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)

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

This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-alpha as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-alpha. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711.
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PMID:Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. 1550 73

The alpha2beta1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, competitively interacts with the alpha2beta1 integrin, thereby inhibiting collagen binding. When immobilized in plate wells, ALT-C supports the adhesion of fibroblasts as well as of human vein endothelial cells (HUVEC) and does not detach cells previously bound to collagen I. ALT-C is a strong inducer of HUVEC proliferation in vitro. Gene expression analysis was done using an Affimetrix HU-95A probe array with probe sets of approximately 10,000 human genes. In human fibroblasts growing on collagen-coated plates, ALT-C up-regulates the expression of several growth factors including vascular endothelial growth factor, as well as some cell cycle control genes. Up-regulation of the vascular endothelial growth factor gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates protein kinase B phosphorylation, a signaling event involved in endothelial cell survival and angiogenesis. In human neutrophils, ALT-C has a potent chemotactic effect modulated by the intracellular signaling cascade characteristic of integrin-activated pathways. Thus, ALT-C acts as a survival factor, promoting adhesion, migration and endothelial cell proliferation after binding to alpha2beta1 integrin on the cell surface. The biological activities of ALT-C may be helpful as a therapeutic strategy in tissue regeneration as well as in the design of new therapeutic agents targeting alpha2beta1 integrin.
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PMID:Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates alpha2beta1 integrin-mediated cell adhesion, migration and proliferation. 1617 43

Although it has been shown that a simultaneous administration of the vascular endothelial growth factor (VEGF); a potent angiogenic factor, could improve the overall survival of chemically induced acute hepatic failure (AHF) in rats, it has not been elucidated yet whether this salvage effect can be observed in the on-going AHF or not. For future clinical application, we examined the effect of VEGF on the on-going AHF. A combination of d-galactosamine (Gal-N) and lipopolysaccharide (LPS) was administered to induce AHF in rats. The survival rate and several indices were compared with or without VEGF treatment at 12 and 24h after the intoxication. Even after the establishment of severe liver injury, the overall survival and the serum ALT elevation were significantly improved by treatment with VEGF. The proliferation of the hepatocytes and sinusoidal endothelial cells (SEC) was also stimulated by VEGF. Furthermore, VEGF prevented the destruction of the architecture of the hepatic sinusoids. Since VEGF significantly improved the survival of the on-going AHF, the exogenous VEGF administration may represent a feasible new therapeutic strategy for AHF in the future.
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PMID:A potent angiogenic factor, vascular endothelial growth factor, improves the survival of the on-going acute hepatic failure in rats. 1671 58

It has been reported that kringle 1-5 (K1-5) has a potent and specific antiangiogenic activity. In the present study, we investigated the antitumor effect of gene transfer of K1-5 for hepatocellular carcinoma in mice. Inhibitory effect by the media of Cos-1 cells containing K1-5 on bovine capillary endothelial (BCE) cell proliferation was evaluated by a tetrazolium-based assay. For tumor growth, intrahepatic metastasis, and survival studies, intravenous injection of liposome-K1-5 cDNA complexes was performed to nude mice implanted with three hepatoma cell lines into the liver. Production of K1-5 was investigated by immunohistochemistry and Western blotting. The number of vessels in the tumor was counted in 0.125 mm2 fields. Expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and -2 in tumors was investigated by Western blotting. Serum ALT levels and body weight of the mice were measured. Proliferation of BCE cells was inhibited by 44% in the media containing K1-5. Gene transfer of K1-5 suppressed tumor growth of the three hepatoma cell lines, respectively. In the K1-5-treated group, survival period was prolonged and the number of intrahepatic metastases was reduced. Expression of K1-5 protein was detected on hepatoma cells and hepatocytes. The number of vessels in tumor tissues was decreased by K1-5 transfection. Expression of angiopoietin-2 in tumor tissues was suppressed by K1-5 transfection. Serum ALT levels and body weight of mice were not influenced by K1-5 transfection. These findings suggest that antiangiogenic gene therapy with K1-5 cDNA will be a safe and effective strategy to suppress the growth of hepatocellular carcinoma.
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PMID:Liposome-mediated gene transfer of K1-5 suppresses tumor development and improves the prognosis of hepatocellular carcinoma in mice. 1682 Nov 44

