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)

We investigated the regulation of antioxidant system under acetaminophen (AAP) toxicity. Twelve male New Zealand rabbits were divided into two groups with the following treatments: Group 1 animals were intraperitoneally injected with single saline (control). Group 2 animals were treated with intraperitoneal injection of AAP at a dose of 250 mg/kg body weight. Four hours following the treatments, blood samples were collected and the rabbits were sacrificed to collect liver samples. Hepatocellular damage was evaluated by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as histopathological examinations and immunohistochemical analysis. Tissue-reduced glutathione (GSH), nitric oxide (NO(.)), and malondialdehyde (MDA) levels were also measured. mRNA expression levels of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) were measured by semi-quantitative RT-PCR. It was found that liver GSH was reduced significantly in AAP-treated rabbits (P < 0.05), while MDA and NO(.) levels were increased when they were compared to control (P < 0.05). Blood AST and ALT levels were also increased following AAP treatment (P < 0.05). Hepatocellular degeneration and severe necrosis were detected in histopathological examinations. Increased immunostaining was observed for inducible nitric oxide synthase (iNOS) and nitrotyrosine in the liver. There were no changes in mRNA expression levels of SOD, CAT, and GSH-Px after AAP treatment compared to control group. These results suggest that the expression of these enzymes, which are involved in the antioxidant system, may not be altered after AAP toxicity, although classical toxic changes such as depletion of GSH, hepatocellular necrosis, and increased immunostaining for iNOS and nitrotyrosine were detected.
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PMID:The effects of acute acetaminophen toxicity on hepatic mRNA expression of SOD, CAT, GSH-Px, and levels of peroxynitrite, nitric oxide, reduced glutathione, and malondialdehyde in rabbit. 1903 54

Endotoxemia caused by LPS is a life-threatening and inflammatory condition contributing to multiple organ failure. Viruses or bacteria require sialic acid (SA) for target-cell binding. We suggest that exogenous SA through masking or mediating the binding of LPS to the target cells may attenuate LPS-induced liver dysfunction and cecal ligation and puncture-induced shock. We found that SA can directly scavenge O2-, H2O2, and NO activity by a chemiluminescence analyzer and bind to LPS with high affinity using surface plasmon resonance. Intravenous SA significantly increased plasma SA concentration within 4 h. We then assessed the potential effect of SA on LPS-induced acute endotoxemia in the rat. Intravenous LPS (10-50 mg/kg) dose-dependently increased plasma endotoxin and reactive oxygen species in the blood, bile, and liver and increased plasma alanine aminotransferase and aspartate aminotransferase levels as well as TNF-alpha, monocyte chemoattractant protein 1, tissue inhibitor of metalloproteinase 1, IL-1beta, and IL-6 levels in the rats. Thirty minutes after LPS stimulation, SA decreased LPS-enhanced endotoxin level, oxidative stress, alanine aminotransferase and aspartate aminotransferase levels, and cytokine concentration and ameliorated histopathologic alteration in the liver. We found that SA increased LPS-depressed Mn-superoxide dismutase, CuZn-superoxide dismutase, and heat shock protein 70 and decreased LPS-enhanced iNOS and proapoptotic Bax protein expression in the liver by Western blot. Sialic acid was given after treatment to rats subjected to cecal ligation and puncture, and the hypotensive effect was blunted for 6 h. In conclusion, SA treatment can counteract LPS-enhanced acute endotoxemia and oxidative injury via a direct scavenging reactive oxygen species activity and neutralization potential.
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PMID:Sialic acid reduces acute endotoxemia-induced liver dysfunction in the rat. 1906 Jul 86

