liver fibrosis,female C57BL/6J mice were fed a 2.5%(v/v)ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbon tetrachloride(CCl4)injection twice weekly(1 mL/kg)for 8 wk.Zinc acetate(100 mg/L)and/or rifaximin(100 mg/L)were orally administered during experimental period.Hepatic steatosis,inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular analyses.Moreover,the direct effects of both agents on Caco-2 barrier function were assessed by in vitro assays.RESULTSIn the ethanol plus CCl4-treated mice,combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4.This combination significantly inhibited the Kupffer cells expansion and the proinflammatory response with blunted hepatic exposure of lipopolysaccharide and the toll-like receptor 4/nuclear factor kB pathway.Consequently,liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2,-9,-13,and Timp1.Both agents improved the atrophic changes and permeability in the ileum,with restoration of tight junction proteins(TJPs)by decreasing the expressions of tumor necrosis factorαand myosin light chain kinase.In the in vitro assay,both agents directly reinforced ethanol or lipopolysaccharide-stimulated paracellular permeability and upregulated TJPs in Caco-2 cells.CONCLUSION Dual therapy with zinc acetate and rifaximin may serve as a strategy to prevent ALD-related fibrosis by maintaining intestinal barrier integrity. | Yuki Fujimoto Kosuke Kaji Norihisa Nishimura Masahide Enomoto Koji Murata Soichi Takeda Hiroaki Takaya Hideto Kawaratani Kei Moriya Tadashi Namisaki Takemi Akahane Hitoshi Yoshiji | 2021 | World Journal of Gastroenterology2021，27，48： | 4 |
| 2 | Combination of sorafenib and angiotensin-II receptor blocker attenuates preneoplastic lesion development in a non-diabetic rat model of steatohepatitis显示文摘 | Hitoshi Yoshiji Ryuichi Noguchi Tadashi Namisaki Kei Moriya Mitsuteru Kitade Yosuke Aihara Akitoshi Douhara Hideto Kawaratani Norihisa Nishimura Hiroshi Fukui | 2014 | Journal of Gastroenterology2014，，： | 1 |
| 3 | DNA methylation of angiotensin Ⅱ receptor gene in nonalcoholic steatohepatitis-related liver fibrosis显示文摘AIM To clarify whether Agtr1 a methylation is involved in the development of nonalcoholic steatohepatitis(NASH)-related liver fibrosis in adult rats.METHODS A choline-deficient amino acid(CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis.Agtr1 a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid(CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR.Hepatic stellate cells(HSCs) were isolated by collagenase digestion of the liver,followed by centrifugation of the crude cell suspension through a density gradient.Agtr1 a methylation and its gene expression were also analyzed during the activation of HSCs.RESULTS The mean levels of Agtr1 a methylation in the livers of CDAA-fed rats(11.5% and 18.6% at 8 and 12 wk,respectively) tended to be higher(P = 0.06 and 0.09,respectively) than those in the livers of CSAA-fed rats(2.1% and 5.3% at 8 and 12 wk,respectively).Agtr1 a was not methylated at all in quiescent HSCs,but was clearly methylated in activated HSCs(13.8%,P < 0.01).Interestingly,although Agtr1 a was hypermethylated,the Agtr1 a m RNA level increased up to 2.2-fold(P < 0.05) in activated HSCs compared with that in quiescent HSCs,suggesting that Agtr1 a methylation did not silence its expression but instead had the potential to upregulate its expression.These findings indicate that Agtr1 a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis.CONCLUSION This is the first study to show that DNA methylation is potential y involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis. | Kiyoshi Asada Yosuke Aihara Hiroaki Takaya Ryuichi Noguchi Tadashi Namisaki Kei Moriya Masakazu Uejima Mitsuteru Kitade Tsuyoshi Mashitani Kosuke Takeda Hideto Kawaratani Yasushi Okura Kosuke Kaji Akitoshi Douhara Yasuhiko Sawada Norihisa Nishimura Kenichiro Seki Akira Mitoro Junichi Yamao Hitoshi Yoshiji | 2016 | World Journal of Hepatology2016，8，28： | 1 |
| 4 | Reduction of endotoxin attenuates liver fibrosis through suppressionof hepatic stellate cell activation and remission of intestinal permeability ina rat non-alcoholic steatohepatitis model显示文摘 | Akitoshi Douhara Kei Moriya Hitoshi Yoshiji Ryuichi Noguchi Tadashi Namisaki Mitsuteru Kitade Kosuke Kaji Yosuke Aihara Norihisa Nishimura Kosuke Takeda Yasushi Okura Hideto Kawaratani Hiroshi Fukui | 2015 | Molecular Medicine Reports2015，，3： | 1 |
