Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation

Eguchi, Akiko; Koyama, Yukinori; Wree, Alexander; Johnson, Casey D.; Nakamura, Ryota; Povero, Davide; Kneiber, David Boulos; Tameda, Masahiko; Contreras, Patricia C.; Spada, Al; Feldstein, Ariel E.

doi:10.1007/s00109-018-1642-9

Cited by 25 publications

(23 citation statements)

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“…Cirrhotic rats received either emricasan (10 mg/kg/day; per os; n = 20) or vehicle (0.9% dimethylcarboxycellulose; per os; n = 20) for 7 days. The dose was selected based on a conversion calculation starting from the dose used in humans and in previous preclinical publications …”

Section: Methodsmentioning

confidence: 99%

“…The dose was selected based on a conversion calculation starting from the dose used in humans and in previous preclinical publications. (20,21) In Vivo Hemodynamics Rats (n = 12 per group) were anesthetized with ketamine hydrochloride (100 mg/kg; Merial Laboratories, Duluth, GA) plus midazolam (5 mg/kg; Laboratorios Reig Jofré, Toledo, Spain) intraperitoneally. A tracheostomy was performed and a polyethylene tube PE-240 was inserted into the trachea to ensure a patent airway.…”

Section: Characterization Of Chronic Liver Disease Rats Treated With mentioning

confidence: 99%

“…Emricasan (IDN‐6556) is an irreversible pan‐caspase inhibitor that primarily targets the liver when orally administered, and is being investigated in clinical trials for chronic liver disease and portal hypertension after pilot studies in patients with chronic hepatitis C suggested a beneficial effect on liver function as well as on portal pressure in patients with severe portal hypertension . Previous preclinical work has shown that inhibition of hepatocyte cell death using caspase inhibitors protects the liver from acute injury, in scenarios of chronic liver disease with mild fibrosis or in cholestatic liver injury . Nevertheless, the possible beneficial effects of this therapeutic option in models of ACLD and portal hypertension are mostly unknown.…”

mentioning

confidence: 99%

“…(15)(16)(17)(18) Previous preclinical work has shown that inhibition of hepatocyte cell death using caspase inhibitors protects the liver from acute injury, (19) in scenarios of chronic liver disease with mild fibrosis (20) or in cholestatic liver injury. (21) Nevertheless, the possible beneficial effects of this therapeutic option in models of ACLD and portal hypertension are mostly unknown.…”

mentioning

confidence: 99%

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Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

et al. 2019

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In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De‐regulated inflammatory and pro‐apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan‐caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7‐day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl 4 administration. The hepato‐protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle‐treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. In vitro experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes’ expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. Conclusion : This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.

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Section: Methodsmentioning

confidence: 99%

Section: Characterization Of Chronic Liver Disease Rats Treated With mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

et al. 2019

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“…In vivo nonviral PD-MSCs PRL-1 alleviate liver brosis in a rat model of BDL BDL is the most common model of cholestasis injury in rodents and results in in ammation, hepatocyte apoptosis and brosis [30]. To analyze the hepatic regeneration of PD-MSCs PRL-1 generated using a nonviral AMAXA system in the BDL model, we established an early cirrhotic model.…”

Section: Improved Mitochondrial Respirational Metabolic States Of Pd-mentioning

confidence: 99%

Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model

Kim

Choi

Jun

et al. 2020

Preprint

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Background: Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as an alternative cell therapy agent that has become a next-generation stem cell treatment. Phosphatase of regenerating liver-1 (PRL-1), an immediate early gene, plays a critical role during liver regeneration. Here, we generated enhanced PRL-1 in PD-MSCs (PD-MSCsPRL-1, PRL-1+) using lentiviral and nonviral gene delivery systems and investigated mitochondrial functions by PD-MSCPRL-1 transplantation for hepatic functions in a rat bile duct ligation (BDL) model. Methods: PD-MSCsPRL-1 were generated by lentiviral and nonviral AMAXA gene delivery systems and analyzed for their characteristics and mitochondrial metabolic functions. Liver cirrhosis was induced in Sprague-Dawley (SD) rats using common BDL for 10 days. PKH67+ naïve and PD-MSCsPRL-1 were intravenously administered into cirrhotic rats using a nonviral system (2x106 cells/animal). The animals were sacrificed at 1, 2, 3, and 5 weeks after transplantation and engraftment of stem cells, and histopathological analysis and hepatic mitochondrial functions were performed. Results: PD-MSCsPRL-1 were successfully generated using lentiviral and nonviral AMAXA systems and maintained characteristics similar to those of naïve cells. Compared with naïve cells, PD-MSCsPRL-1 improved respirational metabolic states of mitochondria. In particular, mitochondria in PD-MSCsPRL-1 generated by the nonviral AMAXA system showed a significant increase in the respirational metabolic state, including ATP production and mitochondrial biogenesis (*p<0.05). Furthermore, transplantation of PD-MSCsPRL-1 using a nonviral AMAXA system promoted engraftment into injured target liver tissues of a rat BDL cirrhotic model and enhanced the metabolism of mitochondria via increased mtDNA and ATP production, thereby improving therapeutic efficacy. Conclusions: Our findings will further our understanding of the therapeutic mechanism of enhanced MSCs and provide useful data for the development of next-generation MSC-based cell therapy and therapeutic strategies for regenerative medicine in liver disease.

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2019

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Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation

Cited by 25 publications

References 21 publications

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model

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