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)

During ischemia-reperfusion an imbalance between endothelin (ET) and nitric oxide (NO) can be responsible for microcirculatory disturbances. The aim of this study was to restore the ET/NO balance to reduce the ischemia-reperfusion injury. Hepatic ischemia was induced for 30 min in 56 Wistar rats. Sham operation, ischemia and treatment groups with the ET receptor antagonist (ERA) bosentan (1 mg/kg body weight i.v.) and the NO donor L-arginine (400 mg/kg body weight i.v.) were performed. For evaluation of hepatic microcirculation in vivo microscopy was carried out 30-90 min after reperfusion. Local hepatic tissue PO2, laser Doppler flow and aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were measured. Increased ET caused sinusoidal constriction after reperfusion to 76% of the sham group (p < 0.05), leading to significant decrease in perfusion rate (82%), liver tissue PO2 (6.9 mmHg) and erythrocyte flux (45.2% of sham group). Hepatocellular damage could be detected 6 h after reperfusion by AST/ALT increase (p < 0.05). Sinusoidal diameters were maintained at baseline in the ERA (98%) and NO (102%) groups (p < 0.05). Increased percentage of leukocytes sticking in sinusoids (144%) and venules (435%) was reduced by therapy to 110/253% (ERA) and 111/324% (NO), respectively (p < 0.05). Perfusion rate was increased to 93 and 94% (p < 0.05 vs ischemia). Local hepatic tissue PO2 was improved 30 min after reperfusion in the ERA (11.0 mmHg) as well as in the NO group (11.5 mmHg; p < 0.05 vs ischemia). Measurement with a laser Doppler flow meter revealed significant improved erythrocyte flux in both therapy groups (p < 0.05 vs ischemia). Also, the post-ischemic AST/ALT increase was reduced by therapy. In conclusion, ET evokes strong constriction of post-ischemic sinusoids, leading to microcirculatory disturbances. The maintenance of the ET/NO balance by blocking ET receptors, or providing an NO donor, protects liver microcirculation and reduces hepatic ischemia-reperfusion injury.
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PMID:Endothelin/nitric oxide balance influences hepatic ischemia-reperfusion injury. 1107 80

S-Nitrosylated compounds (nitrosothiols; RS-NOs) function as nitric oxide (NO) reservoirs and preserve the antioxidant activities of NO. We found remarkable cytoprotection by an S-nitrosylated protease inhibitor from human plasma, S-nitroso-alpha(1)-protease inhibitor (S-NO-alpha(1)-PI) that possesses a completely nitrosylated SH group, in hepatic ischemia-reperfusion injuries in rats. Liver ischemia was induced in rats by occluding both the portal vein and hepatic artery for 30 min and was followed by reperfusion. S-NO-alpha(1)-PI and control compounds such as native alpha(1)-PI, an NO synthase (NOS) inhibitor, and standard RS-NOs were given via the portal vein just after reperfusion was initiated. Liver injury was evaluated by measuring the extracellular release of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Infiltration of neutrophils and induction of apoptosis and heme oxygenase-1 (HO-1) in the liver were also examined. Maximal liver injury occurred at 3 h after reperfusion and then decreased gradually. Not only did S-NO-alpha(1)-PI treatment (0.1 micromol; 5.3 mg/rat) greatly reduce elevation of liver enzymes in plasma, as well as neutrophil accumulation and apoptotic change in liver, it also improved the impaired hepatic blood flow as assessed by laser Doppler flowmetry and potentiated the induction of HO-1 in the liver. Although native alpha(1)-PI moderately reduced liver injury, low molecular weight RS-NOs such as S-nitrosoglutathione and S-nitroso-N-acetyl penicillamine produced no obvious protective effect. An NOS inhibitor exacerbated the hepatic ischemia-reperfusion injuries. These results suggest that S-NO-alpha(1)-PI exerts a potent cytoprotective effect on ischemia-reperfusion liver injury by maintaining tissue blood flow, inducing HO-1, and suppressing neutrophil-induced liver damage and apoptosis.
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PMID:Protective effect of S-nitrosylated alpha(1)-protease inhibitor on hepatic ischemia-reperfusion injury. 1108 23

