EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence points to a causal role for advanced glycation end products (AGEs) in the development of diabetic vascular complications, including retinopathy. Possible pathogenic mechanisms linking AGEs to diabetic retinopathy include protein kinase C (PKC) activation, oxidative stress, and vascular endothelial growth factor (VEGF) expression. In the present study, we investigated the effect of AGEs on VEGF expression in bovine retinal endothelial cells (BRECs) and determined the role of PKC and oxidative stress in this effect. Incubation of BRECs with AGEs led to enhanced VEGF mRNA and protein expression. This treatment also induced PKC translocation in these cells. The AGE-induced increases in VEGF expression and PKC activation were inhibited by the pan-specific PKC inhibitor, calphostin C, and by the antioxidant drug and compounds, gliclazide, N-acetylcysteine, and vitamin E. In contrast, glyburide which does not exhibit antioxidant properties, did not affect the AGE-induced VEGF expression. Exposure of BRECs to AGEs resulted in a significant increase of nuclear protein binding to the NF-kappa B consensus sequence of the VEGF promoter region. Induction of DNA binding activity for NF-kappa B by AGEs was prevented by gliclazide. Treatment of BRECs with AGEs also increased the proliferation of these cells. This effect was abrogated by incubating the cells with an anti-VEGF antibody and was inhibited in the presence of gliclazide. Overall, these data demonstrate that AGEs increase VEGF expression in retinal endothelial cells through generation of oxidative stress and downstream activation of the PKC pathway. Targeting VEGF expression with specific pharmacological agents, such as antioxidants and PKC inhibitors, may prove efficacious for the treatment of diabetic retinopathy.
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PMID:Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor expression in retinal endothelial cells. Inhibitory effect of gliclazide. 1212 87

The objectives of this study were (1) to investigate the transporter inhibition activity of three nonionic surfactants on P-glycoprotein, the human intestinal peptide transporter, and the monocarboxylic acid transporter in Caco-2 cell monolayers, and (2) to evaluate the role of membrane fluidity and protein kinase C in surfactant-induced transporter inhibition. All three surfactants inhibited P-glycoprotein (P-gp). Over a range from 0 to 1 mM, Tween 80 and Cremophor EL increased apical-to-basolateral permeability (AP-BL) and decreased basolateral-to-apical (BL-AP) permeability of the P-gp substrate rhodamine 123. Vitamin E TPGS's effect was equally large, but essentially only reduced the BL-AP permeability of rhodamine 123, and did so at a vitamin E TPGS concentration of only 0.025 mM. These P-gp inhibition effects would appear to be related to these excipients' modulation of membrane fluidity, where Tween 80 and Cremophor EL fluidized cell lipid bilayers, while vitamin E TPGS rigidized lipid bilayers. However, among the three surfactants, only Tween 80 inhibited the peptide transporter, as measured by glycyl sarcosine permeability. Likewise, only Cremophor EL inhibited the monocarboxylic acid transporter, as measured by benzoic acid permeability. Nevertheless, at least one of these three surfactants inhibited each P-gp, the human intestinal peptide transporter, and the monocarboxylic acid transporter. A common functional feature of these three surfactants was their ability to modulate fluidity, although results indicate that even strong membrane fluidity modulation alone was not sufficient to reduce transporter activity. N-octyl glucoside, a nonionic surfactant that did not modulate membrane fluidity, did not affect transporter functioning. Protein kinase C inhibitors failed to affect rhodamine 123 and glycyl sarcosine permeability, suggesting protein kinase C inhibition was not the mechanism of transporter inhibition. These results suggest that surfactants can inhibit multiple transporters but that changes in membrane fluidity may not be a generalized mechanism to reduce transporter activity.
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PMID:Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. 1220 53

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
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PMID:Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. 1237 42

Lysophosphatidylcholine (LPC), a lysolipid contained in oxidized low-density lipoprotein, is an atherogenic molecule that induces endothelial dysfunction and platelet activation and inhibits angiogenesis. Although studies showed that vitamin E has antiatherogenic properties, the effects of vitamin E on LPC-induced endothelial dysfunction and platelet activation are little known. We examined whether vitamin E has protecting actions against LPC-induced alterations of endothelial and platelet functions. Incubation of cultured bovine aortic endothelial cells (BAECs) with LPC (10 microM) significantly inhibited bradykinin (1 microM)-stimulated nitric oxide release, which was prevented by cotreatment with vitamin E (50, 100, and 500 microg/ml) in a concentration-dependent manner. In isolated human platelets, LPC stimulated P-selectin expression and induced leukocyte-platelet interaction, which functionally depends on P-selectin expressed on the platelet surface. Vitamin E treatment significantly prevented the LPC-induced platelet P-selectin expression and leukocyte-platelet interaction. As LPC-induced endothelial dysfunction and platelet activation have been shown to involve the protein kinase C (PKC)-dependent signal transduction pathway, we examined the effects of vitamin E on LPC-induced PKC activation in human platelets and BAECs. Vitamin E significantly inhibited LPC (10 microM)-stimulated PKC activation in a concentration-dependent manner. It is concluded that (a) Vitamin E prevented LPC-induced endothelial dysfunction and preserved endothelial nitric oxide release, (b) vitamin E inhibited LPC-induced platelet activation (P-selectin expression) and leukocyte-platelet interaction, and (c) these mechanisms appeared to be at least partly mediated by suppression of the PKC in endothelial cells and platelets. The present findings may provide new insights into antiatherogenic mechanisms of vitamin E.
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PMID:Vitamin E inhibits lysophosphatidylcholine-induced endothelial dysfunction and platelet activation. 1247 May 7

