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)

Interstitial collagenases, members of the matrix metalloproteinase family, are key initiators of collagen destruction during various disorders such as rheumatoid arthritis. Recently interstitial collagenases were found to efficiently degrade an additional non-collagenous substrate, the serum alpha-1-antitrypsin (AAT also called alpha-1-proteinase inhibitor or serpin). Serpins are major endogenous inhibitors of serine proteinases, particularly neutrophil elastase. Of relevance to neutrophil-mediated collagen degradation, the tetracycline family of antibiotics are now known to inhibit inhibit mammalian collagenases by a mechanism unrelated to their antimicrobial activity. This study identifies an additional mechanism by which tetracyclines may retard tissue breakdown during inflammatory diseases. Doxycycline, added to the reaction mixture as in concentrations as low as 10 microM, which correspond to levels of the drug readily achieved in vivo, produced detectable inhibition of serpinase activity of neutrophil collagenase, although levels of 50-100 microM or greater were required to reduce AAT degradation more than 75%. The concentration of doxycycline to inhibit 50% (IC50 of serpinase activity) of AAT degradation by neutrophil collagenase was found to approximate 20 microM, a value similar to the IC50 for doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline was also found to inhibit at cell level neutrophil-mediated degradation of AAT. The protection of bodies' AAT-shield from serpinolytic activity of collagenase would result in inhibition of serine proteinases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
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PMID:Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase. 845 33

We examined 95 ground squirrels to compare the histological appearance of liver sections from animals that were chronically infected with ground squirrel hepatitis virus (GSHV) (n = 29), uninfected (n = 42), or had recovered from infection (n = 24). We studied the effects of long-term infection because these animals had been infected with GSHV for up to 10 years. Chronic infection generally produced a mild, persistent hepatitis characterized by light lymphocytic and plasmacytic portal infiltrates with occasional individual necrotic hepatocytes and small aggregates of Kupffer cells or mononuclear inflammatory cells in the parenchyma. In a few of the portal tracts from each of the more inflamed livers (grade 2), the inflammatory infiltrate penetrated the limiting plate and extended into the adjacent parenchyma. Hepatitis (grades 1 or 2) was detected more often in chronically infected animals (17 of 29) than in recovered (4 of 24) or uninfected ground squirrels (7 of 42). Fibrosis was generally not increased, but fine strands of collagen extended from the portal tracts and central veins into the parenchyma of about one quarter of the infected and recovered animals. Cytoplasmic pigment accumulation and variation in the size of hepatocyte nuclei appeared to be related to aging, not infection. Serum levels of aspartate and alanine transaminases (AST and ALT) were mildly elevated in samples from seven infected animals compared with seven control animals. Despite many years of chronic infection, liver injury was similar to that reported in previous studies on animals infected for shorter intervals, indicating that liver injury is not progressive in GSHV-infected ground squirrels.
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PMID:Non-neoplastic liver disease associated with chronic ground squirrel hepatitis virus infection. 867 46

In order to elucidate the clinical significance of serum hyaluronan in chronic viral hepatitis, serum hyaluronan concentrations were measured using a sandwich enzyme binding assay in 115 patients with chronic viral hepatitis. These findings were examined in relation to the results of laboratory liver tests, levels of serum markers for fibrosis and liver histological findings. Serum hyaluronan levels increased with the progress of liver disease, particularly in liver cirrhosis. There were no significant differences in serum hyaluronan levels among the cirrhotic patients according to Child's grade. Multivariate analysis showed that the significant independent predictors of serum hyaluronan were serum aspartate aminotransferase (P = 0.020), serum alanine aminotransferase (P = 0.008), serum cholinesterase (P < 0.001), particularly serum type IV collagen 7S domain (P < 0.0001), and the histological degree of liver fibrosis (P < 0.0001). These findings suggest that elevated serum hyaluronan levels are closely related to the severity of liver fibrosis. We assessed the predictive value of serum hyaluronan in differentiating cirrhosis from chronic hepatitis, constructing receiver operating curves; we found that serum hyaluronan was a better test for diagnosing cirrhosis than serum type IV collagen 7S domain and laboratory liver tests.
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PMID:Clinical significance of serum hyaluronan in patients with chronic viral liver disease. 874 18

Liver fibrosis was induced by chronically (7 weeks) administering CCl4 to rats. Animals were divided into four groups: (a) controls, (b) treated with CCl4 alone, (c) treated with CCl4 and colchicine and (d) treated with CCl4 and formyl-colchicine bound to lactosaminated serum albumin (FC-LASA). Liver dysfunction was monitored by biochemical tests (alkaline phosphatase [ALP], gamma-glutamyltransferase [gamma GT], aspartate and alanine transaminases [AST and ALT], albumin and total bilirubin). Fibrosis was evaluated by determining hydroxyproline and by microscopic examination. The exposure to CCl4 produced major alterations of liver structure and collagen deposition. These effects were partially counteracted by colchicine and to a greater extent by FC-LASA. Morphological findings paralleled biochemical data. The information reported here indicates that colchicine has an antifibrotic activity on the liver of intoxicated rats and that FC-LASA is more active than colchicine itself as an antifibrotic agent.
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PMID:Formylcolchicine bound to lactosaminated serum albumin is a more active antifibrotic agent than free colchicine. 889 3