The aims of the present review are to summarize and to discuss the role of hypoxia-inducible factor-1 (HIF-1) and the expression and functions of vasoactive substances in chronic hypoxemia with specific focus in the liver and the carotid body. Vascular remodelling and vasoactive substances play important functional roles in the adaptive response to chronic hypoxemia for the maintenance of oxygen homeostasis in all systems in man. HIF-1 regulates the gene expression of vasoactive substances such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and enzymes for producing nitric oxide (NO). Recent studies have shown the effect of chronic hypoxia on the expression of HIF-1alpha and HIF-1-target genes in multiple organ systems including the liver and the carotid body. Results are consistent with increases in the hematocrit levels, pulmonary arterial pressure and right heart mass developed during chronic hypoxia. In addition, the carotid body is also hyperplastic and increases in organ mass with increased levels of HIF-1alpha and the vasoactive substances. These molecules increase the mitotic activity and modulate the excitability of the chemoreceptor. Intriguingly, the liver morphology, serum alanine aminotransferase and 8-isoprostane levels are within normal range in chronic hypoxia, suggesting the absence of significant oxidative stress. Yet, the HIF-1alpha is upregulated and the mRNA and protein levels of VEGF, ET-1, inducible and constitutive NO synthases are elevated in the liver during chronic hypoxia. In conclusion, the adaptive response to long-term hypoxemia involves compensatory mechanisms mediated by expressing significant levels of HIF-1alpha and vasoactive substances regulated by HIF-1.
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PMID:Expression and functions of vasoactive substances regulated by hypoxia-inducible factor-1 in chronic hypoxemia. 1684 6

The antiangiogenic effect of Lygodium flexuosum extract was evaluated in Wistar rats intoxicated with N-nitrosodiethylamine (NDEA) in preventive and curative models. In preventive groups, NDEA was administered for 20 weeks. Daily doses of L. flexuosumn-hexane extract (200mg/kg) started 1 week before the onset of NDEA intoxication and continued for 20 weeks. In curative animals, NDEA was administered for 20 weeks followed by treatment with the n-hexane extract of L. flexuosum for 28 days. Rats intoxicated with NDEA had elevated levels of serum gamma-GT, AST, ALT, LDH levels and hepatic MDA and decreased levels of hepatic GSH. When treated with L. flexuosum extract had normal levels of gamma-GT, AST, ALT, LDH levels, hepatic MDA and GSH. NDEA administered rat liver showed an overexpressed levels of angiopoietins 1 (Ang-1) and 2 (Ang-2) and its receptor Tie-2 mRNA. L. flexuosum extract treatment significantly (p<or=0.05) reduced the levels of Ang-1 and Ang-2 and Tie-2 in rat livers evidenced by RT-PCR. Immunohistochemical analysis showed that vascular endothelial growth factor (VEGF) was overexpressed and localized around periportal area of liver sections intoxicated with NDEA and its overexpression was effectively reduced by the treatment with L. flexuosum extract. Histopathological observations also substantiated NDEA-induced hepatotoxicity and the effect was significantly (p<or=0.05) reduced by L. flexuosum extract treatment. Thus, L. flexuosum extract at a dose of 200mg/kg effectively reversed the hepatotoxicity induced by N-nitrosodiethylamine in both experimental models.
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PMID:Antiangiogenic effect of Lygodium flexuosum against N-nitrosodiethylamine-induced hepatotoxicity in rats. 1703 75