Nitric oxide (NO) has an important role in controlling heart rate and contributes to the cholinergic antagonism of the positive chronotropic response to adrenergic stimulation. Based on evidence of NO overproduction in cholestasis and also on the existence of bradycardia in cholestatic subjects, this study aimed to evaluate the chronotropic effect of epinephrine in isolated atria of cholestatic rats and determine whether alterations in epinephrine-induced chronotropic responses of cholestatic rats are corrected after systemic inhibition of NO synthase (NOS) with N(G)-nitro-L-arginine (L-NNA). Male Sprague-Dawley rats were used. Cholestasis was induced by surgical ligation of the bile duct under general anesthesia and sham-operated animals were considered as control. The animals were divided into three groups, which received either L-arginine (200 mg/kg/day), L-NNA (10 mg/kg/day) or saline. One week after the operation, a lead II ECG was recorded from the animals, then spontaneously beating atria were isolated and chronotropic responses to epinephrine were evaluated in a standard oxygenated organ bath. The results showed that plasma gamma-glutamyl transpeptidase and alanine aminotransferase activity was increased by bile-duct ligation, and that L-aginine treatment partially, but significantly, prevented the elevation of these markers of liver damage. The results showed that heart rate of cholestatic animals was significantly less than that of sham-operated control rats in vivo and this bradycardia was corrected with daily administration of L-NNA. The basal spontaneous beating rate of atria in cholestatic animals was not significantly different from that of sham-operated rats in vitro. Meanwhile, cholestasis induced a significant decrease in chronotropic effect of epinephrine. These effects were corrected by daily administration of L-NNA. Surprisingly L-arginine was as effective as L-NNA and increased the chronotropic effect of epinephrine in cholestatic rats but not in sham-operated animals. Systemic NOS inhibition corrected the decreased chronotropic response to adrenergic stimulation in cholestatic rats, and suggests an important role for NO in the pathophysiology of heart rate complications in cholestatic subjects. The opposite effect of chronic L-arginine administration in cholestasis and in control rats could be explained theoretically by an amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats.
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PMID:The role of nitric oxide in bradycardia of rats with obstructive cholestasis. 1113 68

Paracetamol (5 mmol kg(-1), i.p.) caused liver damage in rats as indicated by increased plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activities. No change in plasma bilirubin or creatinine was noted. An equimolar dose of nitroparacetamol (a nitric oxide (NO)-releasing derivative of paracetamol) did not alter plasma levels of any of the markers of liver/kidney damage. No difference in plasma or liver paracetamol was apparent in animals injected with paracetamol or nitroparacetamol. These results indicate that NO released from nitroparacetamol exhibits hepatoprotective activity in these animals and suggest that nitroparacetamol may therefore be considered as a safer alternative to paracetamol in the clinic.
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PMID:A comparison of the effect of nitroparacetamol and paracetamol on liver injury. 1115 55

The levels of plasma nitric oxide (NO), endothelin-1 (ET-1) and ALT in the patients with chronic hepatitis B and active cirrhosis and the correlation among them were observed and analyzed. NO3- was restored by using cadmium column assay and NO2- measured by heavy nitrogen assay. The primitive NO3- and total restored NO2- (NO3-/NO2-) in plasma of the patients with chronic hepatitis and cirrhosis. Plasma ET-1 and ALT levels were determined by using radioimmunological assay and Lai's assay, respectively. Compared with normal control group, the plasma levels of NO2-/NO2- and ET-1 in the patients with chronic active hepatitis and active cirrhosis were significantly increased (P < 0.05-0.01). There was a positive correlation between NO and ALT, and ET-1 and ALT in the patients with chronic active hepatitis and active cirrhosis respectively. It was suggested that elevation of both NO and ET-1 levels were closely related with injury severity of liver function.
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PMID:Study on the correlation of plasma NO, ET-1 and ALT in the patients with chronic hepatitis and cirrhosis. 1121 47