Experimental liver cirrhosis was produced by administration of thioacetamide. Cirrhotic animals were divided into two groups: one group was given zinc sulphate and the second kept as cirrhotic control. Zinc-treated animals showed a restoration of normal hepatic and plasma zinc and copper levels. Similarly, plasma levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl aminotransferase, and total bilirubin decreased significantly. Light microscopic studies showed that most of the hepatocytes appeared normal in zinc-treated as compared with untreated cirrhotic animals. The amount of fibrin, reticulin, and collagen, which was high in the cirrhotic livers, decreased following zinc treatment. Staining with periodic acid Schiff's reagent showed the ability of hepatocytes to store glycogen after zinc treatment. These results revealed that zinc may have some beneficial effect in the treatment of liver cirrhosis.
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PMID:Zinc and liver cirrhosis: biochemical and histopathologic assessment. 913 80

For the past few years, we have been investigating polysaccharides from Ganoderma lucidum as antifibrotic agents. In a previous study, we discovered that polysaccharides extracted from G. Iucidum lowered the collagen content in liver but had no effect on serum biochemical parameters in rats subjected to bile duct ligation and scission-induced fibrosis. In this study, we changed the extraction method and obtained polysaccharides extracted from G. Iucidum. The polysaccharide from G. Iucidum reduced the serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and total bilirubin and also reduced the collagen content in liver and improved the morphology. Pentoxifylline, which is reported to exhibit an antifibrotic effect in pigs with fibrosis induced by yellow phosphorus, did not have any antifibrotic effects in fibrosis induced by biliary obstruction. Glycyrrhizin, which is used in the treatment of hepatitis, reduced serum ALT and AST values but there was no significance. It had no effect on liver hydroxyproline content which implies that glycyrrhizin has no antifibrotic effect in the rats with fibrosis induced by bile duct ligation and scission. These data suggest that the polysaccharide from Ganoderma lucidum could be a promising antifibrotic agent. However, further study is needed to understand the inhibition mechanism of collagen deposition of polysaccharides from Ganoderma Iucidum and its clinical applicability remains to be established.
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PMID:Antifibrotic effects of a polysaccharide extracted from Ganoderma lucidum, glycyrrhizin, and pentoxifylline in rats with cirrhosis induced by biliary obstruction. 914 21

SPAAT (short piece of alpha 1-antitrypsin [AAT]), the 44-residue C-terminal peptide of AAT, was originally isolated from human placenta [Niemann et al. (1992): Matrix 12:233-241]. It was shown to be a competitive inhibitor of serine proteases [Niemann et al. (in press): Biochem Biophys Acta]. The binding of SPAAT to one or more proteins of the extracellular matrix (ECM) was initially suggested on the basis of its recovery from tissue residues following a series of extractions designed to remove easily solubilized proteins [Niemann et al. (1992): Matrix 12:233-241]. Our binding studies with the model ECMs, Matrigel and Amgel, suggested that SPAAT might be bound by a specific collagen type as well as one or more non-collagenous ECM proteins. Individual ECM components were screened for their ability to bind SPAAT. When the four commonly occurring fiber-forming collagens (types I, II, III, and V) were evaluated, type III was found to be preferred. In addition, although SPAAT bound to preformed type III collagen fibers in a concentration dependent fashion, it did not bind to type III collagen molecules undergoing fibril formation. This is consistent with a physiological mode of interaction between SPAAT and type III collagen in vivo. Of the non-collagenous ECM macromolecules (laminin-1, fibronectin, entactin, and heparan sulfate) tested, laminin-1 was preferred. The binding of radiolabelled SPAAT to type III collagen and laminin-1 was competitively inhibited by unlabelled SPAAT as well as an unrelated protein, human serum albumin (HSA), to establish binding specificity. The kinetics of the release of the bound radiolabelled SPAAT were also examined to substantiate the non-covalent and reversible nature of this association. These results support the view that susceptible proteins of the ECM may actually be coated with SPAAT in vivo, possibly affording protection against inappropriate protease digestion.
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PMID:Binding of SPAAT, the 44-residue C-terminal peptide of alpha 1-antitrypsin, to proteins of the extracellular matrix. 925 91