Reactive oxygen species play an important role in development of lung injury. Neonates exhibit a high risk of developing acute and/or chronic lung disorder, often associated with surfactant deficiency, and in parallel they show low vitamin E concentration. We investigated whether the vitamin E status of adult rats affects the content of phospholipids (PL) in bronchoalveolar lavage and alveolar type II cells. Phosphatidylcholine (PtdCho) is the dominant and functional most important PL in lung surfactant. Therefore, we determined its formation via de novo synthesis and reacylation of lyso-PtdCho in type II cells. Vitamin E depletion caused a decrease of PL content in bronchoalveolar lavage and type II cells and decreased glycerol-3-phosphate O-acyltransferase (G3P-AT) activity, de novo synthesis of PtdCho, and reacylation of lyso-PtdCho in type II cells. Preincubation of type II cell homogenates with dithiothreitol restored the activity of G3P-AT and de novo synthesis but inhibited reacylation. Reacylation was strongly reduced by chelerythrine-mediated inhibition of protein kinase C. We conclude that antioxidant and PKC-modulating properties of vitamin E regulate de novo synthesis of PtdCho and reacylation of lyso-PtdCho in alveolar type II cells. Vitamin E depletion reduced the two pathways of PL synthesis and caused a decrease of PL content in alveolar surfactant of rats.
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PMID:Vitamin E deficiency reduces surfactant lipid biosynthesis in alveolar type II cells. 1263 43

Glycodelin is a glycoprotein that has immunosuppressive activity. We have shown that K562 cells, hematopoitic progenitor cells, are capable of synthesizing glycodelin peptide (Gp) and, perhaps, contribute to Gp in tissues. In addition, several reproductive and nonreproductive tissues themselves are capable of synthesis of glycodelin. In this study, we report that lipid peroxides induce the synthesis of Gp. Antioxidants vitamin E and pyrrolidine dithiocarbamate (PDTC) and antioxidizing enzymes catalase and superoxide dismutase (SOD) effectively blocked phorbol myristate acetate- (PMA-) and lyso phosphatidic acid- (LPA-) induced synthesis of Gp. Dioctanoin (a mimic of diacylglycerol) activated Gp synthesis, and an inhibitor of protein kinase C (PKC) downregulated the response. Based on these observations, we postulate that oxidants by way of PKC might potentiate the angiogenic process.
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PMID:Oxidants and antioxidants affect the expression of glycodelin. 1265 69

Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922. Since its discovery, studies of the constituent tocopherols and tocotrienols have focused mainly on their antioxidant properties. In 1991 Angelo Azzi's group (Boscoboinik et al. 1991a,b) first described non-antioxidant cell signalling functions for alpha-tocopherol, demonstrating that vitamin E regulates protein kinase C activity in smooth muscle cells. At the transcriptional level, alpha-tocopherol modulates the expression of the hepatic alpha-tocopherol transfer protein, as well as the expression of liver collagen alphal gene, collagenase gene and alpha-tropomyosin gene. Recently, a tocopherol-dependent transcription factor (tocopherol-associated protein) has been discovered. In cultured cells it has been demonstrated that vitamin E inhibits inflammation, cell adhesion, platelet aggregation and smooth muscle cell proliferation. Recent advances in molecular biology and genomic techniques have led to the discovery of novel vitamin E-sensitive genes and signal transduction pathways.
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PMID:Regulation of cell signalling by vitamin E. 1269 Nov 70

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
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PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23

Previous studies have shown that oxidized low-density lipoprotein (LDL) can impair endothelial function and that this can be overcome in vivo by administration of vitamin E. However, it is unclear whether this effect of oxidized LDL is due to lysophosphatidylcholine or other components of oxidized LDL, and it is also uncertain if the protective effect of vitamin E is related to its antioxidant action. The objectives of the current study were to define how much of the effect of extensively oxidized LDL on endothelium-dependent relaxation (EDR) was in fact due to lysophosphatidylcholine, to determine if the effect of oxidized LDL involved oxidant stress to the endothelium, and, if so, to ascertain if this could be blocked by oxyradical scavengers or antioxidants. Endothelial function was assessed by measuring vasodilation in preconstricted rat mesenteric artery rings in response to acetylcholine. In the presence of 100 microg/mL oxidized LDL, 25-fold higher concentrations of acetylcholine were required for the same degree of vasorelaxation. Similar concentrations of native LDL or acetyl LDL had no effect, but 100 microg/mL phospholipase A(2)-treated LDL or 20 microM lysophosphatidylcholine produced a similar inhibition of EDR. Removal of more than 90% of lysophosphatidylcholine from oxidized LDL did not affect its ability to inhibit EDR, nor did treatment of oxidized LDL with borohydride. This effect of oxidized LDL was blocked by preincubation of arterial rings with vitamin E, probucol, or BO-653 (a potent lipophilic antioxidant), but not by superoxide dismutase. In contrast, the inhibition of EDR by lysophosphatidylcholine was unaffected by antioxidants. Calphostin C prevented the inhibition of EDR by oxidized LDL and lysophosphatidylcholine. These studies demonstrate that at least part of the effect of oxidized LDL on EDR is independent of lysophosphatidylcholine, lipid peroxides, and superoxide release but appears to involve intracellular oxidative stress and protein kinase C activation.
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PMID:Oxidized low-density lipoprotein inhibits endothelium-dependent vasodilation by an antioxidant-sensitive, lysophosphatidylcholine-independent mechanism. 1277 62

Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.
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PMID:Copper-inducible transcription: regulation by metal- and oxidative stress-responsive pathways. 1457 86

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