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Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

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World Journal of Gastroenterology 2024年第28期30卷 3428-3446页

作者： Aritoshi Koizumi Kosuke Kaji Norihisa Nishimura Shohei Asada Takuya Matsuda Misako Tanaka Nobuyuki Yorioka Yuki Tsuji Koh Kitagawa Shinya Sato Tadashi Namisaki Takemi Akahane hitoshi yoshiji Department of Gastroenterology Nara Medical UniversityKashihara 634-8521Japan

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver *** proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ***,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary ***,the benefits of EFN for ALD treatment is *** To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse *** ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 ***(3 and 10 mg/kg/day)was orally administered during the experimental *** and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier *** EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based *** The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN *** promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARα***,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)*** improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory *** protective effect on intestinal bar

关键词： Liver fibrosis Ethanol Gut barrier function Apoptosis Autophagy Peroxisome proliferator activated receptor

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Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138

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World Journal of Gastroenterology 2009年第44期15卷 5533-5540页

作者： Tatsuhiro Tsujimoto Hideto Kawaratani Toshiyuki Kitazawa hitoshi yoshiji Masao Fujimoto Masahito Uemura Hiroshi Fukui Third Department of Internal Medicine Nara Medical University840 Shijo-choKashiharaNara 634-8522Japan

AIM:To investigate the possible use of the multiple cytokine production modulator,Y-40138,as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS:We allocated 6-wk-old male F344 rats to choline-supplemented,L-amino acid-defined (CSAA) diet (control group),CSAA diet + Y-40138 (control + Y-40138 group),choline-def icient,L-amino acid-def ined (CDAA) diet (NASH group),or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group,we measured the plasma alanine aminotransferase (ALT) levels,and the plasma and liver levels of tumor necrosis factor-α (TNF-α),interferon-γ (IFN-γ),and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining,Azan staining,Sirius red staining,and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method,and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay ***:In comparison to the NASH group,serumALT elevation was mild,production of serum and liver TNF-α and IFN-γ was inhibited,and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups,whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH ***:Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator,Y-40138,is promising as a novel treatment for NASH.

关键词：细胞因子酒精性调制免疫肝炎

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Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites

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Portal Hypertension & Cirrhosis 2023年第3期2卷 109-114页

作者： 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 Department of Gastroenterology and Hepatology Nara Medical UniversityKashiharaJapan Department of Gastroenterology Nara Prefectural General Medical CenterShichijo-NishimachiJapan

Aims:No solid evidence-based opinion was raised regarding predictors of the degree of ascites reduction with *** retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of ***: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 ***-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 *** laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its ***: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 ***,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%,***:Serum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis.

关键词： ascites copeptin decompensated liver cirrhosis diuretics tolvaptan

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ADAMTS13 and von Willebrand factor are useful biomarkers for sorafenib treatment efficiency in patients with hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2019年第5期11卷 424-435页

作者： Hiroaki Takaya Tadashi Namisaki Naotaka Shimozato Kosuke Kaji Mitsuteru Kitade Kei Moriya Shinya Sato Hideto Kawaratani Takemi Akahane Masanori Matsumoto hitoshi yoshiji Third Department of Internal Medicine Nara Medical University Department of Blood Transfusion Medicine Nara Medical University

