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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged liver ischemia followed by reperfusion (I/R) causes functional and structural damage to liver cells, resulting in necrosis and apoptosis. c-jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK(1)/SAPK(1)) is activated during I/R and participates in the onset of the apoptosis program. Excessive blood loss during surgery can hinder postoperative recovery. Intermittent portal triad clamping (PTC) is better tolerated than prolonged continuous ischemia. This study was designed to demonstrate that intermittent ischemia could improve postischemic survival rates by a decrease of JNK(1)/SAPK(1) and caspase 3 activation, which were involved in the apoptosis process. Rats were subjected to intermittent 1-hour ischemia (15-minute ischemia/5-minute reperfusion, 4 times), followed by 220-minute reperfusion, or to continuous ischemia (1 hour), followed by 240-minute reperfusion. Mortality rates were assessed on day 7. Serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase levels (LDH) were measured 6 hours after ischemia. This study was completed in primary cultured isolated rat hepatocytes, subjected to the same continuous or intermittent hypoxic conditions. The activation status of JNK(1)/SAPK(1) was evaluated by immunoprecipitation or Western blotting experiments. Apoptosis was assessed by measuring caspase activation and by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) reaction. Eighty percent of the intermittent-ischemia group was alive 7 days after surgery and serum enzyme levels were significantly decreased. Intermittent hypoxia or ischemia did not lead to JNK(1)/SAPK(1) activation, but at least 3 hypoxia-reoxygenation (H/R) sets were necessary to inhibit kinase activation. Consequently, caspase 3 activation and apoptosis were dramatically reduced. Intermittent ischemia is a powerful, protective way to reduce I/R damage of the liver, by reduction of JNK(1)/SAPK(1) activation associated with a down-regulation of caspase 3 activity, which leads to inhibition of hepatocyte apoptosis.
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PMID:Intermittent ischemia reduces warm hypoxia-reoxygenation-induced JNK(1)/SAPK(1) activation and apoptosis in rat hepatocytes. 1167 68

Previous studies showed that Pien Tze Huang, a Chinese folk medicine well known for its therapeutic activity in treating liver diseases, protected the liver against carbon tetrachloride (CCl4)-induced damage in mice. In the present study, natural musk, one of the important ingredients of Pien Tze Huang, was replaced by a formulated substitute, and the new formulation of Pien Tze Huang was shown to have similar chromatographic patterns to the original Pien Tze Huang in gas chromatography-mass spectrometry and high performance liquid chromatography. When used in treating mice with CCl4- or galactosamine-induced liver damage, both the original and new formulations of Pien Tze Huang were found to be able to suppress to a similar extent both the histopathological changes in the liver and the elevation of serum alanine aminotransferase and aspartate aminotransferase. Necrosis, cellular ballooning, microvesicular steatosis and lymphocytes infiltration were all significantly reduced in the damaged liver. In hepatoma cells, both formulations activated the activator protein 1 (AP1) enhancer sequence, indicating that both of them were able to act through the JNK signal transduction pathway. The results of the present study showed that the substitution for natural musk does not affect the hepatoprotective activities of Pien Tze Huang. It is also postulated that both formulations protect the liver through regulating signal transduction in the cell.
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PMID:Substitution for natural musk in Pien Tze Huang does not affect its hepatoprotective activities. 1502 14