Reperfusion following liver ischemia results in oxidative stress leading to liver injury. The aim of this study was to investigate the combined effects of two antioxidant agents, rutin and L-arginine, in rat liver ischemia-reperfusion (I/R). Male Wistar rats were divided into five groups: 1) sham operated, 2) I/R, 3) I/R+rutin, 4) I/R+L-arginine, and 5) I/R+rutin+L-arginine. Plasmatic and hepatic levels of alanine transaminase (ALT), aspartate transaminase (AST), lipid peroxides (LOOH), and thiol groups (RSH) were examined, as well as DNA fragmentation and liver histopathology. Furthermore, to elucidate the pathophysiological processes involved in the antioxidant mechanism(s) of rutin and L-arginine, we assessed the expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) isoforms and heme oxygenase-1 (HO-1), both playing key roles in the biochemical cascade of liver injury. Significant increase in plasmatic ALT and AST activities were observed in untreated I/R rats compared with sham-operated animals, whereas treatment with rutin or L-arginine in I/R rats reduced hepatic damage. Interestingly, combined therapy with rutin and L-arginine resulted in a further reduction of plasmatic ALT and AST activities compared with rutin or L-arginine alone. These results were further confirmed by the analysis of DNA fragmentation, LOOH, RSH groups, and liver histopathology, which showed the highest protective effects following the coadministration of rutin and L-arginine. Finally, the combined therapy protocol resulted in a significant induction of liver HO-1 and a concomitant reduction of iNOS expression that may both be responsible for the beneficial effects of the proposed pharmacological protocol.
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PMID:Beneficial effects of rutin and L-arginine coadministration in a rat model of liver ischemia-reperfusion injury. 1910 3

In this study, it was aimed to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on cisplatin hepatotoxicity. Thirty New Zealand rabbits were divided into 5 groups as group 1 (saline-injected control, C), group 2 (1% ethanol; vehicle for CAPE, E), group 3 (CAPE), group 4 (cisplatin, CS) and group 5 (cisplatin plus CAPE, CS+CAPE). Cisplatin caused increased immunoreactivity against inducible nitric oxide synthase (iNOS), but CAPE treatment reduced the immunoreactive hepatocytes. Liver malondialdehide (MDA), nitric oxide (NO(.)) levels and xanthine oxidase (XO) activities were higher in CS than in groups C and E. Cisplatin treatment also significantly decreased the tissue reduced glutathione (GSH) concentration compared to groups C and E. CAPE administration normalized the tissue GSH level and XO activity in group CS+CAPE, whereas CAPE treatment did not affect MDA level in group CS+CAPE. In addition, CAPE treatment significantly depressed the cisplatin-induced NO(.) increase in group CS+CAPE. Histopathologically, cisplatin caused hydropic degenerations, necrosis in hepatocytes, sinusoidal congestion, Kupffer cell proliferation and mononuclear cell infiltration. These alterations were less severe in rabbits receiving CS+CAPE. Parallel to histopathology, cisplatin increased serum AST and ALT levels, whereas CAPE treatment significantly reduced cisplatin-induced AST and ALT rise in the serum. Results suggest that cisplatin causes oxidative and nitrosative damage to hepatocytes. Cisplatin-induced increase in XO and NO(.) could contribute oxidative stress in the hepatotoxicity. CAPE shows partial protection against cisplatin-associated biochemical and histopathological alterations.
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PMID:Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. 1926 59

Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
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PMID:Ketamine-induced hepatoprotection: the role of heme oxygenase-1. 1937 6

GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H(2)S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappaB activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Time-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappaB and STAT-3). These results suggest an anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H(2)S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study.
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PMID:GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. 1937 98

