Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrphostins, derivatives of benzylidene malononitrile are recognized as tyrosine kinase inhibitors that have been applied in some models of acute inflammatory conditions, like LPS and zymosan-induced shock. In the present study, we have investigated the effects of tyrphostin AG-490, on the development of multiple organ failure induced by i.p. injection of zymosan (1 mg/g body weight) in mice. Organ dysfunction and systemic inflammation was estimated 24 h after zymosan administration. Treatment of mice with AG-490 (dose, 5 mg/kg i.p. simultaneously with zymosan) decreased the number of cells and the level of NO in the peritoneal lavage. The substance attenuated the elevation of creatinine (indicator of renal failure), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (indicators for liver dysfunction) and prevented the accelerated coagulation time. The injection of zymosan resulted in a substantial increase in the serum level of TNF-alpha and IL-6, which was strongly inhibited by AG-490. Tyrphostin abolished the expression of iNOS and TNF-alphaR in the liver. Moreover, immunohistochemistry of liver showed decreased phosphorylation of Stat1 and Stat3. In conclusion, the administration of tyrphostin AG-490 in zymosan-induced nonseptic shock significantly improved the rate of survival and lead to less exerted signs of multiple organ failure.
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PMID:Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation. 1865 56

Obesity with insulin resistance and alcohol are the most frequent causes of steatohepatitis. This work investigates the contribution of bioactive TNF and Th1 type cytokines in a mouse model of steatohepatitis induced by FAT alone or FAT+EtOH and endotoxin. The extent of liver injury and cytokine activation induced by endotoxin in chronic FAT-fed mice, FAT+EtOH-fed mice, or mice fed standard chow were analyzed. Endotoxin administration to either FAT-fed or FAT+EtOH-fed mice increased serum ALT and AST compared to standard chow mice. Immunoreactive TNF was strongly activated by LPS in FAT-fed and FAT+EtOH-fed mice which presented the highest levels, but low levels were found in standard chow mice. In contrast, bioactive TNF was only present in serum of FAT-fed and in particular the highest levels were found in FAT+EtOH-fed mice. Moreover, soluble TNFR2 but not TNFR1 was found in lower amounts in serum of FAT+EtOH-fed mice compared to FAT-fed mice. Steatohepatitis was associated with increased IL-6, IFN-gamma, and iNOS mRNA and proteins. Data show that a moderately FAT diet and low-dose EtOH concur to generate steatohepatitis and TNF liver expression after LPS. In this model, changes in the regulation of TNF are associated with increased expression of IL-6, IFN-gamma, and iNOS.
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PMID:Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. 1872 87

The purpose of this study was to investigate possible beneficial effects of morin on CCl(4)-induced acute hepatotoxicity in rats. Rats received a single dose of CCl(4) (150 microL/100 g 1:1 in corn oil). Morin treatment (20 mg/kg) was given at 48, 24, and 2 h before CCl(4) administration. CCl(4) challenge elevated serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels, but these effects were prevented by the pretreatment of rats with morin. To identify the mechanism of protective activity of morin in CCl(4)-induced hepatotoxicity in rats, we investigated expressions of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and inducible nitric oxide (iNOS). The expressions of TNF-alpha, IL-1beta, IL-6, and iNOS were increased by CCl(4) treatment and increased expressions of those were decreased by morin. These findings suggest that morin prevents acute liver damage by inhibiting the production of TNF-alpha, IL-1beta, IL-6, and iNOS.
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PMID:Morin protects acute liver damage by carbon tetrachloride (CCl(4)) in rat. 1880 59

Danshen (DS) is used for treatment of various ischemic events in the traditional Chinese medicine. Hence, this study was designed to investigate its effect on ischemia/reperfusion injury (IRI) after experimental kidney transplantation (eKTx). Nephrectomized Sprague-Dawley rats underwent eKTx. Some animals were infused with 1.5 ml DS 10 min before surgery. Kidney grafts were transplanted after cold storage for 20 h in Histidine-Tryptophane-Ketoglutarate solution. After reperfusion blood samples were collected for blood urinary nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and alanine transaminase. Further, tissue was assessed for morphologic and pathophysiologic changes. Donor preconditioning with DS (DS-d) significantly decreased BUN, creatinine, LDH, and aspartate aminotransferase to 65-97% of controls while preconditioning of the recipient (DS-r) decreased values to 58-82% (P < 0.05). Tubular damage and caspase-3 decreased significantly in both DS-d and DS-r (DS-d: 96% and 67%, DS-r: 83% and 75% of controls) while heat shock protein 72 and superoxide dismutase increased significantly (DS-d: 143% and 173%, DS-r: 166% and 194% of controls). Further, inducible nitric oxide synthase and tumor necrosis factor-alpha decreased (DS-d: 84% and 61%, DS-r: 79% and 67% of controls) after DS. Preconditioning of both donors and recipients with DS significantly reduces IRI and thus improves graft function after eKTx.
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PMID:Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation. 1895 74

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

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

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


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