Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aging and diabetes mellitus (DM) both affect the structure and function of the myocardium, resulting in increased collagen in the heart and reduced cardiac function. As part of this process, hyperglycemia is a stimulus for the production of advanced glycation end products (AGEs), which covalently modify proteins and impair cell function. The goals of this study were first to examine the combined effects of aging and DM on hemodynamics and collagen types in the myocardium in 12 dogs, 9-12 yr old, and second to examine the effects of the AGE cross-link breaker phenyl-4,5-dimethylthazolium chloride (ALT-711) on myocardial collagen protein content, aortic stiffness, and left ventricular (LV) function in the aged diabetic heart. The alloxan model of DM was utilized to study the effects of DM on the aging heart. DM induced in the aging heart decreased LV systolic function (LV ejection fraction fell by 25%), increased aortic stiffness, and increased collagen type I and type III protein content. ALT-711 restored LV ejection fraction, reduced aortic stiffness and LV mass with no reduction in blood glucose level (199 +/- 17 mg/dl), and reversed the upregulation of collagen type I and type III. Myocardial LV collagen solubility (%) increased significantly after treatment with ALT-711. These data suggest that an AGE cross-link breaker may have a therapeutic role in aged patients with DM.
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PMID:Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. 1294 33

Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
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PMID:The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. 1295 2

Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl(4)) in the livers of FGF1- and FGF2-deficient mice. After acute CCl(4) exposure, FGF1(-/-)FGF2(-/-) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(-/-)FGF2(-/-) mice exhibited a normal increase in alpha-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen alpha1(I) synthesis. Liver fibrosis resulting from chronic CCl(4) exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis.
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PMID:Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis. 1450 72

Long-lived structural proteins, collagen and elastin, undergo continual non-enzymatic crosslinking during aging and in diabetic individuals. This abnormal protein crosslinking is mediated by advanced glycation end products (AGEs) generated by non-enzymatic glycosylation of proteins by glucose. The AGE-derived protein crosslinking of structural proteins contributes to the complications of long-term diabetes such as nephropathy, retinopathy, and neuropathy. AGE-crosslinks have also been implicated in age-related cardiovascular diseases. Potential treatment strategies for these AGE-derived complications include prevention of AGE-formation and breaking of the existing AGE-crosslinks. The therapeutic potential of the AGE-inhibitor, pimagedine (aminoguanidine), has been extensively investigated in animal models and in Phase 3 clinical trials. This review presents the pre-clinical and clinical studies using ALT-711, a highly potent AGE-crosslink breaker that has the ability to reverse already-formed AGE-crosslinks. Oral administration of ALT-711 has resulted in a rapid improvement in the elasticity of stiffened myocardium in experimental animals. Topical administration of ALT-711 was effective in improving the skin hydration of aged rats. The therapeutic potential of crosslink breakers for cardiovascular complications and dermatological alterations associated with aging and diabetes is discussed.
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PMID:Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. 1456 12

The aim of this study was to investigate the hematological, hemostatic and biochemical disturbances induced by the injection of Crotalus durissus terrificus venom in dogs under controlled conditions. For this purpose three groups of animals were used: an experimental group (E), which was injected i.m. with C. durissus terrificus venom (1 mg/kg); and two control groups--antivenom (AV) and control (C)--which were injected i.m. with 150 mM NaCl. Groups E and AV were treated i.v. with Crotalus antivenom 2 hours after the first injection. Serum levels of alkaline phosphatase and alanine aminotransferase were increased in groups E and AV at 24 and 48 hours after serumtherapy, respectively. The increased serum levels of myoglobin, creatine kinase and aspartate aminotransferase demonstrated that animals developed rhabdomyolysis. A persistent neutrophilic leukocytosis was already noticeable at 2 hours after envenomation and lasted even after serumtherapy. The animals of groups E and AV presented eosinopenia 24 hours after serumtherapy, and collagen-induced platelet hypoaggregation was observed without thrombocytopenia. Increased levels of fibrinogen/fibrin degradation products (FnDP/FgDP), hypofibrinogenemia, and alpha2-antiplasmin consumption were observed at 2 hours after envenomation, indicating secondary activation of fibrinolysis. Our data suggest that the biochemical and hemostatic disturbances induced by C. durissus terrificus venom in dogs are related to its myotoxic and thrombin-like activities.
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PMID:Hematological, hemostatic and clinical chemistry disturbances induced by Crotalus durissus terrificus snake venom in dogs. 1458 9

Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a pancaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for alpha-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-beta and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by alpha-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-caspase inhibitor IDN-6556 is a promising agent for cholestatic liver injury.
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PMID:The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. 1461 89

Naringenin, a phytoalexin found in grapefruits and tomatoes, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of naringenin on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Oral administration of naringenin (20 and 50 mg/kg daily for 4 weeks) remarkably prevented the DMN-induced loss in body and liver weights and inhibited the elevation of serum alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin levels. Naringenin also restored serum albumin and total protein levels, and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced collagen accumulation, as estimated by histological analysis of liver tissue stained with Sirius red, was reduced in the naringenin-treated rats. A reduction in hepatic stellate cell activation, as assessed by alpha-smooth muscle actin staining, was associated with naringenin treatment. In conclusion, these results demonstrate that naringenin exhibited in vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury. It suggests that naringenin may be useful in preventing the development of hepatic fibrosis.
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PMID:The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. 1470 2

Oxidative stress, in particular lipid peroxidation, induces collagen synthesis. Thus, we administered various antioxidants to bile duct-ligated rats for 28 days and lipid peroxidation, glutathione content, fibrosis, necrosis and cholestasis were evaluated. Extrahepatic cholestasis was induced by double ligation and section of the common bile duct. The study included eight groups (n=6), four groups were bile duct-ligated and received either vitamin C (50 mg/kg/day, orally), vitamin E (400 IU/rat/day, orally), silymarin (50 mg/kg/12 hr, orally) or vehicles; four groups were sham-operated controls. Collagen content was determined by measuring hydroxyproline in liver samples; malondialdehyde was used to estimate lipid peroxidation levels; reduced and oxidized glutathione were determined fluorometrically; alanine aminotransferase and bilirubins colorimetrically. Bilirubins increased several times, alanine aminotransferase once, reduced/oxidized glutathione ratio decreased three times, lipid peroxidation and collagen increased about three-times by biliary obstruction (p<0.05). Silymarin, vitamin E or C failed to prevent these effects significantly. It is not possible to clarify the role of oxidative stress in the fibrotic process induced by chronic biliary obstruction with the present results. Therefore, it seems reasonable to propose that a wide mixture of antioxidants, administered by the parenteral route (because cholestasis decreased the absorption of lipophilic compounds), is needed to counteract the oxidant stress produced by cholestasis.
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PMID:Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat. 1474 53

Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, interacts with the major collagen I receptor, the alpha(2)beta(1) integrin, inhibiting collagen binding. Here we show that ALT-C also inhibits the adhesion of a mouse fibroblast cell line (NIH-3T3) to collagen I (IC(50) 2.2 microm). In addition, when immobilized on plate wells, ALT-C supports the adhesion of this cell line as well as of human vein endothelial cell (HUVEC). ALT-C (3 microm) does not detach cells that were previously bound to collagen I. ALT-C (5 nm) induces HUVEC proliferation in vitro, and it inhibits the positive effect of vascular endothelial growth factor (VEGF) or FGF-2 on the proliferation of these cells, thus suggesting a common mechanism for these proteins. Gene expression analysis of human fibroblasts growing on ALT-C- or collagen-coated plates showed that ALT-C and collagen I induce a very similar pattern of gene expression. When compared with cells growing on plastic only, ALT-C up-regulates the expression of 45 genes including the VEGF gene and down-regulates the expression of 30 genes. Fibroblast VEGF expression was confirmed by RT-PCR and ELISA assay. Up-regulation of the VEGF gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates Akt/PKB phosphorylation, a signaling event involved in endothelial survival and angiogenesis. In conclusion, ALT-C acts as a survival factor, promoting adhesion and endothelial cell proliferation.
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PMID:Alternagin-C, a disintegrin-like protein, induces vascular endothelial cell growth factor (VEGF) expression and endothelial cell proliferation in vitro. 1476 57

The chronic hepatotoxic effects of carbon tetrachloride (CCl(4)) in heat-shock protein (HSP) 70 knock out (HSP70-/-) mice were examined. After repeated intraperitoneal injections of CCl(4) for six weeks, the level of ALT and weight ratio of the liver to body were lower in HSP70-/- mice than in the control (WT) mice. The levels of HSP25 and HSP47 were lowered in HSP70-/- mice as compared with WT mice. The grades of hepatic necrosis and neutrophil infiltration were not significantly different between HSP70-/- and WT mice. The collagen content was not affected significantly by CCl(4) treatment.
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PMID:Chronic hepatotoxicity of carbon tetrachloride in hsp-70 knock out mice. 1499 37


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