Quercetin improves platelet function and ultrastructure in cholestatic liver injury in rats: Role of ORAI1 gene expression

Gene Reports ◽  
2019 ◽  
Vol 17 ◽  
pp. 100485 ◽  
Author(s):  
Noha A. Nassef
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Platelet Function ◽  
Cholestatic Liver Injury

scholarly journals Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury

Hepatology ◽  
2020 ◽  
Vol 72 (6) ◽  
pp. 2219-2227 ◽  
Author(s):  
Nan Wu ◽  
Leonardo Baiocchi ◽  
Tianhao Zhou ◽  
Lindsey Kennedy ◽  
Ludovica Ceci ◽  
...  
Keyword(s):  
Liver Injury ◽  
Functional Role ◽  
Receptor Signaling ◽  
Secretin Receptor ◽  
Cholestatic Liver Injury

scholarly journals Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

2018 ◽  
Vol 314 (3) ◽  
pp. G319-G333 ◽  
Author(s):  
Nadine Gehrke ◽  
Michael Nagel ◽  
Beate K. Straub ◽  
Marcus A. Wörns ◽  
Marcus Schuchmann ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Bile Acids ◽  
Bile Duct Ligation ◽  
Ex Vivo ◽  
Mapk Signaling ◽  
Caspase 8 ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

scholarly journals Inflammation and Cell Death During Cholestasis: The Evolving Role of Bile Acids

2019 ◽  
Vol 19 (3) ◽  
pp. 215-228 ◽  
Author(s):  
Benjamin L. Woolbright ◽  
Hartmut Jaeschke
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Bile Acids ◽  
Primary Role ◽  
Drug Induced ◽  
Chronic Cholestasis ◽  
Biliary Tracts ◽  
Acute Retention ◽  
Cholestatic Liver Injury

Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.

scholarly journals Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanrui Ma ◽  
Jiaqing Xiang ◽  
Guixiao Huang ◽  
Yaxi Zhao ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Cholestatic Liver Disease ◽  
P53 Signaling ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Cholestatic Liver Injury ◽  
P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

The Role of Bile Acid‐Mediated Inflammation in Cholestatic Liver Injury

The Liver ◽  
2020 ◽  
pp. 728-736
Author(s):  
Shi‐Ying Cai ◽  
Man Li ◽  
James L. Boyer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Cholestatic Liver Injury
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