Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been proposed as a mediator of cardiac injury during ischemia and reperfusion. We examined the signalling events initiated by short-term exposure of cardiac myocytes to oxidative stress elicited by hydrogen peroxide. A potent stimulation of tyrosine phosphorylation was observed within 1 to 2 min exposure to 1 m m hydrogen peroxide. Within 5 min, the ERK mitogen-activated protein kinases (ERK MAPKs) were activated. This activation of ERK MAPKs was blocked by N-acetylcysteine (NAC), implicating a role for free radicals in the signalling events. NAC failed to inhibit ERK MAPK activation by the hypertrophic agent, phenylephrine, or hyperosmotic shock. Myxothiazol, an inhibitor of complex III of the mitochondrial electron transport chain, also inhibited ERK MAPK activation by hydrogen peroxide, but not by 12- O -tetradecanoylphorbol-13-acetate (TPA) or hyperosmotic shock. Myxothiazol completely inhibited the increase in tyrosine phosphorylated proteins observed with hydrogen peroxide treatment. A variety of inhibitors which act at different levels of the mitochondrial electron transport chain (rotenone, theonyltrifluoroacetone, antimycin A, cyanide) also inhibited activation of the ERK MAPKs by hydrogen peroxide but not TPA or hyperosmotic shock. These studies suggest a novel mechanism of regulation of the ERK MAPK pathway and oxidative stress signalling by hydrogen peroxide.
J Mol Cell Cardiol 2000 Aug
PMID:Intact mitochondrial electron transport function is essential for signalling by hydrogen peroxide in cardiac myocytes. 1090 Jan 73

One member of the OATP family of transporters, rat Oatp1, functions as an anion exchanger that is driven in part by the glutathione (GSH) electrochemical gradient, indicating that other OATP-related transporters may also be energized by this mechanism. The present study examined whether rat Oatp2 is also an anion exchanger, and, if so, whether it is energized by the GSH electrochemical gradient. As with Oatp1, uptake of 10 microM [(3)H]taurocholate in Oatp2-expressing Xenopus laevis oocytes was trans-stimulated by intracellular 0.2 mM unlabeled taurocholate, indicating bidirectional transport. Interestingly, [(3)H]taurocholate uptake in Oatp2-expressing oocytes was also trans-stimulated when oocytes were preloaded with GSH, S-methylglutathione, S-sulfobromophthalein-glutathione, S-dinitrophenyl glutathione, or ophthalmic acid (a GSH analog) but not by glutarate or N-acetylcysteine, suggesting that GSH derivatives and conjugates may function as intracellular substrates for Oatp2. Support for this hypothesis was provided by the demonstration of enhanced [(3)H]GSH and [(3)H]S-(2,4-dinitrophenyl)-glutathione efflux in Oatp2-expressing oocytes. However, in contrast to Oatp1, extracellular GSH failed to cis-inhibit uptake of [(3)H]taurocholate or [(3)H]digoxin in Oatp2-expressing oocytes, indicating that the stimulatory effect of high intracellular GSH concentrations is not due to a coupled exchange mechanism. Taken together, the results indicate that Oatp2 mediates bidirectional transport of organic anions by a GSH-sensitive facilitative diffusion mechanism and suggest that this transporter may play a role in cellular export of specific organic molecules.
Mol Pharmacol 2000 Aug
PMID:Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione. 1090 1

It was previously shown that 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) enhances the cytotoxic activity of tumor necrosis factor alpha (TNFalpha), doxorubicin and menadione. A feature shared by these anticancer agents is the involvement of reactive oxygen species (ROS) in their action. In this work we found that 1, 25(OH)(2)D(3) acted synergistically with interleukin 1 beta (IL-1beta) or interleukin 6 (IL-6) to inhibit the proliferation of MCF-7 breast cancer cells. The extent of the synergism was maximal at 1 nM, a concentration at which 1,25(OH)(2)D(3), acting singly, only marginally reduced the cell number. The thiol antioxidant, N-acetylcysteine (NAC) abolished the synergism between IL-1beta or IL-6 and 1,25(OH)(2)D(3), but had only a small protective effect when the cytokines acted alone. NAC and reduced glutathione (GSH) protected MCF-7 cells from cytotoxicity induced both by TNFalpha alone and by TNFalpha and 1,25(OH)(2)D(3). A two-day exposure to TNFalpha caused a 27.7+/-3.1% (mean +/- SEM) reduction in GSH content. This effect increased to 46.4+/-5.5% by co-treatment with 1, 25(OH)(2)D(3) which did not affect GSH levels on it own. We conclude that 1,25(OH)(2)D(3) can act synergistically with anticancer cytokines present in the tumor milieu and that ROS plays a mediatory role in this interaction.
J Steroid Biochem Mol Biol 2000 Jun
PMID:Synergistic anticancer activity of 1,25-dihydroxyvitamin D(3) and immune cytokines: the involvement of reactive oxygen species. 1092 9