Sepsis remains the leading cause of death in intensive care units. Uncontrolled systemic inflammation and an impaired protein C pathway are two important contributors to sepsis pathophysiology. Based on the beneficial effects of the saponin fraction from Astragalus membranaceus roots (SAM) against inflammation, liver dysfunction, and endothelium injury, we investigated the potential protective roles and underlying mechanisms of SAM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. SAM, orally administered 1 h before and after CLP, significantly elevated the survival rate of mice. At 96 h after CLP operation, all mice in the model group died, whereas 33.3% of mice in the SAM (400 mg/kg)-treated group survived. SAM attenuated both inflammatory factors and their abilities to induce tissue dysfunction, which was mainly evidenced by decreased infiltration of polymorphonuclear leukocytes, tissue edema, and lung wet-to-dry weight ratio, lowered levels of myeloperoxidase (MPO), nitric oxide (NO), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in serum, as well as downregulated expressions of iNOS and IL-1beta mRNA in livers. Furthermore, we addressed the effects of SAM on the protein C (PC) pathway, closely linked with sepsis. In CLP-induced septic mice, SAM elevated the impaired expression of PC mRNA in livers. In vitro, SAM reversed the decreased expressions of thrombomodulin (TM) and endothelial PC receptor (EPCR) mRNA induced by lipopolysaccharide (LPS) in endothelial cells. These findings suggest that SAM is able to restore the impaired protein C pathway. Taken together, the current study demonstrates that SAM has protective effects on polymicrobial sepsis in mice. The mechanisms of action involve anti-inflammation and upregulation of the PC pathway.
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PMID:Saponin fraction from Astragalus membranaceus roots protects mice against polymicrobial sepsis induced by cecal ligation and puncture by inhibiting inflammation and upregulating protein C pathway. 1954 65

Animal models used to study the pathogenesis of non-alcoholic fatty liver disease (NAFLD) are, in general, either genetically altered, or fed with a diet that is extremely high in fat or carbohydrates. Recent findings support the role of oxidative stress, lipid peroxidation and inflammation as probable causative factors. We hypothesize that not only the amount of dietary fat, but the quality of fat is also important in inducing NAFLD. Based on previous observations that female rats fed a diet comprising unsaturated fatty acids are susceptible to liver injury, we proposed that female rats fed with a diet containing fish oil and dextrose would develop pathological and biochemical features of NAFLD. We fed a highly unsaturated fat diet (30% fish oil) to female Sprague-Dawley rats (180-200g), consumed ad libitum for 8 weeks (NAFLD; n=6-8 ). Control animals (CF; n=6-8) were fed with an isocaloric regular rat chow. At killing, blood and liver samples were collected for serum alanine aminotransferase (ALT), histology and molecular analysis. Each histological sample was evaluated for fatty liver (graded from 0 to 4+ according to the amount of fatty change), necrosis (number of necrotic foci (no./mm2) and inflammation (cells per mm2). The amount of collagen formation was estimated based on the amount of Sirius Red staining. Reverse transcriptase polymerase chain reaction (RT-PCR) was carried out for tumor necrosis factor alpha (TNF-alpha), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), adiponectin, glutathione peroxidase (GPx), superoxide dismutase (Cu/Zn SOD) and catalase (CAT). Western Blot analysis was done for cyclooxygenases-2 (COX-2), inducible nitric oxide synthase (iNOS) and nitrotyrosine. Electrophoretic mobility shift assay was performed for nuclear factor-kappa B (NF-kB) activity. NAFLD rats had a significantly higher serum ALT level, amount of collagen formation, fatty liver, necrosis and inflammation when compared with the chow-fed control rats. mRNA and protein levels of NF-kB regulated genes, which included TNF-alpha, COX-2 and iNOS were also significantly (p<0.01; p<0.01; p<0.05 respectively) upregulated in the NAFLD group when compared with the chow-fed control rats. mRNA levels of antioxidants CAT and GPX were reduced by 35% and 50% respectively in the NAFLD group. However, Cu/Zn SOD mRNA was similar in both groups. The mRNA level of adiponectin was also reduced in NAFLD group. NF-kB activity was markedly increased in the NAFLD rats (p<0.01). The level of oxidative stress, represented by the formation of nitrotyrosine, was significantly elevated in the NAFLD rats (p<0.01). We conclude that NAFLD rats demonstrated several features of NAFLD, which included fatty liver, inflammation, necrosis, increased oxidative stress, an imbalance between pro and antioxidant enzymes mRNAs, reduced adiponectin levels and upregulation of pro-inflammatory mediators. We propose that female rats fed with a diet containing highly unsaturated fatty acids are an extremely useful model for the study of NAFLD.
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PMID:Voluntary oral feeding of rats not requiring a very high fat diet is a clinically relevant animal model of non-alcoholic fatty liver disease (NAFLD). 1960 63

Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.
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PMID:Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose. 1972 5

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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