We have previously demonstrated that alternagin-C (ALT-C), a disintegrin-like protein from the venom of the Brazilian snake Bothrops alternatus, induces human vascular endothelial cell (HUVEC) proliferation by up-regulating the expression of vascular endothelial growth factor (VEGF). Here, we show that ALT-C is also able to induce in vivo angiogenesis using the model of matrigel plug in nude mice. Fibroblast growth factor (FGF) alone or supplemented with ALT-C was mixed with melted matrigel and subcutaneously injected in nude mice. After two weeks, the matrigel plugs were removed and analyzed to verify endothelial cell migration and new vessel formation. ALT-C (1 and 10 ng) strongly induced endothelial cell migration as well as the formation of new vessels. However, in higher concentrations, ALT-C strongly inhibited angiogenesis. In low concentrations (1 and 10nM), ALT-C also up-regulates the expression of VEGF receptor 2 (VEGFR2, KDR) mostly after 48 h, but it did not affect VEGFR1 (Ftl-1) in HUVEC cells as demonstrated by real-time PCR analysis. However, in higher concentrations (100 nM) the expression of both receptors is down-regulated. A peptide derived from ALT-C primary structure also affects HUVEC proliferation in vitro and angiogenesis in vivo. In conclusion, the present study shows for the first time the in vivo angiogenesis induced by a disintegrin-like molecule and the modulation of VEGFRs as well.
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PMID:Modulation of in vitro and in vivo angiogenesis by alternagin-C, a disintegrin-like protein from Bothrops alternatus snake venom and by a peptide derived from its sequence. 1742 38

Alcohol consumption is implicated in the genesis of a spectrum of liver abnormalities, which are associated with a number of factors. In the present study, time-dependent effects of ethanol on cytokines (TNF-alpha, IL-2, IL-4, IL-10, IFN-gamma, VEGF-A and TGF-beta1) in serum, and blood oxidative stress parameters such as reduced glutathione content, TBARS level and activities of GPx, GR, GST, catalase and SOD in 8-10 weeks-old male BALB/c mice have been investigated. Ethanol administered @ 1.6 g/kg body wt/day significantly increased the activities of liver marker enzymes AST, ALT and ALP. Serum nitrite levels and haemolysate TBARS level also increased, while total antioxidant status in serum and GSH content in whole blood hemolysate decreased from 4th week onwards of exposure. In spite of the increased serum nitrite level and GST activity in the haemolysate, albumin level in serum, GPx and GR activities in haemolysate decreased after 12 weeks of exposure. Chronic ethanol treatment did not show any effect on IL-2, but IL-4 level was reduced and other cytokines such as IL-10, TNF-alpha, IFN-gamma, TGF-beta1 and VEGF-A levels were increased significantly after 12 weeks. The study indicates a relationship between free radical generation and immune response, and suggests that ethanol-induced liver damage is associated with oxidative stress and immunological alterations in a time-dependent manner.
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PMID:Time-dependent effects of ethanol on blood oxidative stress parameters and cytokines. 1937 64

We reported previously that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant VEGF (hrVEGF) on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 microg s.c.) or vehicle 30 min before receiving APAP (200 mg/kg i.p.) and were sacrificed at 2, 4, and 8 h. Toxicity was comparable at 2 and 4 h, but reduced in the APAP/hrVEGF mice at 8 h (p < 0.05) compared with the APAP/vehicle mice. Hepatic glutathione (GSH) and APAP protein adduct levels were comparable between the two groups of mice, with the exception that GSH was higher at 8 h in the hrVEGF-treated mice. Subsequently, mice received two doses (before and 10 h) or three doses (before and 10 and 24 h) of hrVEGF; alanine aminotransferase values and necrosis were reduced at 24 and 36 h, respectively, in the APAP/hrVEGF mice (p < 0.05) compared with the APAP/vehicle mice. Proliferating cell nuclear antigen expression was enhanced, and interleukin-6 expression was reduced in the mice that received hrVEGF (p < 0.05) compared with the APAP/vehicle mice. In addition, treatment with hrVEGF lowered plasma hyaluronic acid levels and neutrophil counts at 36 h. Cumulatively, the data show that treatment with hrVEGF reduced toxicity and increased hepatocyte regeneration in APAP toxicity in the mouse. Attenuation of sinusoidal cell endothelial dysfunction and changes in neutrophil dynamics may be operant mechanisms in the hepatoprotection mediated by hrVEGF in APAP toxicity.
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PMID:Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. 2036 54


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