BACKGROUND Many advanced hepatocellular carcinoma(HCC) patients are receiving sorafenib treatment. Sorafenib reportedly improves overall survival(OS) significantly in patients with HCC. Prediction of sorafenib response and prognosis in patients with HCC receiving sorafenib treatment are important due to the potentially serious side effects of sorafenib. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13(ADAMTS13) and von Willebrand factor(VWF) are associated with the pathophysiology of liver cirrhosis and HCC through their roles in hypercoagulability; they are also associated with angiogenesis via vascular endothelial growth factor(VEGF). The imbalance between ADAMTS13 and VWF was associated with prognosis of various cancers in patients undergoing *** To investigate ADAMTS13 and VWF as potential biomarkers for sorafenib response and prognosis in patients with HCC receiving sorafenib *** Forty-one patients with HCC receiving sorafenib treatment were included in this study. The initial daily sorafenib dose was 400 mg in all patients. ADAMTS13 activity(ADAMTS13:AC), VWF antigen(VWF:Ag), VEGF levels were determined by enzyme-linked immunosorbent assay. Univariate andmultivariate analyses were used to determine predictive factors for sorafenib response and prognosis in patients with HCC receiving sorafenib *** ADAMTS13:AC was significantly higher in patients with stable disease(SD),partial response(PR), and complete response(CR) than in those with progressive disease(PD)(P < 0.05). In contrast, VWF:Ag and the VWF:Ag/ADAMTS13:AC ratio were significantly lower in patients with SD, PR, and CR than in those with PD(P < 0.05 for both). Multivariate analysis showed that the VWF:Ag/ADAMTS13:AC ratio was the only predictive factor for sorafenib response and ADAMTS13:AC was the only prognostic factor in patients with HCC receiving sorafenib treatment. The patients with a low ADAMTS13:AC(<78.0) had significantly h

关键词： ADAMTS13 Von Willebrand factor Biomarkers Hepatocellular carcinoma Sorafenib

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Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

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World Journal of Gastroenterology 2017年第47期23卷 8355-8366页

作者： Kosuke Kaji Hiroaki Takaya Soichiro Saikawa Masanori Furukawa Shinya Sato Hideto Kawaratani Mitsuteru Kitade Kei Moriya Tadashi Namisaki Takemi Akahane Akira Mitoro hitoshi yoshiji Third Department of Internal Medicine Nara Medical University

AIM To determine the efficacy of rifaximin for hepatic encephalopathy(HE) with the linkage of gut microbiome in decompensated cirrhotic *** Twenty patients(12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis(Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test(NCT)-A. Changes in whole blood endotoxin activity(EA) was analyzed by endotoxinactivity assay. Fecal microbiome was assessed by 16 S ribosome RNA(rR NA) gene *** Treatment with rifaximin for 4 wk improved hyperammonemia(from 90.6 ± 23.9 μg/d L to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT(from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced(from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels(r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator(Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups(3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were *** Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

关键词： gut microbiome Hepatic encephalopathy Liver cirrhosis Endotoxin Rifaximin

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Dual therapy with zinc acetate and rifaximin prevents from ethanolinduced liver fibrosis by maintaining intestinal barrier integrity

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World Journal of Gastroenterology 2021年第48期27卷 8323-8342页

作者： Yuki Fujimoto Kosuke Kaji Norihisa Nishimura Masahide Enomoto Koji Murata Soichi Takeda Hiroaki Takaya Hideto Kawaratani Kei Moriya Tadashi Namisaki Takemi Akahane hitoshi yoshiji Department of Gastroenterology Nara Medical UniversityKashihara 6348521NaraJapan

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 ***,targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of *** 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 ***,only few studies focused on their efficacies in preventing the ALD-related fibrosis *** To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD *** 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 *** acetate(100 mg/L)and/or rifaximin(100 mg/L)were orally administered during experimental *** steatosis,inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular ***,the direct effects of both agents on Caco-2 barrier function were assessed by in vitro *** the ethanol plus CCl4-treated mice,combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and *** 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 ***,liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2,-9,-13,and *** agents improved the atrophic changes and permeability in the ileum,with restoration of tight junction proteins(TJPs)

关键词： Liver fibrosis Intestinal permeability Alcoholic liver disease Lipopolysaccharide Toll-like receptor Tight junction protein

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Serum angiotensin-converting enzyme level for evaluating significant fibrosis in chronic hepatitis B

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World Journal of Gastroenterology 2017年第36期23卷 6705-6714页

