Liver Injury During Acute Pancreatitis, , The Role of Pancreatitis-Associated Ascitic Fluid (PAAF), p38-MAPK, and Caspase-3 in Inducing Hepatocyte Apoptosis

2003 ◽  
Vol 7 (2) ◽  
pp. 200-208 ◽  
Author(s):  
J Yang
Keyword(s):  
Acute Pancreatitis ◽  
Liver Injury ◽  
P38 Mapk ◽  
Ascitic Fluid ◽  
Caspase 3 ◽  
Hepatocyte Apoptosis

scholarly journals Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia

2021 ◽  
Vol 10 (12) ◽  
pp. 2718
Author(s):  
Omid Madadi-Sanjani ◽  
Gunnar Bohlen ◽  
Fabian Wehrmann ◽  
Julia Andruszkow ◽  
Karim Khelif ◽  
...  
Keyword(s):  
Liver Injury ◽  
Biliary Atresia ◽  
Caspase 3 ◽  
Serum Levels ◽  
Healthy Individuals ◽  
Serological Detection ◽  
Caspase Activation ◽  
Hepatocyte Apoptosis ◽  
Non Invasive ◽  
Cholestatic Diseases

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis

2021 ◽  
Author(s):  
Tetsuo Takehara ◽  
Naoki Mizutani ◽  
Hayato Hikita ◽  
Yoshinobu Saito ◽  
Yuta Myojin ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Liver Injury ◽  
Cell Viability ◽  
Liver Regeneration ◽  
Adaptor Protein ◽  
Chronic Liver ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Injury ◽  
The Impact

Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration.

Protective effect of Trillium tschonoskii saponin on CCl4-induced acute liver injury of rats through apoptosis inhibition

2016 ◽  
Vol 94 (12) ◽  
pp. 1291-1297 ◽  
Author(s):  
Hao Wu ◽  
Yong Qiu ◽  
Ziyang Shu ◽  
Xu Zhang ◽  
Renpeng Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Caspase 3 ◽  
Acute Liver Injury ◽  
Protective Role ◽  
High Dose ◽  
Dependent Manner ◽  
Hepatocyte Apoptosis ◽  
Liver Index ◽  
Tnf Α ◽  
Trillium Tschonoskii

To explore hepatoprotective role and underlying mechanisms of Trillium tschonoskii Maxim (TTM), 36 rats were randomly divided into control, CCl4-induced liver injury model, and biphenyl dimethyl dicarboxylate (DDB) and low-, moderate-, and high-dose TTM treatment groups. After CCl4-induced model establishment, the rats from DDB and TTM groups were administrated with DDB at 0.2 g/kg per day and TTM at 0.1, 0.5, and 1.0 g/kg per day, while the rats from control and model groups were administrated with saline. After 5 days of treatments, all rats were sacrificed for determining serum ALT and AST levels and liver index, examining histopathological changes in liver through HE and TUNEL staining, and evaluating TNF-α and IL-6 mRNA expression by real-time PCR, and caspase-3, Bcl-2, and Bax expression by Western blot. Results indicated that CCl4 could induce acute liver injury and abnormal liver function in rats with obvious hepatomegaly, increased liver index, high ALT and AST levels, up-regulated TNF-α and IL-6, and overexpressed Bax and caspase-3. However, DDB and TTM could execute protective role in CCl4-induced liver injury in rats through reducing ALT and AST levels, rescuing hepatomegaly, down-regulating inflammatory factors and inhibiting hepatocyte apoptosis in a dose-dependent manner. Therefore, TTM has obvious protective role in CCl4-induced liver injury of rats through inhibiting hepatocyte apoptosis.

The role of ROS in microcystin-LR-induced hepatocyte apoptosis and liver injury in mice

Toxicology ◽  
2007 ◽  
Vol 232 (1-2) ◽  
pp. 15-23 ◽  
Author(s):  
Dan Weng ◽  
Yan Lu ◽  
Yinna Wei ◽  
Ying Liu ◽  
Pingping Shen
Keyword(s):  
Liver Injury ◽  
Hepatocyte Apoptosis

Mechanisms of Liver Injury. I. TNF-α-induced liver injury: role of IKK, JNK, and ROS pathways

2006 ◽  
Vol 290 (4) ◽  
pp. G583-G589 ◽  
Author(s):  
Robert F. Schwabe ◽  
David A. Brenner
Keyword(s):  
Liver Injury ◽  
Liver Regeneration ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatocyte Proliferation ◽  
Liver Mass ◽  
Hepatocyte Apoptosis ◽  
Signaling Mechanisms ◽  
Tnf Α

TNF-α activates several intracellular pathways to regulate inflammation, cell death, and proliferation. In the liver, TNF-α is not only a mediator of hepatotoxicity but also contributes to the restoration of functional liver mass by driving hepatocyte proliferation and liver regeneration. This review summarizes recent advances in TNF-α signaling mechanisms that demonstrate how the IKK, ROS, and JNK pathways interact with each other to regulate hepatocyte apoptosis and proliferation. Activation of these pathways is causatively linked to liver injury induced by concanavalin A, TNF-α, and ischemia-reperfusion and to liver regeneration and hepatocarcinogenesis. In light of recent findings, pharmacological inhibitors of JNK and IKK and antioxidants may be promising new tools for the treatment of hepatitis, ischemia-reperfusion injury, and hepatocellular carcinoma.

scholarly journals SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yingting Zhang ◽  
Xidai Long ◽  
Xin Ruan ◽  
Qian Wei ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Liver Injury ◽  
Protein Expression ◽  
Nicotinamide Adenine Dinucleotide ◽  
Target Gene ◽  
Alcoholic Liver Injury ◽  
Protein Acetylation ◽  
Hepatocyte Apoptosis ◽  
Enhancer Binding Protein

AbstractProtein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.

scholarly journals The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Pang ◽  
Hao Jin ◽  
Xiquan Ke ◽  
Zhongran Man ◽  
Yong Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Concanavalin A ◽  
Serum Levels ◽  
Hepatocyte Apoptosis ◽  
Con A ◽  
Serotonin 2A Receptor ◽  
Serotonin 2A

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

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