Osteopontin (OPN) is an acidic phosphoprotein synthesized by osteoblasts and osteoclastic cells that are localized in the mineralized phase of bone matrix. OPN is thought to bind to the vitronection receptor on the osteoclast membrane and regulates bone resorption by the osteoclast. In this study, we investigated whether or not OPN can relate to osteoclast differentiation and bone resorption in a co-culture system. When C57Black/6N mouse bone marrow cells suspended on ivory slices coated with collagen were inoculated onto a MC3T3-G2/PA6 cell layer, colonies containing TRAP(+) mononuclear and multinuclear cells were formed in the presence of 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. At the end of culture period the number of TRAP(+) osteoclast-like cells were counted and the resorption pits were evaluated by reflected light microscopy. The mRNA of OPN was detected by in situ hybridization. Osteoclast-like cells expressed OPN mRNA. The addition of an OPN antisense oligomer (5' AAT CAC TGC CAA TCT CAT 3') at the start of the co-culture period decreased the number of TRAP(+) cells present after 7 d (30.3 +/- 3.4 vs 56.9 +/- 12.4), and the ratio of mononuclear and multinucleated cells was changed (77.6:23.2 vs 60.8:39.3). The total area of pits per ivory slice was also decreased by adding the OPN antisense oligomer (246813 vs 303139 microns2). These results showed that OPN can be an important mechanism for regulating differentiation and bone resorption.
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PMID:Osteopontin antisense deoxyoligonucleotides inhibit bone resorption by mouse osteoclasts in vitro. 937 15

Liver injury due to bile duct ligation (BDL) is histologically characterized by cholestasis, bile ductular proliferation, hepatocellular damage, portal fibrosis, and ultimately biliary cirrhosis. Stem cells within the liver may act as progenitor cells for small epithelial cells termed oval cells that can differentiate into bile duct cells or hepatocytes, whereas myofibroblasts are the principal source of collagen production in fibrosis. The aims of this study were to determine 1) whether BDL induces oval cell proliferation and 2) whether blockade of Kupffer cells affects oval cell proliferation, bile duct proliferation, and myofibroblast transformation in experimental biliary obstruction. Male Sprague-Dawley rats were divided into two groups to receive either a single dose of gadolinium chloride (a selective Kupffer cell blocking agent) or vehicle. One day later, the gadolinium- and vehicle-treated groups were further subdivided to receive either BDL or sham operation. The rats were sacrificed on day 7 postoperatively. Serum was collected for measurement of aspartate aminotransferase, gamma-glutamyl transpeptidase, and bilirubin levels. Liver tissue was taken for evaluation of fibrosis, bile ductular cells, oval cells, and myofibroblasts. BDL resulted in elevated aspartate aminotransferase, gamma-glutamyl transpeptidase, and bilirubin in serum, and gadolinium pretreatment did not modify these effects. BDL induced marked oval cell proliferation, which was completely prevented by gadolinium pretreatment. Gadolinium did not affect the induction of bile duct expansion or myofibroblasts after BDL. We conclude that experimental biliary obstruction induces oval cell proliferation, which can be prevented by gadolinium pretreatment. This suggests that bile ductular proliferation and myofibroblast transformation are not mediated by Kupffer cells and that ductular proliferation can proceed in the absence of oval cells. Alternatively, gadolinium may directly affect oval cell proliferation after BDL.
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PMID:Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction. 946 59

Chronic liver disease is often accompanied by hypoxaemia. We investigated the clinical factors that were related to the arterial oxygen tension (PaO2) in 40 women, all non-smokers with chronic liver disease. They were positive for hepatitis C virus (HCV) antibody and had no evidence of cardiopulmonary disease. Arterial blood was collected from patients at rest (> 15 min) for analysis of blood gases. We determined the correlation between blood gas tension and the clinical variables, i.e. the presence or absence of skin manifestations such as cutaneous spider nevi and palmar erythema, the presence or absence of splenomegaly, vital capacity, forced expiratory volume in one second, V25/body height, serum alanine aminotransferase (AST), serum asparate aminotransferase (ALT), serum cholinesterase, serum gamma-globulin/total protein, excretion of indocyanine green at 15 min (15-min retention rate, ICG level), blood level of ammonia, blood level of endotoxin, plasma level of glucagon and the serum level of type IV collagen-7S. The mean level of PaO2 was 78 +/- 11 (range: 43-95) torr. The mean alveolar-arterial oxygen tension gradient (A-aDO2) was 19 +/- 13 (range: 2-60) torr. Multiple regression analysis used PaO2 and A-aDO2 as objective variables, and the clinical findings as explanatory variables. The explanatory variables that were significantly correlated with blood gas values were ICG level, blood level of endotoxin and presence of skin manifestations. The ICG level showed a high correlation with blood gas values; the ICG level increased, the PaO2 decreased (r = -0.69), while the A-aDO2 showed a high positive correlation (r = +0.78, P < 0.001). Findings suggest that a reduction in hepatic blood flow and hepatocellular function interfere with the inactivation of vasoactive substances such as endotoxin by the liver, leading to the development of skin manifestations, the dilatation of intrapulmonary capillaries and the induction of hypoxaemia.
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PMID:Clinical factors that affect blood gases in non-smoking women with chronic liver disease. 951 26


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