Recent evidence suggests that the hepatic expression of heme oxygenase-1 (HO-1) may preserve hepatocellular integrity after hemorrhagic shock and resuscitation (HR). Because nitric oxide (NO) has been shown to modulate HO-1 expression in cultured cells in vitro, we determined its potential role in the regulation of HO-1 expression after HR in the rat liver in vivo. HO-1 mRNA and protein were highly induced and HO enzyme activity was higher after HR when compared with time-matched sham controls. Administration of the NO donor, molsidomine (MOL) (3 mg. kg(-1)), during resuscitation attenuated the accumulation of HO-1 mRNA and protein and the rise in HO activity. In addition, MOL prevented the shock-induced increase in DNA binding activity of the transcription factor, activator protein-1 (AP-1), but did not alter the activity of nuclear factor-erythroid 2 related factor (Nrf-2), nuclear transcription factor-kappaB (NF-kappaB), and hypoxia-inducible factor-1 (HIF-1). The suppressing action of MOL was not confined to HO-1, because the hepatic expression of the 70-kd major heat shock protein (HSP) in response to HR was also diminished. Moreover, MOL prevented the HR-induced increase in the serum activity of alanine transaminase (ALT) and alpha-glutathione-S-transferase (alpha-GST) that could otherwise be observed after HR. In contrast, the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg.kg(-1)), had either no or only minor effects on the primary experimental endpoints. These findings would be consistent with a reduction of shock-induced liver damage by exogenous NO, which in turn prevents the subsequent activation of injury-sensitive transcription factors, thus attenuating the expression of stress-inducible proteins such as HO-1.
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PMID:Effect of nitric oxide on shock-induced hepatic heme oxygenase-1 expression in the rat. 1128 57

Hepatic Kupffer cells and pulmonary alveolar macrophages together constitute a macrophage-axis involved in the regulation of regional and systemic inflammatory responses. Systemic inflammatory response syndrome induced by overproduced pro-inflammatory mediators is the major cause of adult respiratory distress syndrome. In the present study, we examined the anti-inflammatory role of nitric oxide (NO) in a rat model of acute lung injury induced by hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia by clamping the relevant branches of hepatic artery and portal vein, followed by a 4-h reperfusion achieved by removal of the vascular clamp. Four groups of animals were studied: sham control + saline; sham control + N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v., 10 min before reperfusion); HI/R + saline; HI/R + L-NAME. Results show that (1) administration of L-NAME to rats subjected to HI/R decreased plasma NO levels; however, the attenuation of NO increased plasma alanine aminotransferase (ALT) activity and superoxide generation in the ischemic lobes of liver, compared to HI/R alone. (2) Inhibition of NO synthesis with L-NAME in rats subjected to HI/R also enhanced systemic inflammatory response as assessed by the increase in the number of circulating leukocytes and levels of plasma tumor necrosis factor-alpha (TNFalpha) and interleukin 1-beta (IL-1beta). (3) The overwhelming systemic inflammatory response induced by administration of L-NAME in rats subjected to HI/R also augmented pulmonary vascular permeability and superoxide generation in the lung tissue. (4) Pulmonary alveolar macrophages isolated from rats subjected to HI/R + L-NAME produced higher levels of TNFalpha and IL-1beta in the supernatant of culture medium than that of rats subjected to HI/R alone. (5) There were no differences between the groups of sham + saline and sham + L-NAME in terms of plasma NO levels and ALT activity, circulating leukocytes, superoxide generation in the liver and lung, lavage protein levels, and TNFalpha and IL-1beta levels in plasma and bronchoalveolar lavage fluid. Our results suggest that inhibition of NO synthesis by L-NAME in rats subjected to HI/R not only augments ischemic liver injury, but also enhances the systemic inflammatory response and exacerbates remote lung injury. The increase in TNFalpha and IL-1beta production by alveolar macrophages may, in part, account for L-NAME-induced enhancement of acute lung injury.
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PMID:Inhibition of nitric oxide synthesis by L-name exacerbates acute lung injury induced by hepatic ischemia-reperfusion. 1153 Oct 23

