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Akifumi Kuwano, Motoyuki Kohjima, Hideo Suzuki, Akihiro Yamasaki, Tomoko Ohashi, Koji Imoto, Miho Kurokawa, Yusuke Morita, Masaki Kato, Yoshihiro Ogawa, Recombinant human soluble thrombomodulin ameliorates acetaminophen-induced liver toxicity in mice., Experimental and therapeutic medicine, 10.3892/etm.2019.7665, 18, 2, 1323-1330, 2019.08, Recombinant human soluble thrombomodulin alpha (rhTM) has been developed as an anticoagulant with anti-inflammatory activity. Notably, acetaminophen (APAP) -induced liver disease (AILI) is caused by direct metabolite-induced hepatotoxicity as well as hepatic hyper-coagulation. To evaluate the utility of anticoagulant for the treatment of AILI, rhTM was administered in a mouse AILI model and liver damage was analyzed. AILI was induced in 8-week-old mice by intraperitoneal injection of APAP. rhTM (20 mg/kg) or placebo was injected at the same time as APAP administration. Serum alanine aminotransferase, fibrin degradation products and high-mobility group box 1 levels were significantly decreased in the rhTM-treated group compared with the control group. Furthermore, rhTM reduced the necrotic area and fibrin deposition in liver sections. rhTM suppressed the mRNA expression of heme oxygenase-1, plasminogen activator inhibitor type-1, tissue factors, and inflammatory cytokines compared with the control group. rhTM did not change the hepatic GSH content at 2 h after APAP injection, but restored them at 4 h after the insult. rhTM ameliorated liver damage in mice with AILI, probably via the improvement in liver perfusion induced by it's anticoagulant acitivity, which can lead to the suppression of secondary liver damage.. |
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Akifumi Kuwano, Masatake Tanaka, Hideo Suzuki, Miho Kurokawa, Koji Imoto, Shigeki Tashiro, Takeshi Goya, Motoyuki Kohjima, Masaki Kato, Yoshihiro Ogawa, Upregulated expression of hypoxia reactive genes in peripheral blood mononuclear cells from chronic liver disease patients., Biochemistry and biophysics reports, 10.1016/j.bbrep.2021.101068, 27, 101068-101068, 2021.09, Liver fibrosis induces intrahepatic microcirculation disorder and hypoxic stress. Hypoxic stress has the potential for an increase in the possibility of more liver fibrosis and carcinogenesis. Liver biopsy is a standard method that evaluates of intrahepatic hypoxia, however, is invasive and has a risk of bleeding as a complication. Here, we investigated the hypoxia reactive gene expressions in peripheral blood mononuclear cells (PBMC) from chronic liver disease patients to evaluate intrahepatic hypoxia in a non-invasive manner. The subjects enrolled for this study were composed of 20 healthy volunteers (HV) and 48 patients with chronic liver disease (CLD). CLD patients contained 24 patients with chronic hepatitis（CH）and 24 patients with liver cirrhosis (LC). PBMC were isolated from heparinized peripheral blood samples. We measured the transcriptional expression of hypoxia reactive genes and inflammatory cytokines by quantitative RT-PCR. mRNA expression of adrenomedullin (AM), vascular endothelial growth factor A (VEGFA) superoxide dismutase (SOD), glutathione peroxidase (GPx) (p |
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Akifumi Kuwano, Miho Kurokawa, Motoyuki Kohjima, Koji Imoto, Shigeki Tashiro, Hideo Suzuki, Masatake Tanaka, Seiji Okada, Masaki Kato, Yoshihiro Ogawa, Microcirculatory disturbance in acute liver injury., Experimental and therapeutic medicine, 10.3892/etm.2021.10028, 21, 6, 596-596, 2021.06, Microcirculatory disturbance is thought to be involved in the pathogenesis of acute liver injury (ALI). The current study examined the pathophysiologic role of hepatic microcirculatory disturbance in patients with ALI and in mouse models of ALI. Using serum aminotransferase (ALT)/lactate dehydrogenase (LDH) ratio as a hypoxic marker, 279 patients with ALI were classified into the low ALT/LDH ratio (ALT/LDH ≤1.5) and high ALT/LDH ratio group (ALT/LDH >1.5). In the low ALT/LDH ratio group, serum ALT, LDH, fibrinogen degradation products and prothrombin time-international normalized ratio were increased relative to the high ALT/LDH ratio