Constipation is a risk factor of colorectal cancer. Mucin is a major component of lumenal mucus, which protects the colorectal mucosa against mechanical and chemical damage. The aim of this study was to evaluate mucus production and to quantitate lumen mucus in a rat model of spastic constipation. We induced constipation with loperamide (1.5 mg/kg), and histochemically evaluated mucus production and the thickness of the mucus layer at the fecal surface. We quantitated the mucus attached to the mucosal surface using colonic perfusion with N-acetylcysteine. While more feces remained in the colon, there was less fecal excretion and lower fecal water content in loperamide-administered rats than in control rats. Crypt epithelial cells contained less mucus in constipated rats than in control rats. The mucus layer at the fecal surface was thinner and less mucus was recovered from the mucosal surface in constipated rats than in control rats. Mucus production of crypt epithelial cells and mucus at the fecal and mucosal surface were reduced by loperamide-induced constipation.
Comp Biochem Physiol A Mol Integr Physiol 2000 Jun
PMID:Decreased colonic mucus in rats with loperamide-induced constipation. 1093 60

The underlying cause of the selective death of the nigral dopaminergic neurons in Parkinson's disease is not fully understood. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of dopamine and nitric oxide. Because BH4 contributes to the syntheses of these two potential oxidative stressors and also undergoes autoxidation, thereby producing reactive oxygen species, it was possible that BH4 may play a role in the selective vulnerability of dopaminergic cells. BH4 given extracellularly was cytotoxic to catecholamine cells CATH. a, SK-N-BE(2)C, and PC12, but not to noncatecholamine cells RBL-2H3, CCL-64, UMR-106-01, or TGW-nu-1. This was not caused by increased dopamine or nitric oxide, because inhibition of their syntheses did not attenuate the damage and BH4 did not raise their cellular levels. Dihydrobiopterin and biopterin were not toxic, indicating that the fully reduced form is responsible. The toxicity was caused by generation of reactive oxygen species, because catalase, superoxide dismutase, and peroxidase protected the cells from the BH4-induced demise. Furthermore, thiol agents, such as reduced glutathione, dithiothreitol, beta-mercaptoethanol, and N-acetylcysteine were highly protective. The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage. BH4 was spontaneously released from the cells of its synthesis to a large extent, and the release was not further enhanced by calcium influx. This BH4-induced cytotoxicity may represent a mechanism by which selective degeneration of dopaminergic terminals and neurons occur.
Mol Pharmacol 2000 Sep
PMID:Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. 1095 58

The main purpose of this study was to investigate the effect of free radicals and experimental diabetes on cytosolic creatine kinase activity in rat heart, muscle and brain. Hydrogen peroxide decreased creatine kinase activity in a dose dependent manner which was reversed by catalase. Xanthine/xanthine oxidase, which produces superoxide anion, lowered the creatine kinase activity in the same manner whose effect was protected by superoxide dismutase. N-acetylcysteine and dithiothreitol also significantly ameliorated the effect of Xanthine/xanthine oxidase and hydrogen peroxide. Experimental diabetes of twenty-one days (induced by alloxan), also caused a similar decrease in the activity of creatine kinase. This led us to the conclusion that the decrease in creatine kinase activity during diabetes could be due to the production of reactive oxygen species. The free radical effect could be on the sulfhydryl groups of the enzyme at the active sites, since addition of sulfhydryl groups like N-acetylcysteine and dithiothreitol showed a significant reversal effect.
Mol Cell Biochem 2000 Jul
PMID:Effects of free radicals on cytosolic creatine kinase activities and protection by antioxidant enzymes and sulfhydryl compounds. 1097 54

Vascular cell adhesion molecule-1 (VCAM-1) is expressed in early stages of atherosclerosis; however, the mechanisms of its upregulation are not fully understood. In the present study, we examined the effects of interleukin-4 (IL-4) on VCAM-1 gene expression and its transcriptional regulatory mechanism in human umbilical vein endothelial cells (HUVEC). Reverse transcription-polymerase chain reaction showed that VCAM-1 mRNA was induced in IL-4-treated HUVEC in a time- and dose-dependent manner. Among known transcription factors that have binding sites in the promoter region of the VCAM-1 gene, IL-4 activated only SP-1. In contrast, nuclear factor- kappa B (NF- kappa B), activator protein-1 (AP-1) and interferon regulatory factor-1 (IRF-1), which also have consensus binding sequences in the 5'-flanking region of the human VCAM-1 gene, were not activated. The role of SP-1 in IL-4-induced VCAM-1 expression was confirmed in HUVEC transfected with a reporter construct of the VCAM-1 promoter with mutated SP-1 binding site. As IL-4 treatment of HUVEC enhanced the intracellular oxidizing potential, as indicated by an increase in 2',7'-dichlorofluorescein (DCF) fluorescence, we studied the effect of antioxidants on IL-4-induced VCAM-1 expression. Pretreatment of HUVEC with pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC) completely prevented IL-4-induced VCAM-1 expression. In addition, PDTC inhibited IL-4-related activation of SP-1. These results suggest that IL-4-induced oxidative stress upregulates the expression of VCAM-1 gene in HUVEC at transcriptional levels via activation of SP-1 transcription factor. In contrast, NF- kappa B, AP-1 or IRF-1 do not appear to be involved in the signal transduction cascade.
J Mol Cell Cardiol 2001 Jan
PMID:IL-4-induced oxidative stress upregulates VCAM-1 gene expression in human endothelial cells. 1113 25

