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)

The effects of NO on LTC4 generation during hepatic ischemia-reperfusion (I/R) are largely unclear. Sprague-Dawley rats were divided into control, I/R and sodium nitroprusside (SNP, 2.5, 5 and 10 microg/kg/min)+I/R groups. Liver was subjected to I/R injury, saline or SNP administered intravenously. The protein expressions of LTC4 synthesis enzymes including LTC4 synthase (LTC4S), microsomal glutathione-S-transferase (mGST)2 and mGST3 were detected with immunoblotting, the LTC4 synthesis enzymes' activities and LTC4 content were measured by RP-HPLC, the mRNA expressions of inducible nitric oxide synthase (iNOS) and endogenous nitric oxide synthase (eNOS) in liver were measured by RT-PCR. Tissue injuries were assessed by serum ALT and AST and histological changes. Serum NO(2)(-) and liver tissue GSH were also examined. Compared with I/R group, SNP markedly decreased LTC4 content, LTC4S protein and iNOS mRNA levels, and the LTC4 synthesis enzymes' activities (P<0.05), but significantly enhanced eNOS mRNA expression in liver (P<0.05). The decline in serum ALT, AST and NO(2)(-) levels (P<0.05) together with hepatic GSH elevation (P<0.05) in SNP+I/R groups were also observed. LTC4S expression in hepatocytes and sinusoidal endothelial cells in SNP+I/R groups was lower than that in I/R group. But no significant differences in the protein expressions of mGST3 and mGST2 existed between control, I/R and SNP+I/R groups (P>0.05). These results demonstrated that the decline in LTC4 production by SNP treatment during hepatic I/R could be partially resulted from SNP down-regulating the protein expression of LTC4S rather than mGST2 or mGST3 and its inhibiting the LTC4 synthesis enzymes' activities.
 ...
PMID:Sodium nitroprusside decreased leukotriene C4 generation by inhibiting leukotriene C4 synthase expression and activity in hepatic ischemia-reperfusion injured rats. 1719 56

Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P<0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P<0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P<0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity.
 ...
PMID:Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress. 1722 28

Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor alpha, which causes liver damage. In this study, we investigated the effect of sesame oil on Pb-plus-LPS (Pb + LPS)-induced acute liver damage in mice. Mice were given sesame oil (8 mL/kg orally) just after Pb acetate (10 mmol/kg i.p.) plus LPS (5 mg/kg i.p.). Aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor-alpha, interleukin-1beta, nitric oxide, and inducible nitric oxide synthase levels were examined. Sesame oil significantly decreased serum aspartate aminotransferase and alanine aminotransferase levels in Pb + LPS-stimulated mice. Sesame oil reduced Pb + LPS-induced tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide production in serum and liver tissue. Furthermore, sesame oil decreased inducible nitric oxide synthase expression in leukocytes and liver tissue in Pb + LPS-treated mice. We hypothesize that the inhibition of proinflammatory cytokines and nitric oxide might be involved in sesame oil-associated protection against Pb + LPS-induced acute hepatic injury in mice.
 ...
PMID:Sesame oil protects against lead-plus-lipopolysaccharide-induced acute hepatic injury. 1730 16

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been shown to be induced during oxidative injury, and its induction acts as an important cellular defense mechanism against such injuries. In this study, we examined the functional roles of HO-1 induction in a rat model of d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced liver injury. We found that GalN/LPS treatment of rats produced severe hepatic injury, whereas upregulation of HO-1 by hemin pretreatment prevented rats from liver damage, as evidenced by decreased serum ALT, AST levels and ameliorated histological signs in the liver. Induction of HO-1 resulted in a significant decrease in hepatic malondialdehyde (MDA) contents, tumor necrosis factor-alpha (TNF-alpha) levels, iNOS/NO production, as well as the levels of caspase-3. In contrast, inhibition of HO activity by zinc protoporphyrin-9 (ZnPP, a specific inhibitor of HO) completely reversed HO-1-induced hepatoprotective effect. These data therefore suggested that HO-1 induction provided critical protection against GalN/LPS-induced liver injury, and the protection seemed to be mediated through the anti-oxidant, anti-inflammatory and anti-apoptotic functions.
 ...
PMID:Upregulation of heme oxygenase-1 with hemin prevents D-galactosamine and lipopolysaccharide-induced acute hepatic injury in rats. 1758 81

