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)

Hemorrhagic shock and resuscitation cause endotoxemia and hepatocellular damage. Because lipopolysaccharide-binding protein (LBP) enhances cellular responses to endotoxin, our aim was to determine whether LBP contributes to hemorrhage/resuscitation-induced injury by comparing LBP knockout and wild-type mice. Under pentobarbital anaesthesia, wild-type and LBP-deficient mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer solution. Serum alanine aminotransferase (ALT) necrosis, neutrophil infiltration, and 4-hydroxynonenal by histology/cytochemistry and stress kinase activation by immunoblot analysis were then determined. ALT in wild-type mice was 2,461 +/- 383 and 1,418 +/- 194 IU/l (means +/- SE), respectively, at 2 and 6 h after resuscitation versus sham ALT of 102 +/- 6 IU/l. In LBP-deficient mice, ALT was blunted at both time points to 1,108 +/- 340 and 619 +/- 171 IU/l (P < 0.05). Liver necrosis after 6 h was also attenuated from 3.5 +/- 0.8% in wild-type mice to 1.3 +/- 0.5% in LBP-deficient mice (P < 0.05). After hemorrhage/resuscitation, neutrophil infiltration increased 71% more in wild-type than LBP knockout mice. Similarly, hepatic 4-hydroxynonenal staining, indicative of lipid peroxidation, decreased from 33.8 +/- 4.5% in wild-type mice to 11.6 +/- 1.9% in knockout mice (P < 0.05). After hemorrhage/resuscitation, activation of MAPKs, JNK and ERK, occurred in wild-type mice, which was largely blocked in LBP-deficient mice. However, endotoxin in portal blood after resuscitation was not significantly different between wild-type and knockout mice. In conclusion, hemorrhagic shock and resuscitation to mice cause severe, LBP-mediated hepatocellular damage. An absence of LBP blunts hepatocellular injury with decreased neutrophil infiltration, oxidative stress, and c-Jun and ERK activation.
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PMID:Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. 1661 72

Scutellarin is a natural compound from a Chinese herb. The purpose of this paper was to study the protective effect of scutellarin on concanavalin A (Con A)-induced immunological liver injury and its effect on liver nuclear factor kappaB (NF-kappaB), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and inducible nitric oxide synthase (iNOS) expression in mice. Mouse liver injury was produced by injection of Con A 25 mg kg-1 via the tail vein. Scutellarin 50 or 100 mg kg-1 was peritoneally administered to mice 9 or 1 h before injection of Con A. The levels of serum alanine aminotransferase (ALT) and asparatate aminotransferase (AST), NO2-/NO3- and TNF-alpha were determined with biochemical kits, and ELISA using Quantikine Mouse TNF-alpha kit according the manufacturer's instructions. Liver lesions were examined by light microscope. The expression of TNF-alpha, IFN-gamma, iNOS and Fas mRNA in the livers was detected by RT-PCR; and the expression of c-Fos, c-Jun, iNOS and IkappaB proteins was measured by Western Blotting. As a result, pretreatment with scutellarin 100 mg kg-1 significantly decreased the serum ALT, AST, NO2-/NO3- and TNF-alpha levels, and also reduced liver lesions induced by Con A. Scutellarin 100 mg kg-1 down-regulated expression of TNF-alpha and iNOS mRNA, and c-Fos, c-Jun and iNOS protein, while scutellarin enhanced the degradation of IkappaB in the livers of mice injected with Con A. The results suggest that scutellarin has a protective action against Con A-induced liver injury in mice, and its active mechanism may be related to the inhibition of the NF-kappaB-TNF-alpha-iNOS transduction pathway.
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PMID:The protective action of scutellarin against immunological liver injury induced by concanavalin A and its effect on pro-inflammatory cytokines in mice. 1722 28