The involvement of alpha-synuclein in neurodegenerative diseases was first suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD). Later, two different alpha-synuclein mutations were shown to be associated with autosomal-dominant Parkinson's disease (PD), but only in a small number of families. However, the discovery that alpha-synuclein is a major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD, confirmed its role in PD pathogenesis. Pathological aggregation of the protein might be responsible for neurodegeneration. In addition, soluble oligomers of alpha-synuclein might be even more toxic than the insoluble fibrils found in Lewy bodies. Multiple factors have been shown to accelerate alpha-synuclein aggregation in vitro. Therapeutic strategies aimed to prevent this aggregation are therefore envisaged. Although little has been learned about its normal function, alpha-synuclein appears to interact with a variety of proteins and membrane phospholipids, and may therefore participate in a number of signaling pathways. In particular, it may play a role in regulating cell differentiation, synaptic plasticity, cell survival, and dopaminergic neurotransmission. Thus, pathological mechanisms based on disrupted normal function are also possible.
Cell Mol Life Sci 2000 Dec
PMID:Alpha-synuclein and Parkinson's disease. 1121 16

The radioprotective aminothiols 2-[(aminopropyl)amino] ethanethiol (WR-1065) and cysteamine (CSM) potentiate the induction of chromosomal damage by the radiomimetic compound bleomycin (BLM) in G0 human lymphocytes. To investigate the mechanism of potentiation, we measured the clastogenic activity of BLM in the cytokinesis-block micronucleus assay in the presence and absence of amines, thiols, and aminothiols. The hydroxy analog of WR-1065, 2-(3-aminopropylamino) ethanol (WR-OH), potentiates BLM only slightly, indicating the critical nature of the thiol group. As thiols, WR-1065 and CSM may donate electrons for the activation of Fe(+2)-BLM or for the regeneration of Fe(+2)-BLM from inactive Fe(+3)-BLM. The amines putrescine, spermidine, and spermine all potentiate BLM, but they are weaker potentiators than the aminothiols, and they are effective only at high concentrations. Their activity, like that of WR-OH, is probably a consequence of conformational alteration of DNA. Dithioerythritol (DTE) and 2-mercaptoethanol (2-ME), thiols lacking an amino group, are less effective potentiators of BLM than are the aminothiols. The thiol group of WR-1065 and CSM is therefore essential, but insufficient, for explaining the strong enhancement of BLM activity. The cationic nature of CSM and WR-1065, conferred by the amino groups, evidently concentrates the active thiol function at the site of BLM action on DNA. As expected on this basis, the diamine WR-1065 is a more effective potentiator of BLM than is the monoamine CSM, whereas cysteine and N-acetylcysteine (NAC), which lack a net positive charge, potentiate BLM only weakly. These studies suggest that potentiation of the clastogenic action of BLM by aminothiols can be explained by the combination of a thiol-mediated redox mechanism and an amine-mediated targeting of the thiol function to DNA.
Environ Mol Mutagen 2001
PMID:Structure-activity analysis of the potentiation by aminothiols of the chromosome-damaging effect of bleomycin in G0 human lymphocytes. 1124 18

We have shown that endogenous nitrogen oxides (NOx) modulate excitation-contraction coupling in diaphragm. Because cyclic GMP (cGMP) is a second messenger for nitric oxide (NO) inhibition of smooth muscle contraction, we rested the hypothesis that NO acts via cGMP in diaphragm. Fiber bundles from rat diaphragm were studied in vitro. Immunohistochemical analysis using a cGMP-specific monoclonal antibody confirmed the presence of cGMP in the subsarcolemmal region, near nitric oxide synthase (NOS). cGMP measured by ELISA in control muscle (0.27 pmol/mg +/- 0.01 SE) was significantly increased by the NO donor S-nitroso-N-acetylcysteine 1 mM (0.55+/-0.05; N = 6; P < 0.001). Contractile studies showed that the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) 10 mM increased submaximal (40 Hz) tetanic force (P < 0.0001). L-NNA effects were exaggerated by the guanylate cyclase inhibitor LY83583 5-10 microM; force at 40 Hz was increased (P < 0.001). L-NNA effects were partially reversed by 8-bromo-cGMP 1 mM (8-Br-GMP; a cell-permeable cGMP analogue; P < 0.0001) or dipyridamole 10 microM (DPM; a phosphodiesterase inhibitor; P < 0.0001). 8-Br-GMP and DPM produced more-complete L-NNA reversal in combination (P < 0.0001). We conclude that cGMP functions as a second messenger by which NO inhibits diaphragm contraction.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jan
PMID:Cyclic GMP is a second messenger by which nitric oxide inhibits diaphragm contraction. 1125 83


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