group. Histologically, hepatic expression of tissue factor (TF) and hypoxia-related proteins was enhanced in the low ALT/LDH ratio group, and this was accompanied by sinusoidal fibrin deposition. Sinusoidal hypercoagulation and intrahepatic hypoxia was also analyzed in two different mouse models of ALI; Concanavalin A (ConA) mice and Galactosamine/tumor necrosis factor (TNF)-α (G/T) mice. Serum ALT/LDH ratio in ConA mice was significantly lower compared with G/T mice. Pimonidazole staining revealed the upregulation of hypoxia-related proteins in ConA mice. Recombinant human soluble thrombomodulin improved liver damage in ConA mice in association with reduced sinusoidal hypercoagulation and intrahepatic hypoxia. The present study provides evidence that serum ALT/LDH ratio aids in the identification of patients with ALI and intrahepatic hypoxia as a result of microcirculatory disturbance. The results facilitate the improved understanding of the pathogenesis of ALI, thereby offering a novel therapeutic strategy against ALI, which arises from sinusoidal hypercoagulation.. |
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Takeshi Goya, Koji Imoto, Shigeki Tashiro, Tomomi Aoyagi, Motoi Takahashi, Miho Kurokawa, Hideo Suzuki, Masatake Tanaka, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa, The Efficacy of Tofogliflozin on Metabolic Dysfunction-Associated Fatty Liver Disease, GASTROENTEROLOGY INSIGHTS, 10.3390/gastroent13010003, 13, 1, 20-26, 2022.03, The increasing number of patients with fatty liver disease is a major health problem. Fatty liver disease with metabolic dysfunction has been recognized as nonalcoholic fatty liver disease (NAFLD). Although there is no standard therapy for NAFLD, previous reports support the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on NAFLD. Recently, fatty liver disease with metabolic dysfunction was proposed to be defined as a novel concept, "metabolic associated fatty liver disease (MAFLD)", and it was proposed that new criteria for MAFLD diagnosis be established. To clarify the effect of SGLT2 inhibitors on MAFLD, we analyzed the efficacy of tofogliflozin in patients with MAFLD. We conducted a single-center, retrospective study to evaluate the efficacy of tofogliflozin in patients with MAFLD treated at Kyushu University Hospital between 2017 and 2019. Tofogliflozin was used to treat 18 patients with MAFLD. To determine the efficacy of tofogliflozin, we evaluated glucose metabolism, insulin resistance, liver injury, hepatic steatosis, and body composition three and six months after drug initiation. Although our study was a preliminary study because of some limitations (e.g., retrospective, observational, single-arm study, small sample size), we show that tofogliflozin could improve liver injury in patients with MAFLD by improving glucose metabolism and insulin resistance without causing muscle loss.. |
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Takeshi Goya, Tomoyuki Kurashige, Miho Kurokawa, Masatake Tanaka, Tomomi Aoyagi, Motoi Takahashi, Koji Imoto, Shigeki Tashiro, Hideo Suzuki, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa, The Combination of Nucleotide Analog Therapy and Steroid Pulse Therapy for Acute HBV Infection Effectively Promotes HBV Clearance, GASTROENTEROLOGY INSIGHTS, 10.3390/gastroent13010001, 13, 1, 1-8, 2022.03, Acute hepatitis B virus (HBV) infection occasionally progresses to acute liver failure, often with poor prognosis. The appropriate pharmacological approach is yet to be established. Although nucleotide analogs (NA) and corticosteroids are candidates for the treatment of acute HBV infection, their therapeutic effects, especially their effect on HBV clearance, remain unclear. To clarify effects on the HBV clearance of combination therapy of NA and steroid pulse therapy (SPT) for acute HBV infection, we first analyze the effectiveness of this therapy in patients with HBV infection compared with NA monotherapy (NAM). Of the 57 consecutive patients with acute hepatitis B infection from May 2007 to December 2018, we have included 25 patients for this study, whom we followed up until HBV clearance. According to the administration of NA and SPT, we divided patients into two groups (NAM group and NA + SPT