Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125, a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained JNK activation. Administration of SP600125 diminished JNK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha, and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FHF by downregulating Bad and inhibiting Bid cleavage.
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PMID:An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. 1730 Aug 14

Acute liver failure caused by viruses, drugs, or liver resection, is marked by a massive degree of hepatocyte apoptosis and impaired hepatocyte proliferation, the mechanisms of which, however, still remain to be understood. The choice between life and death is associated with events in regulation of the immune system. The liver is continuously exposed to a large antigenic load that includes pathogens, toxins and dietary antigens. Bacterial toxins, including endotoxin and staphylococcal enterotoxin, have been implicated in the pathogenesis of multi-organ failure associated with liver damage through production of cytokines and chemokines. Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Among pro-inflammatory mediators, tumor necrosis factor-alpha (TNF-alpha)/TNF receptor (TNFR) systems play central roles in the physiological regulation of apoptosis as well as inflammation and immunity. These pleiotropic biological effects of TNF-alpha result from its ability to initiate different intracellular signaling pathways, which induce both pro-apoptotic and anti-apoptotic molecules. Hepatocytes appear to be poorly responsive to pro-apoptotic stimuli by TNF-alpha. Tumor necrosis factor-alpha, however, induces excessive hepatocyte apoptosis, once cells are sensitized by D-galactosamine or actinomycin D, suggesting that TNF-alpha itself also induces molecules that protect cells from apoptosis by TNF-alpha. Besides the apoptosis-inducing signal, the binding of TNF-alpha to TNFR1 triggers a series of intracellular events that result in the activation of nuclear factor-kappaB (NF-kappaB), phosphatidylinositol 3-kinase (PI3K)/Akt, and c-Jun NH(2)-terminal kinase (JNK). Inhibition of NF-kappaB may be a two-edged sword against liver injury, which inhibits pro-inflammatory gene expression in leukocytes and causes the sensitization of hepatocytes to TNF-alpha-induced apoptosis. A variety of mechanisms exist to modulate the activity of intracellular molecules and thereby affect the ultimate outcome of a liver cell's fate.
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PMID:Implication of cytokines: Roles of tumor necrosis factor-alpha in liver injury. 1912 46