Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cell dysfunction is a key factor in oxidative stress-related pathology. Disruption of Ca2+ homeostasis is thought to be responsible for much of the endothelial cell dysfunction in oxidative stress. The expression of molecular chaperones (MC), which stabilize protein structures in normal and in stress conditions, reflects the Ca(2+)-dependent and -independent stress effects in the different cell compartments. By two-dimensional (2-D) gel electrophoresis combined with immunoblotting or microsequencing, we have identified 12 major MC in human umbilical vein endothelial cells (HUVEC): (i) the endoplasmic reticulum-located MC GRP78, GRP94, protein disulfide isomerase, and calreticulin; (ii) the mitochondrial MC HSP65 and GRP75; and (iii) the cytosolic/nuclear MC HSP27, HSC70, HSP70, HSP90, cyclophilin, and ubiquitin. To differentiate oxidative stress- and Ca(2+)-mediated effects, HUVEC were exposed to 1) xanthine oxidase plus hypoxanthine to generate oxidative stress, 2) ionomycin plus ethylene glycol-bis(beta-aminoethylether)-N,N,N', N'-tetraacetic acid (EGTA) to deplete intracellular Ca2+ stores, or 3) thrombin to increase cytosolic Ca2+. De novo protein synthesis after exposure was quantified by the incorporation of [35S]methionine. Image processing with the MELANIE system was used to create and compare the 2-D maps of [35S]methionine-labeled proteins under conditions 1)-3) with those of the controls. In a total of 24 2-D gels, 9 different MC were detected in at least 5 out 6 experimental replicates and were subjected to numeric analysis. The statistics showed a > 10% increase in GRP78 (p < 0.05), HSP27, cyclophilin, and ubiquitin after oxidative stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of oxidative stress and Ca2+ agonists on molecular chaperones in human umbilical vein endothelial cells. 749 68

A number of immunomodulating agents of different origin have been shown to reduce liver injury of various etiologies. Immunostimulants like levamisole, BCG, a protein polysaccharide from myceria Coriolus vesicolor PS-K, a streptoccocal preparation OK-432 and immunomodulators like N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and its analogs. Selective T-cell suppressors like the polypeptide cyclosporine A (CsA) and the macrolide FK 506 (tacrolimus) have also been claimed to possess hepatoprotrophic or hepatoprotective properties at low doses. The aim of this review article is to highlight the interplay between the administration of immunomodulating agents and the amelioration of hepatic injuries. Hepatic effects of exogenous immunomodulators are discussed with special focus on the most widely used immunosuppressive agents, CsA and tacrolimus. An important question exists as to whether these potential hepatoprotective effects are related mechanistically to the immune system or are working at different levels. Due to the differences in effects and modes of actions of various immunoactive substances presented herein, a common mechanism for their cytoprotective effects cannot be formulated at this stage. Levamisole and cyanidanol may protect cells against necrosis by acting as free radical scavengers. MDP and its analogs reduce carbon tetrachloride-elevated (CCl4) lipid peroxides and their protective effects are primarily on hepatic cytoplasmic membranes where lipid peroxidation and calcium homeostasis interact. MDP reduced CCl4-elevated calcium in both intact hepatocytes and in the post microsomal supernatant suggest that the influx of extracellular calcium across plasma membrane is affected. Elevations of intracellular calcium above a threshold are involved in: the stimulation of Ca2+-sensitive enzymes such as phospholipase A2, endonucleases and proteases, the conversion of xanthine dehydrogenase to xanthine oxidase and the formation of free radicals, all of which disturb biomembranes. MDP and its analogs, in a specific dose range, may act to maintain intracellular calcium within physiological ranges. Highly complex cellular signalling systems, including calcium, are involved in the explanation of the mechanism of the immunosuppressive effect of CsA and tacrolimus. The hepatoprotective effects of these selective immunosuppressive agents, however, are independent of the inhibition of T-cell activation. The cyclophilin and tacrolimus binding proteins of the mitochondria are the receptors for these compounds and play a key role in the regulation of mitochondrial permeability transition pores. CsA or tacrolimus inhibition of mitochondrial permeability transition pores does not require interaction with calcineurin, indicating a dissociation between immunosuppression and mitochondrial protection. The involvement of intracellular or intramitochondrial proteins in the modulation of mitochondrial permeability transition pores with the creation of a partially impermeable state for Ca2+ movement in drug-treated mitochondria and the dissociation of this effect from immunomodulatory actions potentially offers new and promising approaches for the development of new pharmacologicals targeted at therapeutic intervention. Clinical trials of these drugs as hepatoprotective agents are limited. Use of CsA in patients with primary biliary cirrhosis and autoimmune chronic hepatitis and in cirrhotic animal models produced by chronic administration of CCl4 have yielded encouraging results. It seems that this class of compounds may be of substantial benefit in liver protection against many pathological conditions where disturbance in mitochondrial function and in Ca2+ homeostasis appear to be prerequisites for cell injury.
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PMID:Immunopharmacologic agents in the amelioration of hepatic injuries. 973 Feb 49