group) and compared their results. Of the 25 patients, 10 received NAM, whereas 15 received NA + SPT. There were no appreciable adverse effects related to SPT. The time required for the clearance of HBsAg (76 (43-116) days vs. 26 (14-51) days, p = 0.0418) and HBV-DNA (NAM group vs. NA + SPT group: 180 (83.5-220) vs. 69 (43-136) days, p = 0.0420) was significantly shorter in the NA + SPT group than in the NAM group. The hazard ratio of NA + SPT for the clearance of HBsAg and HBV-DNA were 0.45 (0.19-1.09) and 0.35 (0.14-0.89), respectively. In conclusion, we showed that NA + SPT promoted HBV elimination. These findings support the use of the NA + SPT combination for acute HBV infection without the concern of persistent HBV infection.. |
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Shigeki Tashiro, Masatake Tanaka, Takeshi Goya, Tomomi Aoyagi, Miho Kurokawa, Koji Imoto, Akifumi Kuwano, Motoi Takahashi, Hideo Suzuki, Motoyuki Kohjima, Masaki Kato, Yoshihiro Ogawa, Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation., Toxicology and applied pharmacology, 10.1016/j.taap.2021.115817, 434, 115817-115817, 2022.01, Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury. In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions. In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.. |
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Takeshi Goya, Miho Kurokawa, Tomonobu Hioki, Tomomi Aoyagi, Motoi Takahashi, Koji Imoto, Shigeki Tashiro, Hideo Suzuki, Masatake Tanaka, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa, Elevated Pancreatic Enzymes Associated with Acute Liver Injury Were Mediated by Tumor Necrosis Factor-Alpha Signaling, HEPATITIS MONTHLY, 10.5812/hepatmon-128106, 22, 1, 2022.12, Background: Acute liver failure (ALF) is caused by massive hepatocyte death and accompanied by severe coagulation disorder and encephalopathy. It often leads to multiple organ failure and subsequently death. However, the association between ALF and other organ failure remains unclear.Objectives: Here, we evaluated patients with acute liver injury (ALI) and elevated pancreatic enzymes to demonstrate the association between ALI and pancreatic disorder.Methods: We conducted a single-center retrospective study to analyze patients with ALI. Between 2012 and 2017, 163 patients with ALI were treated in our hospital. We stratified patients based on whether serum amylase and lipase were elevated above 1.5 times the upper limit of normal. We compared the baseline characteristics, severity, prognosis, and serum cytokine levels between the two groups.Results: Of the 163 patients, 75 (54.0%) presented elevated pancreatic enzymes above 1.5 times the upper limit of normal. Computed tomography imaging findings associated with pancreatitis were observed in 29 patients (17.8%). The elevation of pancreatic enzymes was associated with ALI severity. High level of serum tumor necrosis factor-alpha (TNF-alpha) was associated with the elevation of pancreatic enzymes (elevation group Vs. no elevation group: 134.0 +/- 177.2 pg/mL Vs. 89.4 +/- 159.8 pg/mL).Conclusions: The elevation of pancreatic enzymes was often accompanied by ALI and associated with ALI severity. TNF-alpha signaling was involved in the elevation of pancreatic enzymes. It is possible that the pancreatic disorder reflected ALI severity, consequently correlated with mortality, and did not directly aggravate ALI pathogenesis. These findings provide novel insights into the pathogenesis of ALF.. |
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Koji Imoto, Masatake Tanaka, Takeshi Goya, Tomomi Aoyagi, Motoi Takahashi, Miho Kurokawa, Shigeki Tashiro, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa, Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency., BMC gastroenterology, 10.1186/s12876-022-02213-0, 22, 1, 144-144, 2022.03, BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is most common among urea cycle disorders (UCDs), defined by defects in enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is suggested to be avoided, as it may induce life-threatening hyperammonemia. The mechanism has been considered nitrogen overload due to the catabolic effect of corticosteroids; however, the pathophysiological process is