Carbon tetrachloride (CCl(4): 4 ml/kg body weight as a 1:1 mixture of CCl(4) and mineral oil) was orally administered to rats. After 12 h the activity of plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) was significantly higher than that of the control group and plasma AST and ALT activities increased thereafter. These results indicated that the necrotic process was active at about 12 h and developed thereafter. After 2-24 h of CCl(4) administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced as early as 2 h after CCl(4) intoxication and thereafter. Phosphorylated JNK (c-Jun NH(2)-terminal kinase) and phospho-ERK1/2 (extracellular signal-regulated kinase1/2) were significantly increased transiently 1-3 h after treatment with CCl(4), while phosphorylated p38 decreased significantly 1-24 h after CCl(4) treatment. These results indicated that the change in MAPKs (mitogen activated protein kinases) slightly preceded that in vitamin C, the most sensitive chemical indicator of oxidative stress.
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PMID:Activation of mitogen activated protein kinase (MAPK) during carbon tetrachloride intoxication in the rat liver. 1728 12

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

Oxidant stress is critically involved in various liver diseases. Superoxide formation causes c-Jun NH2-terminal kinase (JNK)- and caspase-dependent apoptosis in cultured hepatocytes. To verify these findings in vivo, male Fisher rats were treated with diquat and menadione. The oxidant stress induced by both compounds was confirmed by increased formation of glutathione disulfide and 4-hydroxynonenal protein adducts. Plasma alanine aminotransferase activities increased from 46+/-4 U/l in controls to 955+/-90 U/l at 6 h after diquat treatment. Hematoxylin and eosin staining of liver sections revealed large areas of necrotic cells at 3 and 6 h. DNA strandbreaks, evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, showed clusters of TUNEL-positive cells, where the staining was predominantly cytosolic and the cells were swollen, indicating oncotic necrosis. There was no significant increase in caspase-3 activities or relevant release of DNA fragments into the cytosol at any time between 0 and 6 h after diquat treatment. Despite the activation of JNK after high doses of diquat, the JNK inhibitor SP-600125 did not protect against diquat-induced necrosis. Menadione alone did not cause liver injury, but, in combination with phorone and FeSO4, induced moderate oncotic necrosis. On the other hand, if animals were treated with galactosamine/endotoxin as positive control for apoptosis, caspase-3 activities were increased by 259%, the number of TUNEL-positive cells with apoptotic morphology was increased 103-fold, and DNA fragmentation was enhanced 6-fold. The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation.
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PMID:Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation. 1913 81

Inhibition of c-Jun N-terminal kinase (JNK) by a cell-penetrating, protease-resistant JNK peptide (D-JNKI-1) before hemorrhage and resuscitation (H/R) ameliorated the H/R-induced hepatic injury and blunted the proinflammatory changes. Here we tested the hypothesis if JNK inhibition at a later time point-after hemorrhagic shock but before the onset of resuscitation-in a rat model of H/R also confers protection. Twenty-four male Sprague-Dawley rats (250 - 350 g) were randomly divided into 4 groups: 2 groups of shock animals were hemorrhaged to a MAP of 32 to 37 mmHg for 60 min and randomly received either D-JNKI-1 (11 mg/kg i.p.) or sterile saline as vehicle immediately before the onset of resuscitation. Two groups of sham-operated animals underwent surgical procedures without H/R and were either D-JNKI-1 or vehicle treated. Rats were killed 2 h later. Serum activity of alanine aminotransferase and serum lactate dehydrogenase after H/R increased 3.5-fold in vehicle-treated rats as compared with D-JNKI-1-treated rats. Histopathological analysis revealed that hepatic necrosis and apoptosis (hematoxylin-eosin, TUNEL, and M30, respectively) were significantly inhibited in D-JNKI-1-treated rats after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as markers of inflammation (hepatic and serum IL-6 levels and hepatic infiltration with polymorphonuclear leukocytes) were also reduced in D-JNKI-1-treated rats. LPS-stimulated TNF-alpha release from whole blood from hemorrhaged and resuscitated animals was higher in vehicle-treated rats as compared with D-JNKI-1-treated rats. c-Jun N-terminal kinase inhibition after hemorrhage before resuscitation resulted in a reduced activation of c-Jun. Taken together, these results indicate that D-JNKI-1 application after hemorrhagic shock before resuscitation blunts hepatic damage and proinflammatory changes during resuscitation. Hence, JNK inhibition is even protective when initiated after blood loss before resuscitation. These experimental results indicate that the JNK pathway may be a possible treatment option for the harmful consequences of H/R.
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PMID:Inhibition of c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damage and inflammatory response in male rats. 1929 84

Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 +/- 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet-induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH(2)-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function.
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PMID:Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. 2020 61

Drug induced liver injury (DILI) accounts for more than 50% of the cases of acute liver failure in this country, and is the major cause of drug withdrawal from the market. DILI has been associated with the induction of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). Pro-inflammatory cytokines activate the mitogen activated protein kinase, c-Jun-N-terminal kinase (JNK) in the liver. Recent studies have shown that JNK can regulate the hepatotoxicity of the analgesic, acetaminophen (APAP). Several reports have shown that inflammation induced by the endotoxin, lipopolysaccharide (LPS) augments the toxic response to hepatotoxicants in vivo. However, the mechanism by which inflammation alters drug-induced hepatotoxicity is not known. This study investigated the role of inflammatory mediators in regulating the toxicity of the hepatotoxic drugs, APAP or chlorpromazine (CPZ) in primary mouse hepatocytes. We found that, pre-treatment with TNF-alpha resulted in approximately 50 to 60% increase in alanine aminotransferase (ALT) levels by APAP or CPZ, while interleukin-1beta (IL-1beta) or IL6 treatments showed only 15-20% increase in ALT release. The bacterial components, LPS or lipoteichoic acid (LTA) increased ALT release by approximately 35 to 38% upon drug treatment of the hepatocytes. The JNK inhibitor, SP600125 significantly diminished APAP and CPZ toxicity with or without TNF-alpha. Pre-treatment with TNF-alpha resulted in prolonged activation of JNK (upto 2 hr) in the presence of APAP or CPZ. These results show that TNF-alpha is the major cytokine involved in sensitizing hepatocytes to APAP- or CPZ-induced hepatotoxicity, likely by a mechanism involving sustained activation of JNK.
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PMID:Role of c-Jun N-terminal kinase (JNK) in regulating tumor necrosis factor-alpha (TNF-alpha) mediated increase of acetaminophen (APAP) and chlorpromazine (CPZ) toxicity in murine hepatocytes. 2037 67

Rat liver was subjected to two-thirds warm ischemia for 45 min and reperfusion (I/R) to evaluate the resulting oxidative stress. The plasma alanine aminotransferase and aspartate aminotransferase activities were significantly higher than those in the sham group 1.5-24 h after I/R, showing extensive liver cell death. The level of oxidative stress was compared between the ischemic and non-ischemic regions based on the change in antioxidative vitamins C and E. The vitamin C level was significantly decreased during I/R in both the ischemic and non-ischemic regions 0, 1.5, 3, 6, 12, and 24 h after the start of reperfusion, showing enhanced oxidative stress even in the non-ischemic lobules. This decrease of vitamin C in the ischemic region was significantly higher than that in the non-ischemic lobules, while the vitamin E content was decreased only in the ischemic lobes, demonstrating higher oxidative stress in the ischemic region than that in the non-ischemic region. Early transient activation of cytoprotective extracellular signal-related kinase (ERK) was apparent in both the ischemic and non-ischemic lobules, reflecting oxidative stress in both regions. Early transient activation of c-Jun NH(2)-terminal kinase (JNK) was only apparent in the ischemic region, corresponding to extensive oxidative stress and liver cell death. These results demonstrate that significant oxidative stress was induced, but that JNK leading to cell death was not activated in the non-ischemic part of the liver.
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PMID:Oxidative stress in the ischemic and non-ischemic parts of the rat liver after two-thirds ischemia/reperfusion. 2046 Jul 29

Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-A(y) mice, an animal model of metabolic syndrome. Twelve-week-old male KK-A(y) and C57Bl/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun NH(2)-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichloro-dihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-A(y) mice than in C57Bl/6 mice and significantly increased serum alanine aminotransferase levels in KK-A(y) mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-A(y) mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-A(y) mice. Exposure to 20 microM tert-butyl hydroperoxide did not kill hepatocytes isolated from C57Bl/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-A(y) mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-A(y) mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury.
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PMID:Diabetic KK-A(y) mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen. 2053 6


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