Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic oxidative stress plays a critical role in metabolic forms of steatohepatitis. Phyllanthus urinaria, an herbal medicine, has been reported to have potential antioxidant properties. We tested the effects of P. urinaria on nutritional steatohepatitis both in vitro and in vivo. Immortalized normal hepatocytes (AML-12) or primary hepatocytes were exposed to control, the methionine-and-choline-deficient (MCD) culture medium, in the presence or absence of P. urinaria for 24 hours. Hepatocyte triglyceride, release of alanine aminotransferase, lipoperoxides, and reactive oxygen species production were determined. Age-matched C57BL/6 and db/db mice were fed control or MCD diet for 10 days with or without P. urinaria. Hepatic steatosis, necroinflammation, triglycerides, and lipid peroxide levels were determined. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. P. urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus prevented MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450-2E1, pro-inflammatory tumor necrosis factor alpha, interleukin-6, dampened activation of inflammatory c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB), increased expression of lipolytic cytochrome P450 (Cyp4a10), and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by P. urinaria. In conclusion, P. urinaria effectively alleviated the steatohepatitis induced by the MCD, probably through dampening oxidative stress, ameliorating inflammation, and decreasing lipid accumulation.
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PMID:Phyllanthus urinaria ameliorates the severity of nutritional steatohepatitis both in vitro and in vivo. 1815 36

Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P < 0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.
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PMID:A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. 1862 89

The c-Jun N-terminal kinase (JNK) pathway enhances graft injury after liver transplantation (LT). We hypothesized that the JNK2 isoform promotes graft injury via the mitochondrial permeability transition (MPT). Livers of C57BL/6J (wild-type, WT) and JNK2 knockout (KO) mice were transplanted into WT recipients after 30 h of cold storage in UW solution. Injury after implantation was assessed by serum ALT, histological necrosis, TUNEL, Caspase 3 activity, 30-day survival, and cytochrome c and 4-hydroxynonenal immunostaining. Multiphoton microscopy after LT monitored mitochondrial membrane potential in vivo. After LT, ALT increased three times more in WT compared to KO (p < 0.05). Necrosis and TUNEL were more than two times greater in WT than KO (p < 0.05). Immunostaining showed a >80% decrease of mitochondrial cytochrome c release in KO compared to WT (p < 0.01). Lipid peroxidation was similarly decreased. Every KO graft but one survived longer than all WT grafts (p < 0.05, Kaplan-Meier). After LT, depolarization of mitochondria occurred in 73% of WT hepatocytes, which decreased to 28% in KO (p < 0.05). In conclusion, donor JNK2 promotes injury after mouse LT via the MPT. MPT inhibition using specific JNK2 inhibitors may be useful in protecting grafts against adverse outcomes from ischemia/reperfusion injury.
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PMID:C-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation. 1867 79

In the present work, we investigated the protective effects of the ethanol extract of Aralia continentalis roots (AC) on tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in a cultured Hepa1c1c7 cell line and in mouse liver. Pretreatment with AC prior to the administration of t-BHP significantly prevented the increase in serum levels of hepatic enzyme markers (ALT, AST) and lipid peroxidation and reduced oxidative stress, as measured by glutathione content, in the liver. Histopathological evaluation of the livers also revealed that AC reduced the incidence of liver lesions. The in vitro study showed that AC significantly reduced t-BHP-induced oxidative injury in Hepa1c1c7 cells, as determined by cell cytotoxicity, intracellular glutathione content, lipid peroxidation, reactive oxygen species (ROS) levels, and caspase-3 activation. Also, AC up-regulated phase II genes including heme oxygenase-1 (HO-1), NAD(P)H:quinone reductase, and glutathione S-transferase. Moreover, AC induced Nrf2 nuclear translocation and ERK1/2 and p38 activation, pathways that are involved in inducing Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of AC against t-BHP-induced hepatotoxicity may, at least in part, be due to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the ERK1/2 and p38/Nrf2 signaling pathways.
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PMID:Protective mechanisms of Aralia continentalis extract against tert-butyl hydroperoxide-induced hepatotoxicity: in vivo and in vitro studies. 1882 57

Alcoholic liver disease is multifactorial and oxidative stress is believed to play an intimate role in the initiation and progression of this pathology. The goals of this study were to investigate the effect of chronic ethanol treatment on inducing hepatic oxidative stress and peroxiredoxin 6 expression. After 9 weeks of treatment with an ethanol-containing diet, significant increases in serum ALT activity, liver to body weight ratio, liver triglycerides, CYP2E1 protein expression, and CYP2E1 activity were observed. Chronic ethanol feeding resulted in oxidative stress as evidenced by decreases in hepatic glutathione content and increased deposition of 4-hydroxynonenal and 4-oxononenal protein adducts. In addition, novel findings of decreased PRX6 protein and mRNA and increased levels of carbonylated PRX6 protein were observed in the ethanol-treated animals compared to the pair-fed controls. Lastly, NF-kappaB activity was found to be significantly increased in the ethanol-treated animals. Concurrent with the increase in NF-kappaB activity, decreases in both MEK1/2 and ERK1/2 phosphorylation were also observed in the ethanol-treated animals compared to the pair-fed controls. Together, these data demonstrate that chronic ethanol treatment results in oxidative stress, implicating NF-kappaB activation as an integral mechanism in the negative regulation of PRX6 gene expression in the mouse liver.
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PMID:Decreased expression of peroxiredoxin 6 in a mouse model of ethanol consumption. 1885 41

