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

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Respiratory syncytial virus (RSV) is worldwide the most frequent cause of bronchiolitis and pneumonia in infants requiring hospitalization. In the present study, we supply evidence that human lung microvascular endothelial cells, human pulmonary lung aorta endothelial cells, and HUVEC are target cells for productive RSV infection. All three RSV-infected endothelial cell types showed an enhanced cell surface expression of ICAM-1 (CD54), which increased in a time- and RSV-dose-dependent manner. By using noninfectious RSV particles we verified that replication of RSV is a prerequisite for the increase of ICAM-1 cell surface expression. The up-regulated ICAM-1 expression pattern correlated with an increased cellular ICAM-1 mRNA amount. In contrast to ICAM-1, a de novo expression of VCAM-1 (CD106) was only observed on RSV-infected HUVEC. Neither P-selectin (CD62P) nor E-selectin (CD62E) was up-regulated by RSV on human endothelial cells. Additional experiments performed with neutralizing Abs specific for IL-1alpha, IL-1beta, IL-6, and TNF-alpha, respectively, excluded an autocrine mechanism responsible for the observed ICAM-1 up-regulation. The virus-induced ICAM-1 up-regulation was dependent on protein kinase C and A, PI3K, and p38 MAPK activity. Adhesion experiments using polymorphonuclear neutrophil granulocytes (PMN) verified an increased ICAM-1-dependent adhesion rate of PMN cocultured with RSV-infected endothelial cells. Furthermore, the increased adhesiveness resulted in an enhanced transmigration rate of PMN. Our in vitro data suggest that human lung endothelial cells are target cells for RSV infection and that ICAM-1 up-regulated on RSV-infected endothelial cells might contribute to the enhanced accumulation of PMN into the bronchoalveolar space.
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PMID:Respiratory syncytial virus infection of human lung endothelial cells enhances selectively intercellular adhesion molecule-1 expression. 1590 83

Diazoxide is a selective mitochondria ATP-sensitive potassium (K(ATP)) channel opener, which has been reported to preserve the microvascular integrity of ischemia-reperfusion (I/R)-injured tissues. Our study aimed to assess diazoxide's effects on I/R-injured cremaster muscles and to further elucidate its underlying mechanisms. Male Sprague Dawley (SD) rats were randomized (n = 8 per group) into four groups: sham-operated control group, I/R group (4 h of pudic epigastic artery ischemia followed by 2 h of reperfusion), diazoxide + I/R group, and chelerythrine (PKC inhibitor)+diazoxide+I/R group. Microscopically, we observed that I/R markedly increased the number of rolling, adhering, and transmigrating leukocytes. I/R also markedly decreased the number of functional capillaries. Biochemically, we found that I/R significantly increased TNF-alpha, E-selectin,L-selectin and P-selectin expressions. However, I/R did not cause significant changes in ICAM-1 and PECAM-1 expressions. On the other hand, in I/R + diazoxide group, we found that diazoxide reduced the number of rolling, adhering, and transmigrating leukocytes. Furthermore, biochemical study revealed that diazoxide caused only a decrease in L-selectin expression but had no effect on TNF-alpha, E-selectin, P-selectin, ICAM-1, and PECAM-1 expressions. Finally, in chelerythrine + diazoxide + I/R group, we observed that diazoxide's protective effects were blocked by the addition of chelerythrine. Diazoxide's ability to protect against I/R injury was confirmed by the observation that it reduced the number of rolling, adhering, and transmigrating leukocytes, and increased the number of functional capillaries. Our results indicated that diazoxide operated via a PKC-dependent pathway to achieve protection against I/R injury.
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PMID:Diazoxide ameliorates microcirculatory disturbances through PKC-dependent pathway in I/R-injured rat cremaster muscles. 1595 30

In this study the effects of stable and intermittent high glucose concentrations on ICAM-1, VCAM-1 and E-selectin production, PKC activity and PKCbetaI, betaII and delta isoforms expression in cultured HUVEC have been examined. In stable high glucose ICAM-1, VCAM-1 and E-selectin concentration and mRNA expression increased, and this effect was even more evident in intermittent high glucose. PKC activity increased in fluctuating glucose compared to stable high glucose, due to an over-expression of betaI, betaII and delta isoforms. ICAM-1, VCAM-1 and E-selectin, after the adding of total PKC inhibitor bisindolylmaleimide-I (BIMI-I) and LY379196, a specific inhibitor of PKCbeta, were equally reduced. 8-Hydroxydeoxyguanosine (8-OHdG), a sensitive indicator of oxidative damage to DNA, increased in stable and even more in intermittent high glucose and was reduced by both BIMI-I and LY379196. However, when thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial complex II and the SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) were added, all adhesion molecules, any PKC isoforms expression and 8-hydroxydeoxyguanosine were normalized in both constant and oscillating glucose. In conclusion intermittent high glucose induces a greater expression of the adhesion molecules than stable high glucose; this effect seems to be related to an activation of PKCbeta, but completely dependent from mitochondrial free radicals over-production.
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PMID:Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. 1628 92

