Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease, which leads to cirrhosis of liver and hepatocellular carcinoma. The HCV core protein, a viral nucleocapsid, has been shown to affect various intracellular events, including cell proliferation and apoptosis. However, the precise mechanisms of the effects are not fully understood. In this study, we show that HCV core protein sensitizes human hepatocellular carcinoma cell line, Huh7, conferred sensitivity to TRAIL-, but not Fas ligand-mediated apoptosis. Huh7 cells are resistant to TRAIL, despite the induction of caspase-8 after TRAIL engagement. However, HCV core protein induces TRAIL apoptosis signaling via sequential induction of caspase-8, Bid cleavage, activation of mitochondrial pathway, and effector caspase-3. HCV core protein also induces activation of caspase-9 after TRAIL engagement, and the induction of TRAIL sensitivity by HCV core protein could be reversed by caspase-9 inhibitor. Therefore, the HCV core protein-induced TRAIL-mediated apoptosis is dependent upon activation of caspase-8 downstream pathway to convey the death signal to mitochondria, leading to activation of mitochondrial signaling pathway and breaking the apoptosis resistance. These results combined indicate that the HCV core protein enhances TRAIL-, but not Fas ligand-mediated apoptotic cell death in Huh7 cells via a mechanism dependent on the activation of mitochondria apoptosis signaling pathway. These results suggest that HCV core protein may have a role in immune-mediated liver cell injury by modulation of TRAIL-induced apoptosis.
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PMID:Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway. 1569 47

Most chronic liver diseases are accompanied by oxidative stress, which may induce apoptosis in hepatocytes and liver injury. Oxidative stress induces heme oxygenase-1 (HO-1) expression. This stress-responsive cytoprotective protein is responsible for heme degradation into carbon monoxide (CO), free iron, and biliverdin. CO is an important intracellular messenger; however, the exact mechanisms responsible for its cytoprotective effect are not yet elucidated. Thus, we investigated whether HO-1 and CO protect primary hepatocytes against oxidative-stress-induced apoptosis. In vivo, bile duct ligation was used as model of chronic liver disease. In vitro, primary hepatocytes were exposed to the superoxide anion donor menadione in a normal and in a CO-- containing atmosphere. Apoptosis was determined by measuring caspase-9, -6, -3 activity and poly(ADP-ribose) polymerase cleavage, and necrosis was determined by Sytox green staining. The results showed that (1) HO-1 is induced in chronic cholestatic liver disease, (2) superoxide anions time- and dose-dependently induce HO-1 activity, (3) HO-1 overexpression inhibits superoxide-anions-induced apoptosis, and (4) CO blocks superoxide-anions-induced JNK phosphorylation and caspase-9, -6, -3 activation and abolishes apoptosis but does not increase necrosis. We conclude that HO-1 and CO protect primary hepatocytes against superoxide-anions-induced apoptosis partially via inhibition of JNK activity. CO could represent an important candidate for the treatment of liver diseases.
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PMID:Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform. 1820 60

Metformin is a biguanide used in the treatment of type 2 diabetes mellitus and obesity. The main mechanism of action is to decrease the intestinal glucose absorption and the hepatic glucose production, however, it does not influence insulin secretion. Metformin also increases the affinity of the insulin receptor, reduces high insulin levels and improves insulin resistance. Additionally, it promotes weight loss. Metformin is a pleiotropic compound but acts, largely, by activating 5 adenosine monophosphate (AMP)-activated protein kinase (AMPK). Data suggest that the therapeutic effects of this compound are mediated, at least in part, through an upregulation of paraoxonase-1 (PON1) synthesis. PON1 is a thiolactonase that degrades lipid peroxides, and downregulates the chemokine (C-C motif) ligand 2 (CCL2) which is a pro-inflammatory chemokine that stimulates the migration of monocytes to areas of inflammation where they differentiate into macrophages. However, the prescription of metformin in patients with liver disease is controversial since, in some cases, this drug causes worsening of liver function. Patients with chronic liver disease have decreased hepatic PON1 activity. A study in mice deficient in PON1 showed that in this experimental model, metformin administration increased the severity of steatosis, increased CCL2 expression, did not activate AMPK, and increased the expression of the apoptosis marker caspase-9. These results suggest that PON1 is essential for the successful activation of AMPK in the liver, and for metformin to demonstrate its therapeutic function.
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PMID:Relationships Between Metformin, Paraoxonase-1 and the Chemokine (C-C Motif) Ligand 2. 2763 39