Bacterial LPS (endotoxin) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygenase (COX)-2 in LPS-induced liver injury, we generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector and the animals produced were subjected to a standard experimental protocol of LPS-induced acute fulminant hepatic failure (i.p. injection of low dose of LPS in combination with d-galactosamine (d-GalN)). The COX-2 transgenic mice exhibited earlier mortality, higher serum aspartate aminotransferase and alanine aminotransferase levels and more prominent liver tissue damage (parenchymal hemorrhage, neutrophilic inflammation, hepatocyte apoptosis, and necrosis) than wild-type mice. Western blot analysis of the liver tissues showed that LPS/d-GalN treatment for 4 h induced much higher cleavage of poly(ADP-ribose) polymerase, caspase-3, and caspase-9 in COX-2 transgenic mice than in wild-type mice. Increased hepatic expression of JNK-2 in COX-2 transgenic mice suggest that up-regulation of JNK-2 may represent a potential mechanism for COX-2-mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP(1), prevented LPS/d-GalN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP(1) showed less LPS/d-GalN-induced liver damage and less hepatocyte apoptosis with prolonged survival when compared with the wild-type mice. These findings demonstrate that COX-2 and its downstream prostaglandin receptor EP(1) signaling pathway accelerates LPS-induced liver injury. Therefore, blocking COX-2-EP(1) pathway may represent a potential approach for amelioration of LPS-induced liver injury.
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PMID:Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure. 1901 95

Previous results showed that pyrazole potentiates lipopolysaccharide (LPS)-induced liver injury in mice. Mechanisms involved the overexpression of cytochrome P450 2E1 (CYP2E1), oxidative stress, and activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The current study was carried out to test the hypothesis that the mitochondria permeability transition (MPT) plays a role in this pyrazole plus LPS toxicity. Mice were injected intraperitoneally with pyrazole for 2 days, followed by a challenge with LPS with or without treatment with cyclosporin A (CsA), an inhibitor of the MPT. Serum alanine aminotransferase and aspartate aminotransferase were increased by pyrazole plus LPS treatment, and CsA treatment could attenuate these increases. CsA also prevented pyrazole plus LPS-induced hepatocyte necrosis. Formation of 4-hydroxynonenal protein adducts and 3-nitrotyrosine protein adducts in liver tissue was increased by the pyrazole plus LPS treatment, and CsA treatment blunted these increases. Swelling, cytochrome c release from mitochondria to the cytosol, and lipid peroxidation were increased in mitochondria isolated from the pyrazole plus LPS-treated mice, and CsA treatment prevented these changes. CsA did not prevent the increased levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), pp38 MAPK, and p-JNK2. In conclusion, although CsA does not prevent elevations in upstream mediators of the pyrazole plus LPS toxicity (iNOS, TNF-alpha, CYP2E1, MAPK), it does protect mice from the pyrazole plus LPS-induced liver toxicity by preventing the MPT and release of cytochrome c and decreasing mitochondrial oxidative stress. These results indicate that mitochondria are the critical targets of pyrazole plus LPS in mediating liver injury.
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PMID:Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. 1902 39

Carbon tetrachloride (1 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 ALT (alanine aminotransferase) was significantly higher than that of the control group, and plasma ALT and AST (aspartate aminotransferase) activities significantly increased 24 h after CCl(4) administration. These results indicated that the necrotic process had initiated at about 12 h and developed thereafter. After 6-24 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 6 h after CCl(4) intoxication and thereafter. Oral administration of vitamin E (1 ml/kg body weight as a 1:1 mixture of alpha-tocopherol and mineral oil) 12 h before CCl(4) administration caused a significant elevation of liver vitamin E level and ameliorated liver necrosis 24 h after CCl(4) intoxication based on plasma AST and ALT. Vitamin E also significantly restored the hepatic vitamin C concentration 12 and 24 h after CCl(4) intoxication, demonstrating that vitamin E functioned as an antioxidant. The liver vitamin E concentration was not changed by vitamin E supplementation to rats that did not receive CCl(4). This result indicated that vitamin E accumulated in the damaged liver. The activation of JNK, ERK1/2 and p38 MAPK took place 1.5 h after CCl(4) administration. Co-administration of alpha-tocopherol with CCl(4) did not affect these early changes in MAPKs.
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PMID:Effect of alpha-tocopherol on carbon tetrachloride intoxication in the rat liver. 1906 52

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

Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 microM) concentration-dependently attenuated TNF-alpha- and LPS-stimulated alpha-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-alpha-induced collagen collagen deposition, NFkappaB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic alpha-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1alpha2, TGF-beta1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-kappaB activation pathways.
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PMID:Inhibitory effects of armepavine against hepatic fibrosis in rats. 1972 40


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