作者： Ryuichi Noguchi Kosuke Kaji Tadashi Namisaki Kei Moriya Mitsuteru Kitade Kosuke Takeda Hideto Kawaratani Yasushi Okura Yosuke Aihara Masanori Furukawa Akira Mitoro hitoshi yoshiji Third Department of Internal Medicine Nara Medical University

AIM To evaluate the diagnostic performance of angiotensinconverting enzyme(ACE)on significant liver fibrosis in patients with chronic hepatitis B(CHB). METHODS In total,100 patients with CHB who underwent liver biopsy in our hospital were enrolled,and 70 patients except for 30 patients with hypertension,fatty liver or habitual alcoholic consumption were *** compared histological liver fibrosis and serum ACE levels and evaluated the predictive potential to diagnose significant liver fibrosis by comparison with several biochemical marker-based indexes such as the aspartate aminotransferase(AST)-to-platelet ratio index(APRI),the fibrosis index based on four factors(FIB-4),the Mac-2 binding protein glycosylation isomer(M2BPGi)level and the number of platelets(Plt). RESULTS Serum ACE levels showed moderately positive correlation with liver fibrotic stages(R2=0.181).Patients with significant,advanced fibrosis and cirrhosis(F2-4)had significantly higher serum ACE levels than those with early-stage fibrosis and cirrhosis(F0-1).For significant fibrosis(≥F2),the 12.8 U/L cut-off value of ACE showed 91.7%sensitivity and 75.0%*** receiver-operating characteristic(ROC)curves analysis revealed that the area under the curve(AUC)value of ACE was 0.871,which was higher than that of APRI,FIB-4,M2BPGi and Plt. CONCLUSION The serum ACE level could be a novel noninvasive,easy,accurate,and inexpensive marker of significant fibrosis stage in patients with CHB.

关键词： Angiotensin-converting enzyme Hepatitis B virus Liver fibrosis Noninvasive fibrosis marker Aspartate aminotransferase-to-platelet ratio index Fibrosis index based on four factors Mac-2 binding protein glycosylation isomer

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Eosinophilic cholecystitis as a rare manifestation of visceral larva migrans

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World Journal of Gastroenterology 2007年第45期13卷 6119-6119页

作者： hitoshi yoshiji Masahide Yoshikawa Kosuke Kaji Hiroshi Fukui Department of Internal Medicine Nara Medical University Nara Japan Department of Parasitology Nara Medical University Nara Japan

Eosinophilic cholecystitis is an infrequent form of cholecystitis. The etiology of eosinophilic cholecystitis is still obscure, and it is sometimes accompanied with several complications, but a simultaneous onset with pericarditis is very rare. We would like to make an alternative interpretation of our recent report "Kaji K, yoshiji H, Yoshikawa M, Yamazaki M, Ikenaka Y, Noguchi R, Sawai M, Ishikawa M, Mashitani T, Kitade M, Kawaratani H, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Yoshida M, Fukui H. Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report. World J Gastroenterol 2007; 13: 3760-3762."

关键词：胆囊炎内脏幼虫蛔虫

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Acylcarnitine: Useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients

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World Journal of Gastrointestinal Oncology 2019年第10期11卷 887-897页

作者： Hiroaki Takaya Tadashi Namisaki Mitsuteru Kitade Naotaka Shimozato Kosuke Kaji Yuki Tsuji Keisuke Nakanishi Ryuichi Noguchi Yukihisa Fujinaga Yasuhiko Sawada Soichiro Saikawa Shinya Sato Hideto Kawaratani Kei Moriya Takemi Akahane hitoshi yoshiji Third Department of Internal Medicine Nara Medical University