unclear. METHODS: To elucidate the mechanism of hyperammonemia induced by corticosteroid administration in OTCD patients, we analyzed a mouse model by administering corticosteroids to OTCspf-ash mice deficient in the OTC gene. Dexamethasone (DEX; 20 mg/kg) was administered to the OTCspf-ash and wild-type (WT) mice at 0 and 24 h, and the serum ammonia concentrations, the levels of the hepatic metabolites, and the gene expressions related with ammonia metabolism in the livers and muscles were analyzed. RESULTS: The ammonia levels in Otcspf-ash mice that were administered DEX tended to increase at 24 h and increased significantly at 48 h. The metabolomic analysis showed that the levels of citrulline, arginine, and ornithine did not differ significantly between Otcspf-ash mice that were administered DEX and normal saline; however, the level of aspartate was increased drastically in Otcspf-ash mice owing to DEX administration (P |
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Akifumi Kuwano, Tasuku Okui, Motoyuki Kohjima, Miho Kurokawa, Takeshi Goya, Masatake Tanaka, Tomomi Aoyagi, Motoi Takahashi, Koji Imoto, Shigeki Tashiro, Hideo Suzuki, Nobuhiro Fujita, Yasuhiro Ushijima, Kousei Ishigami, Shoji Tokunaga, Masaki Kato, Yoshihiro Ogawa, Transcatheter arterial steroid injection therapy improves the prognosis of patients with acute liver failure., Medicine, 10.1097/MD.0000000000033090, 102, 10, e33090, 2023.03, Acute liver failure (ALF) is a disorder defined by coagulopathy and encephalopathy with a poor prognosis. No effective therapies have been established except for liver transplantation. We previously reported a subgroup of patients with acute liver injury who developed microcirculatory disturbance. We also established and reported transcatheter arterial steroid injection therapy (TASIT) as a new treatment of ALF. Here, we analyze the effectiveness of TASIT in a larger cohort and evaluate the impact on ALF patients with or without microcirculatory disturbance. We conducted a single-center retrospective study to evaluate the effectiveness of TASIT in patients with ALF admitted at Kyushu University Hospital between January 2005 and March 2018. TASIT is performed by injecting methylprednisolone via the proper hepatic artery for 3 days. One hundred ninety-4 patients with ALF were enrolled and analyzed in this study. Of the 87 patients given TASIT, 71 (81.6%) recovered without any complications and 16 (18.4%) died or underwent liver transplantation. Of the 107 patients not administered TASIT, 77 (72.0%) recovered and 30 (28.0%) progressed to irreversible liver failure. In the high-lactate dehydrogenase subgroup, 52 (86.7%) of the 60 patients with TASIT recovered, and the survival rate was significantly higher than that in patients who did not receive TASIT. Multivariate regression analysis revealed that the TASIT procedure was one of the significant prognostic factors in the high-lactate dehydrogenase subgroup and was significantly associated with prothrombin activity percentage improvement. TASIT is an effective treatment for patients with ALF, especially in those with microcirculatory disturbance.. |
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Miho Kurokawa, Tomonobu Hioki, Tomomi Aoyagi, Motoi Takahashi, Koji Imoto, Takeshi Goya, Masatake Tanaka, Motoyuki Kohjima, Yoshihiro Ogawa, Clinicopathologic Features of Adult-onset Still's Disease Complicated by Severe Liver Injury., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.2043-23, 2023.06, Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder. Severe liver injury has rarely been reported, although liver enzyme elevation is a common complication of AOSD. We herein report four cases of relapsed AOSD with severe liver disorder by tapering or terminating corticosteroids. Liver specimens revealed robust infiltration of inflammatory cells throughout the lobule, especially cluster of differentiation (CD) 8-positive cells. Relapsed AOSD was refractory to corticosteroid reintroduction and required immunosuppressants. Severe liver injury with AOSD is pathologically characterized by extensive lobular infiltration of CD8-positive cells, and we should consider additive immunosuppressive agents on corticosteroids for treatment.. |