| 5 | Association between ADAMTS13 activity-VWF antigen imbalance and the therapeutic effect of HAIC in patients with hepatocellular carcinoma显示文摘BACKGROUND Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma(HCC).The progression of HCC is related to hypercoagulability and angiogenesis.It is known that ADAMTS13 and von Willebrand factor(VWF)are related to hypercoagulability.In addition,previous study reported that the association between ADAMTS13 and VWF,and angiogenesis via vascular endothelial growth factor(VEGF).Recently,ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing chemotherapy.AIM To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC treatment.METHODS Seventy-two patients were enrolled in this study.ADAMTS13 activity(ADAMTS13:AC),VWF antigen(VWF:Ag)and VEGF levels were determined via enzyme-linked immunosorbent assay.Univariable and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC treatment.RESULTS ADAMTS13:AC levels in HCC patients with stable disease(SD)+partial response(PR)of HAIC treatment were significantly higher than those with progressive disease(PD)(P<0.05).In contrast,VWF:Ag/ADAMTS13:AC ratio and VEGF levels in HCC patients with SD+PR were significantly lower than those with PD(both P<0.05).Patients with high VWF:Ag/ADAMTS13:AC ratio(>2.7)had higher VEGF levels than those with low ratio(≤2.7).Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment response.CONCLUSION VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment. | Hiroaki Takaya Tadashi Namisaki Kei Moriya Naotaka Shimozato Kosuke Kaji Hiroyuki Ogawa Koji Ishida Yuki Tsuji Daisuke Kaya Hirotestu Takagi Yukihisa Fujinaga Norihisa Nishimura Yasuhiko Sawada Hideto Kawaratani Takemi Akahane Masanori Matsumoto Hitoshi Yoshiji | 2020 | World Journal of Gastroenterology2020，26，45： | 0 |
| 6 | Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites显示文摘Aims:No solid evidence-based opinion was raised regarding predictors of the degree of ascites reduction with tolvaptan.This retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of this.Methods:The study population consisted of 80 patients with liver cirrhosis treated with tolvaptan for hepatic ascites effusions at Nara Medical University Hospital from May 2014 to December 2018.Forty-three patients who lost>1.5 kg of body weight in the first week after starting tolvaptan were classified as good responders and the remaining 37 as poor responders.Various laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its efficacy.Results:In the univariate analysis,no significant differences with respect to age(67.6 vs.69.8 years,p>0.05),sex,body mass index(24.8 vs.23.7 kg/m^(2),p>0.05),Child-Pugh score(9.4 vs.9.7,p>0.05),and Model for End-stage Liver Disease score(11 vs.12,p>0.05)were found between the two groups.Conversely,aspartate transferase and alanine transaminase(ALT)levels were significantly lower in the good response group(52.9±56.3 vs.68.8±50.7 U/L,p<0.05;26.2±30.6 vs.40.5±33.5 U/L,p<0.01),whereas serum copeptin and serum sodium concentrations were significantly higher(57.1±15.0 vs.45.8±16.0 pg/mL,p<0.01;136.3±3.4 vs.133.8±5.8 mEq/L,p<0.05).In the multivariate analysis,serum copeptin concentration and ALT were statistically significant factors(p<0.01,p<0.05).Regression analysis of the association between the tolvaptan efficacy for refractory ascites and pretreatment serum copeptin concentration showed that a copeptin concentration cutoff of 45.9 pg/mL could predict treatment efficacy with a sensitivity,specificity,and area under the curve of 76.7%,59.5%,and 0.71%,respectively.Conclusion:Serum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis. | Fumimasa Tomooka Kei Moriya Takahiro Kubo Akihiko Shibamoto Jyunya Suzuki Satoshi Iwai Soichi Takeda Yuki Fujimoto Masahide Enomoto Koji Murata Yuki Tsuji Yukihisa Fujinaga Koh Kitagawa Norihisa Nishimura Hiroaki Takaya Kosuke Kaji Hideto Kawaratani Tadashi Namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji | 2023 | Portal Hypertension & Cirrhosis2023，2，3： | 0 |
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