BACKGROUND Early diagnosis of hepatocellular carcinoma(HCC)is necessary to improve the prognosis of ***,the currently available tumor biomarkers are insufficient for the early detection of *** is essential in fatty acid metabolic pathways.A recent study reported that a high level of acylcarnitine may serve as a useful biomarker for the early diagnosis of HCC in steatohepatitis(SH)*** contrast,another study reported that the level of acetylcarnitine(AC2)-one of the acylcarnitine species-in non-SH patients with HCC was decreased vs that reported in those without *** To investigate the usefulness of acylcarnitine as a biomarker for the early diagnosis of HCC in non-SH *** Thirty-three non-SH patients(14 with HCC and 19 without HCC)were enrolled in this *** samples were obtained from patients at the time of *** levels of acylcarnitine and AC2 in the serum were determined through tandem mass *** levels of vascular endothelial growth factor(VEGF)and VEGF receptor 2(VEGFR-2)were determined by enzymelinked immunosorbent *** and multivariate analyses were used to determine early diagnostic factors of *** The level of acylcarnitine was significantly lower in non-SH patients with HCC vs those without HCC(P<0.05).In contrast,the level of lens culinaris agglutininreactive fraction ofα-fetoprotein(AFP)-AFP-L3%-was significantly higher in non-SH patients with HCC vs those without HCC(P<0.05).However,the levels of total carnitine,free carnitine,AFP,des-γ-carboxy prothrombin,VEGF,and VEGFR-2 were not different between patients with and without *** multivariate analysis showed that a low level of acylcarnitine was the only independent factor for the early diagnosis of *** patients with a low level of AC2 had a significantly higher level of VEGF vs those with a high level of AC2(P<0.05).CONCLUSION The metabolic pathways of fatty acids may differ between SH HCC and non-SH HCC

关键词： Acylcarnitine Acetylcarnitine Biomarker Hepatocellular carcinoma Angiogenesis Carnitine palmitoyltransferase 1 Oxidative stress

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Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet

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World Journal of Gastroenterology 2008年第43期14卷 6655-6661页

作者： Hideto Kawaratani Tatsuhiro Tsujimoto Toshiyuki Kitazawa Mitsuteru Kitade hitoshi yoshiji Masahito Uemura Hiroshi Fukui Third Department of Internal Medicine Nara Medical University840 Shijo-choKashiharaNara 634-8522Japan

瞄准：调查肿瘤坏死 factor-alpha (TNF-alpha ) 的天生的有免疫力的反应，像使用费的受体 4 (TLR4 ) ，并且在非酒精的 steatohepatitis (NASH ) 的肝的 CD14 为老鼠建模。方法：男 F344 老鼠被喂一本胆碱缺乏的 L-amino-acid-defined ... 详细信息

瞄准：调查肿瘤坏死 factor-alpha (TNF-alpha ) 的天生的有免疫力的反应，像使用费的受体 4 (TLR4 ) ，并且在非酒精的 steatohepatitis (NASH ) 的肝的 CD14 为老鼠建模。方法：男 F344 老鼠被喂一本胆碱缺乏的 L-amino-acid-defined (CDAA ) 食谱。老鼠在食谱的 4 或 8 wk 以后被打死，并且他们的肝为免疫被移开组织化学的调查和 RNA 抽取。肝标本是为 TNF-alpha， TLR4，和 CD14 染色的免疫。TNF-alpha， TLR4，和 CD14 的基因表情被 reverse-transcriptase 聚合酶链反应(RT-PCR ) 决定。Kupffer 房间被 Percoll 坡度远心沉淀从肝孤立，并且当时是有教养的测量 TNF-alpha 生产。结果：在老鼠作为与控制相比显著地增加了的 CDAA-fed 的 TNF-alpha 的浆液和肝层次组织，，与 steatohepatitis 的前进做了免疫组织化学的值和 TNF-alpha， TLR4，和 CD14 的基因表达式。从 CDAA-fed 老鼠的孤立的 Kupffer 房间的 TNF-alpha 生产被脂肪的多糖刺激提高。结论：TNF-alpha， TLR4，和 CD14 的表情在 NASH 模型增加了，建议 TLR4 和调停 CD14 的内毒素肝损坏可以也发生在 NASH。

关键词：非酒精性脂肪肝受体 CD14 内毒素

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