Recent evidence indicates that inhibition of the Na+/H+ exchanger improves heart and brain injuries induced by I/R. Studies were performed to investigate whether FR183998, a Na/H exchanger inhibitor, has protective effects on hepatic I/R injury in rats. Male Sprague-Dawley rats were subjected to 70% hepatic ischemia by occluding the hepatic artery, portal vein, and bile duct associated with the left and median liver lobes with a microvascular clip for 2 h. FR183998 (1 mg/kg) was administered i.v. 10 min before the hepatic ischemia. Hepatic I/R increased the serum levels of aspartate transaminase, alanine transaminase, and lactate dehydrogenase, which peaked at 9 h after reperfusion. FR183998 reduced these injury markers and recovered liver functions. Histopathologic analysis revealed that FR183998 prevented the incidences of hepatic necrosis, apoptosis, and neutrophil infiltration at 6 and 9 h (P < 0.05). FR183998 reduced the increases in proinflammatory cytokines such as TNF-alpha (1-6 h), IL-6 (1-12 h), interferon-gamma (6-12 h), IL-1beta (1-3 h), and cytokine-induced neutrophil chemoattractant 1 (1-3 h), but enhanced the anti-inflammatory cytokine IL-10 (1 h). FR183998 inhibited the hepatic I/R-induced activation of the transcription factor nuclear factor-kappaB at 1 to 6 h and reduced the induction of iNOS at 6 to 12 h, followed by inhibition of nitric oxide production. Furthermore, FR183998 decreased the expression of the iNOS gene antisense transcript, which is involved in the stability of iNOS messenger RNA, at 9 to 12 h in the liver of hepatic I/R rats. These results demonstrate that FR183998 reduces the induction of proinflammatory cytokines and iNOS at least in part through inhibition of nuclear factor-kappaB activation and iNOS antisense transcript expression, thereby preventing hepatic I/R injury.
 ...
PMID:Protective effect of FR183998, a Na+/H+ exchanger inhibitor, and its inhibition of iNOS induction in hepatic ischemia-reperfusion injury in rats. 1827 53

Many factors could potentially affect the process of arsenic-induced liver fibrosis. The present study was undertaken to examine the effect of high fat diet on arsenic-induced liver fibrosis and preneoplastic changes. Mice were given sodium arsenite (As3+, 200 ppm) or sodium arsenate (As5+, 200 ppm) in the drinking water for 10 months, and provided a normal diet or a diet containing 20% added fat. Serum aspartate aminotransferase (AST), indicative of liver injury, was elevated in both arsenite and arsenate groups, and a high fat diet further increased these levels. Histopathology (H&E and Masson stain) showed that liver inflammation, steatosis (fatty liver), hepatocyte degeneration, and fibrosis occurred with arsenic alone, but their severity was markedly increased with the high fat diet. Total liver RNA was isolated for real-time RT-PCR analysis. Arsenic exposure increased the expression of inflammation genes, such as TNF-alpha, IL-6, iNOS, chemokines, and macrophage inflammatory protein-2. The expression of the stress-related gene heme oxygenase-1 was increased, while metallothionein-1 and GSH S-transferase-pi were decreased when arsenic was combined with the high fat diet. Expression of genes related to liver fibrosis, such as procollagen-1 and -3, SM-actin and TGF-beta, were synergistically increased in the arsenic plus high fat diet group. The expression of genes encoding matrix metalloproteinases (MMP2, MMP9) and tissue inhibitors of metalloproteinases (TIMP1, TIMP2) was also enhanced, suggestive of early oncogenic events. In general, arsenite produced more pronounced effects than arsenate. In summary, chronic inorganic arsenic exposure in mice produces liver injury, and a high fat diet markedly increases arsenic-induced hepatofibrogenesis.
 ...
PMID:High dietary fat exacerbates arsenic-induced liver fibrosis in mice. 1829 43

The effect of Sivelestat, a neutrophil elastase inhibitor, on hepatic ischemia-reperfusion injury was examined in a pig hepatectomy model. An internal jugular vein-splenic vein bypass was prepared in male pigs and about 40% hepatic resection (left lobe) was performed under 15-min liver ischemia and 5-min intermittent reperfusion. Six animals received Sivelestat (10 mg/kg/h) intravenously and six control animals received physiological saline (10 mg/kg/h) from commencement of laparotomy. Hemodynamics, blood chemistry, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), lactic acid, hyaluronic acid, nitrite/nitrate (NOS), and tumor necrosis factor-alpha (TNF-alpha) were compared between the groups. The effects of Sivelestat on NOS generation and expression of iNOS mRNA and TNF-alpha mRNA were also assessed in J774 cells. Expression of TNF-alpha mRNA in hepatic tissues was examined using RT-PCR. The blood pressure of control animals was significantly lower immediately and 3 h after ischemia-reperfusion, compared with that at commencement of laparotomy, whereas there was no decrease of blood pressure in animals administered Sivelestat. Serum AST (P=0.0045), NOS (P=0.0098), and TNF-alpha (P=0.041) levels were significantly lower 3 h after hepatectomy in animals receiving Sivelestat. Sivelestat inhibited NOS production in J774 cells, but did not inhibit expression of iNOS mRNA or TNF-alpha mRNA. In hepatic tissues, Sivelestat showed a greater tendency to inhibit expression of TNF-alpha mRNA and fewer TUNEL-positive cells were present in the hepatic sinusoidal endothelium after Sivelestat treatment, although these differences were not statistically significant. We conclude that Sivelestat inhibits production of TNF-alpha and NO by inhibiting neutrophil elastase, and thus reduces hepatic injury and stabilizes hemodynamics after ischemia-reperfusion.
 ...
PMID:Protective effect of Sivelestat in a porcine hepatectomy model prepared using an intermittent Pringle method. 1837 31

Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. However, there is no direct evidence on the role of CYP2E1 in TAA-mediated hepatotoxicity. To clarify this, TAA-induced hepatotoxicity was investigated using Cyp2e1-null mice. Male wild-type and Cyp2e1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and hepatotoxicity examined 24 and 48 h after TAA treatment. Relative liver weights of Cyp2e1-null mice were significantly different at 24 h compared to wild-type mice (p<0.01). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in Cyp2e1-null mice were significantly different at both time points compared to wild-type mice (p<0.01). Histopathological examination showed Cyp2e1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was also only limited to wild-type mice (p<0.01). Similarly, TNF-alpha, IL-6 and glutathione peroxidase mRNA expression in Cyp2e1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p<0.01). Western blot analysis further revealed no increase in iNOS expression in Cyp2e1-null mice. These results reveal that CYP2E1 mediates TAA-induced hepatotoxicity in wild-type mice as a result of increased oxidative stress.
 ...
PMID:Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity. 1837 80

To elucidate the roles of enteric bacteria and immunological interactions among liver, spleen and intestine in the pathogenesis of liver injury during obstructive jaundice, we studied the effects of antibiotics and splenectomy on bile-duct-ligated C57BL mice. When animals were subjected to bile-duct-ligation (BDL), plasma levels of bilirubin, alanine aminotransferase and aspartate aminotransferase increased markedly. However, the increases in plasma transaminases were significantly lower in splenectomized or antibiotics-treated groups than in the control BDL group. Histological examination revealed that liver injury was also low in the two groups. BDL markedly increased plasma level of interferon-gamma (IFN-gamma) and the expression of inducible nitric oxide synthase (iNOS) in liver and spleen. These changes were suppressed either by splenectomy or administration of antibiotics. Kinetic analysis revealed that BDL-induced liver injury and the increase of interleukin-10 (IL-10) and INF-gamma were lower in iNOS(-/-) than in wild type animals. BDL markedly increased the expression of IgA in colonic mucosa. These observations suggest that enteric bacteria, nitric oxide and cytokines including IFN-gamma and IL-10 derived from spleen and intestines form a critical network that determines the extent of liver injury during obstructive jaundice.
 ...
PMID:Mechanism of Liver Injury during Obstructive Jaundice: Role of Nitric Oxide, Splenic Cytokines, and Intestinal Flora. 1839 95

Emodin, 1,3,8-trihydroxy-6-methyl-anthraquinone, is an anthraquinone derivative from the roots of Rheum officinale Baill that has been used to treat many diseases in digestive system for thousands of years. This study is to disclose the mechanism of Emodin to treat cholestatic hepatitis via anti-inflammatory pathway. Rats were divided into Emodin, ursodeoxycholic acid, Dexamethasone, model and blank control groups with treatment of respective agent after administration of alpha-naphthylisothiocyanate. At 24 h, 48 h and 72 h time points after administration, liver function, pathological changes of hepatic tissue, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage inflammatory protein (MIP)-2, intercellular adhesion molecule (ICAM)-1, nuclear factor (NF)-kappaB and early growth response (Egr)-1, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) were detected. As a result, compared to the controls, Emodin had a notable effect on rat's living condition, pathological manifestation of hepatic tissue, total bilirubin, direct bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P<0.05), but had little effect on alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT) and total bile acid. With Emodin intervention, levels of TNF-alpha, IL-6, MPO, MDA, CINC-1, MIP-2, ICAM-1 and translocation of NF-kappaB were remarkably decreased, and levels of NO and iNOS were markedly increased (P<0.05). Emodin had no effect on Egr-1. In conclusion, Emodin has a protective effect on hepatocytes and a restoring activity on cholestatic hepatitis by anti-inflammation. The effects are mainly due to antagonizing pro-inflammatory cytokines and mediators, inhibiting oxidative damage, improving hepatic microcirculation, reducing impairment signals, and controlling neutrophil infiltration.
 ...
PMID:Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. 1859 Jul 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>