Orally-Administered Caspase Inhibitor PF-03491390 Is Retained in the Liver for Prolonged Periods With Low Systemic Exposure, Exerting a Hepatoprotective Effect Against α-Fas-Induced Liver Injury in a Mouse Model

Ueno, Yoshinobu; Ohmi, Tetsuo; Yamamoto, Mitsuko L.; Kato, Naoto; Moriguchi, Yukiko; Kojima, Masashi; Shimozono, Rieko; Suzuki, Sachiko; Matsuura, Tomomi; Eda, Hiroyuki

doi:10.1254/jphs.sc0070207

Cited by 22 publications

(17 citation statements)

References 12 publications

(11 reference statements)

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“…Subsequent experiments evaluating possible paracrine effects from emricasan‐treated hepatocytes evidenced a positive crosstalk, leading to marked de‐activation of HSC, together with partial improvements in LSECs and HMϕs. These observations are in agreement with previous works demonstrating the modulation of paracrine effectors in response to pan‐caspase inhibitors . Nevertheless, our study adds a significant piece of knowledge in this process.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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

et al. 2019

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“…SMAC mimetics are the most exciting clinical candidates that have emerged. Conversely, clinical caspase inhibitor Emricasan is a liver-targeted agent (111,112), probably limiting its general utility. New classes of caspase inhibitors (and especially caspase-8-specific molecules) will be undoubtedly very useful.…”

Section: Discussionmentioning

confidence: 99%

RIPK1 and RIPK3 - emerging targets in cancer?

Gurol

Shah

Degterev

2018

MCT

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“…Emricasan is an irreversible pan-caspase inhibitor that is orally active and retained in the liver 67. Caspases play an important role in apoptosis and it has been demonstrated that steatotic hepatocytes undergo apoptosis 68.…”

Section: Medicationsmentioning

confidence: 99%

Perspectives on Nonalcoholic Fatty Liver Disease: An Overview of Present and Future Therapies

Vizuete¹,

Camero²,

Malakouti³

et al. 2017

Journal of Clinical and Translational Hepatology

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Nonalcoholic fatty liver disease (NAFLD) represents a major public health epidemic. Pharmacologic therapies for this condition are scarce, but multiple agents with novel mechanisms of action are in development. Here we review the pathophysiology and natural history of NALFD, diagnostic testing and data for currently available treatment strategies. We then turn our attention to promising developmental drugs and their respective trials. As the prevalence of fatty liver disease increases, clinicians will have more tools at hand for management of this condition. We conclude the horizon is bright for patients and doctors who deal with NAFLD. Citation of this article: Vizuete J, Camero A, Malakouti M, Garapati K, Gutierrez J. Perspectives on nonalcoholic fatty liver disease: an overview of present and future therapies.

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Orally-Administered Caspase Inhibitor PF-03491390 Is Retained in the Liver for Prolonged Periods With Low Systemic Exposure, Exerting a Hepatoprotective Effect Against α-Fas-Induced Liver Injury in a Mouse Model

Cited by 22 publications

References 12 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

RIPK1 and RIPK3 - emerging targets in cancer?

Perspectives on Nonalcoholic Fatty Liver Disease: An Overview of Present and Future Therapies

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