Ischemia-reperfusion injury (I/R-I), which is unavoidable in liver transplantation, impairs liver regeneration and predisposes to liver failure. The three major mitogen-activated protein-kinases (MAPKs): ERK, p38, and JNK, are critical in the transmission of signals triggered by proinflammatory cytokines, by stress, and by growth factors. JNK and p38alpha activation have been associated with apoptosis; p38beta with cell survival; and ERK with proliferation. Previous studies have demonstrated gender dimorphism in hepatocellular dysfunction after experimental trauma and hemorrhage. Female mice are protected to a much greater extent from I/R-I than male mice. We assessed the effects of 17beta-estradiol (17beta-E) on liver function, host survival, and cellular activation of MAPK in a murine model of I/R-I in reduced-size livers. C57BL/6 mice were subjected to 45 minutes of warm ischemia (70% of the liver mass). After reperfusion, the nonischemic lobes were excised. Vehicle, 17beta-E or the estrogen receptor antagonist ICI-182780, was delivered 1 hour before the injury. We evaluated AST and apoptosis as well as activation of JNK, p38, and ERK. Female mice showed a lower level of hepatocellular injury (AST = 445 +/- 82 IU/L) after I/R-I compared with male mice (AST = 1400 +/- 210). 17beta-E decreased the liver injury in male mice (AST = 522 +/- 77), an effect that was partially reversed by ICI-182,780 (910 +/- 92). A higher rate of apoptosis was observed in male animals given saline (enrichment factor = 7.22 +/- 0.8) versus those treated with 17beta-E (5.85 +/- 0.3, P < .05). A significant increase in liver regeneration, as assessed by the percentage of liver weight/body weight was demonstrated in females (184% +/- 24%) and male mice given 17beta-E (168% +/- 22%) compared with male mice given vehicle (9% +/- 4%). 17beta-E significantly down-regulated JNK and p38alpha activities, whereas I/R-I promoted p38beta and ERK activation. These results suggest that the cytoprotective effects of 17beta-E on I/R-I to reduced-size livers are associated with selective modulation of MAPK kinases.
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PMID:17beta-estradiol differentially activates mitogen-activated protein-kinases and improves survival following reperfusion injury of reduced-size liver in mice. 1580 58

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

Cisplatin is one of the most effective antineoplastic drugs, but it has undesirable side effects such as hepatotoxicity at high doses. This study investigated the protective effect of macelignan, isolated from Myristica fragrans HOUTT. (nutmeg), against cisplatin-induced hepatotoxicity and the possible mechanisms involved in these effects in mice. Pretreatment with macelignan for 4 d significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. The results also showed that the protective effects of macelignan on cisplatin-induced hepatotoxicity may be associated with the mitogen activated protein kinase (MAPK) signaling pathway. Cisplatin-induced phosphorylation of c-Jun N-terminal kinase1/2 (JNK1/2) and extracellular signal-regulated kinase1/2 (ERK1/2) was abrogated by pretreatment with macelignan, however, that of p38 was not significantly affected. It was also found that macelignan attenuated the expression of phosphorylated c-Jun in cisplatin-treated mice. Accordingly, it is suggested that the hepatoprotective effects of macelignan could be related to activation of the MAPK signaling pathway, especially JNK and c-Jun, its substrate. The present findings suggest that co-treatment of cisplatin with macelignan may provide more advantage than cisplatin treatment alone in cancer therapy.
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PMID:Protective Effects of macelignan on cisplatin-induced hepatotoxicity is associated with JNK activation. 1823 86

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

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

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

Asiaticoside (AS), a triterpenoid product isolated from Centella asiatica, has been described to exhibit anti-in fl ammatory activities in several inflammatory models. However, the effects of AS on liver injury are poorly understood. The present study was undertaken to investigate whether AS is efficacious against Lipopolysaccharide (LPS) /D-galactosamine (D-GalN)-induced acute liver injury in mice and its potential mechanisms. AS (5, 10 and 20 mg/kg/d) was pretreated orally once daily for 3 days before LPS/D-GalN injected in mice. The mortality, hepatic tissue histology, plasma levels of Tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic tissue TNF-alpha and caspase-3 activity were measured. Besides, western blotting analysis of phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK), phospho-c-jun N-terminal kinase (phospho-JNK) and phospho-extracellular signal regulated kinase (phospho-ERK) were determined. As a result, AS showed significant protection as evidenced by the decrease of elevated aminotransferases, hepatocytes apoptosis and caspase-3, alleviation of mortality and improvement of liver pathological injury in a dose-dependent manner. Further, we found that AS dose-dependently reduced the elevation of phospho-p38 MAPK, phospho-JNK, phospho-ERK protein and TNF-alpha mRNA expression in liver tissues and plasma TNF-alpha. These results suggest that AS has remarkable hepatoprotective effects on LPS/D-GalN-induced liver injury and the possible mechanism is related to inhibition of TNF-alpha and MAPKs.
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PMID:Protective effects of Asiaticoside on acute liver injury induced by lipopolysaccharide/D-galactosamine in mice. 2017 Oct 71

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


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