We recently reported that nitrotyrosine and acetaminophen (APAP)-cysteine protein adducts colocalize in the hepatic centrilobular cells following a toxic dose of APAP to mice. Whereas APAP-adducts are formed by reaction of the metabolite N-acetyl-p-benzoquinone imine with cysteine, nitrotyrosine residues are formed by reaction of tyrosine with peroxynitrite. Peroxynitrite is formed from nitric oxide (NO) and superoxide. This manuscript examines APAP (300 mg/kg) hepatotoxicity in mice lacking inducible nitric oxide synthase activity (NOS2 null or knockout mice; C57BL/6-Nos2(tm1Lau)) and in the wildtype mice. In a time course the ALT levels in the exposed NOS2 null mice were approximately 50% of the wildtype mice; however, histological examination of liver sections indicated similar levels of centrilobular hepatic necrosis in both wild-type and NOS2 null mice. Serum nitrate plus nitrite levels (NO synthesis) were identical in saline-treated NOS2 null and wild-type mice (53 +/- 2 microM). APAP increased NO synthesis in wild-type mice only. The increases paralleled the increases in ALT levels with peak levels of serum nitrate plus nitrite at 6 h (168 +/- 27 microM). In wild-type mice hepatic tyrosine nitration was greatly increased relative to saline treated controls. Tyrosine nitration increased in NOS2 null mice also, but the increase was much less. APAP increased hepatic malonaldehyde levels (lipid peroxidation) in NOS2 null mice only. The results suggest the presence of multiple pathways to APAP-mediated hepatic necrosis, one via nitrotyrosine, as in the wild-type mice, and another that is not dependent upon inducible nitric oxide synthase activity, but which may involve increased superoxide.
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PMID:Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity. 1158 58

Antigen presenting cells, especially the antigen presenting dendritic cells (DC) in the tissue, regulate the magnitude of antigen-specific immune response. A role of impaired and narrowly focused specific immune response has been implicated in the pathogenesis of chronic hepatitis due to hepatitis B virus and hepatitis C virus. In order to clarify this role, we studied liver DC from interferon gamma (IFN-gamma) transgenic mouse (TgM), an animal model of chronic hepatitis. These mice had high serum levels of alanine transaminase and histological evidence of chronic hepatitis. Transgene negative offspring (littermate control) with normal serum transaminase levels and without any evidence of hepatitis were used as controls. The stimulatory capacity of the liver DC from IFN-gamma TgM in allogenic mixed leukocyte reaction was significantly lower than that of the liver DC from control mouse. The endocytosis capacity was significantly lower in liver DC from IFN-gamma TgM than in that from the control mouse. Most importantly, liver DC from IFN-gamma TgM were unable to induce antigen-specific proliferation. The impaired function of liver DC from these mice may be attributable to increased production or induction of suppressor cytokines such as interleukin-10 and nitric oxide. Defective capacity of liver DC from mouse with chronic hepatitis (IFN-gamma TgM) may be related to impaired magnitude of specific immune response in the liver.
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PMID:Loss of immunogenecity of liver dendritic cells from mouse with chronic hepatitis. 1174

O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective nitric oxide (NO)-donating prodrug, is metabolized by hepatic enzymes to release NO within the liver. This study was undertaken to examine the effects of V-PYRRO/NO on D-galactosamine/lipopolysaccharide (GlaN/LPS)-induced liver injury in mice. Mice were given injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after GlaN/LPS (700 mg/30 microg/kg, i.p.). V-PYRRO/NO administration dramatically reduced GlaN/LPS-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase activity and improved pathology. To examine the mechanisms of the protection, cDNA microarray was performed to profile the gene expression pattern in livers of mice treated with GlaN/LPS, GlaN/LPS plus V-PYRRO/NO, or controls. V-PYRRO/NO administration greatly ameliorated GlaN/LPS-induced alterations in the expression of genes encoding the stress response, DNA damage/repair response, and drug-metabolizing enzymes in accordance with hepatoprotection. Gel shift assay and Western blot analysis supported microarray results, showing that V-PYRRO/NO suppressed GlaN/LPS-induced activation of nuclear factor-kappaB and GlaN/LPS-induced increases in caspase-1, caspase-8, tumor necrosis factor receptor 1 (TNFR1)-associated death domain, and TNF-related apoptosis-inducing ligand. Immunohistochemical analysis further revealed that GlaN/LPS-induced activation of TNFR1, caspase-3, and hepatocellular apoptosis was ameliorated by V-PYRRO/NO treatment. GlaN/LPS-induced elevation of hepatic caspase-3 activity was diminished by V-PYRRO/NO treatment. In addition, V-PYRRO/NO alone suppressed the basal expression of genes encoding inducible NO synthase and TNF-alpha-related components, as revealed by mouse 1.2 array. In summary, this study demonstrates that the liver-selective NO donor, V-PYRRO/NO, is effective in blocking GlaN/LPS-induced hepatotoxicity in mice, and that this protection appears to involve, at least in part, the suppression of the TNF-alpha-mediated cell death pathways.
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PMID:O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate protection against D-galactosamine/endotoxin-induced hepatotoxicity in mice: genomic analysis using microarrays. 1175 92


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