Neutrophil-endothelial adhesion is a crucial step in vascular inflammation and is recognized as a direct cause of serious atherosclerosis-mediated diseases. We previously demonstrated that high concentrations of glucose increased adhesion in a protein kinase C (PKC)-dependent manner within 48 h of administration by increasing the surface expression of endothelial adhesion molecules. In this study, we focused on the effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and on the surface expression of endothelial adhesion molecules mediated by high glucose levels. Histamine 2 receptor antagonists have pleiotropic effects; they not only block the secretion of gastric acid, but also inhibit cell-cell adhesion, resulting in inhibition of metastasis. However, relevant mechanisms of action are not yet fully understood. Of three histamine 2 receptor antagonists (cimetidine, ranitidine, and famotidine), only cimetidine significantly attenuated adhesion mediated by 48-h incubation with 27.8 mM glucose. Cimetidine was found to decrease the surface expression of endothelial adhesion molecules intercellular adhesion molecule-1 and P-selectin, but not E-selectin. To determine the effects of cimetidine on intracellular level, we examined the effects of cimetidine on PKC-induced changes in adhesion, as well as the effects of nitric oxide (NO) synthase inhibitors on cimetidine. We found that NO synthase inhibitors reduced the inhibitory effects of cimetidine, whereas cimetidine did not affect adhesion mediated by a PKC activator. These data suggest that cimetidine acts directly on endothelial cells to inhibit high-glucose-induced expression of adhesion molecules and neutrophil adhesion mediated by increasing endothelial NO production, but not by inhibiting PKC.
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PMID:Effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and surface expression of endothelial adhesion molecules induced by high glucose levels. 1718 74

Glycated human serum albumin (Glc-HSA) has previously been reported (Higai K., et al., 2006) to induce E-selectin expression on human umbilical vein endothelial cells through activation of NADPH oxidase; however, Glc-HSA signaling in monocytes remains obscure. To clarify the influence on human monocyte-derived U937 cells, U937 cells were stimulated with Glc-HSA and glycoaldehyde-dimer-modified HSA (GA-HSA) for 2 h in the absence and presence of the protein kinase C (PKC) inhibitor calphostin and the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and NADPH oxidase inhibitor apocynin; interleukin-8 (IL-8) mRNA expression was determined by RT-PCR. As a result, IL-8 mRNA expression in U-937 cells was time- and dose-dependently enhanced by stimulation with Glc-HSA and GA-HSA. Furthermore, promoter activity of the IL-8 reporter gene was enhanced approximately 2-fold by stimulation with Glc-HSA and GA-HSA. Nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1) reporter genes were also enhanced although CCAAT/enhancer binding protein (C/EBP) was not affected. IL-8 mRNA expression was suppressed by NAC and apocynin but not calphostin in cells stimulated with Glc-HSA; however, its expression in cells stimulated with GA-HSA was suppressed by calphostin but not NAC. These results indicated that IL-8 mRNA expression was upregulated by NFkappaB and AP-1 in U937 cells stimulated with Glc-HSA and GA-HSA, but the signaling pathways were different.
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PMID:Glycated human serum albumin induces interleukin 8 mRNA expression through reactive oxygen species and NADPH oxidase-dependent pathway in monocyte-derived U937 cells. 1791 46

The modes of action of the novel anti-skin tumor agent ingenol-3-angelate (PEP005) are incompletely understood. Crucially, the cytotoxic functions of neutrophils recruited to the tumor in response to topical application of PEP005 are necessary for effective ablation of the treated lesion. Here, we investigated the hypothesis that the phorbol ester-like properties of PEP005 and its ability to activate PKC could directly activate endothelial cells (EC) so that they support the recruitment of neutrophils. Exposure of EC to PEP005 induced mRNA and/or protein for E-selectin, ICAM-1 and IL-8 in a dose dependent manner, while in a flow based adhesion assay, PEP005 treated EC supported the recruitment of neutrophils at levels comparable to EC stimulated with TNF-alpha. Neutrophil adhesion was inhibited by antibody against E-selectin but not P-selectin. Activation of EC was inhibited by the PKC inhibitor bisindolylmaleimide-1 and confocal immuno-fluorescent studies demonstrated translocation of PKC-delta from the cytosol to the peri-nuclear membrane in response to PEP005. Importantly, the knock down of PKC-delta using siRNA completely abolished neutrophil recruitment to EC subsequently treated with PEP005. Thus, we describe a novel route by which the anti-tumor agent PEP005 regulates the recruitment of cytotoxic leukocytes by directly activating EC in a PKC-delta dependent manner.
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PMID:The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner. 1826 80

Superoxide has been reported to be involved in vascular dysfunction in diabetes. The Ins2(Akita) mouse is an autosomal dominant mutant diabetic model that can serve as an excellent substitute for the Type 1 diabetic mouse model induced by chemical diabetogens. The purpose of the present study was to investigate the role of superoxide on vascular dysfunction using this new diabetic model. Compared with age-matched normal C57BL/6 mice, in Ins2(Akita) diabetic mice arterial superoxide, lipid peroxidation production (1.2 +/- 0.1 vs 17.4 +/- 1.9 mmol/mg tissue, respectively; P < 0.01) and plasma lipid peroxidation production (0.08 +/- 0.02 vs 0.40 +/- 0.03 mmol/L, respectively; P < 0.01) were increased. Meanwhile, expression of vascular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 in the aorta and/or plasma was elevated. The contraction of carotid arteries to U46619 in Ins2(Akita) diabetic mice was significantly enhanced compared with control mice (P < 0.05). Tempol (a scavenger of superoxide), apocynin (an inhibitor of NADPH oxidase) and allopurinol (an inhibitor of xanthine oxidase) all not only decreased superoxide in carotid arteries, but also suppressed arterial contractions to U46619 in Ins2(Akita) diabetic mice. Indomethacin, an inhibitor of cyclo-oxygenase, and chelerythrine, an inhibitor of protein kinase C, also suppressed the enhanced vascular contraction. These results suggest that increased arterial superoxide generated from diverse sources may potentiate the contractions of carotid arteries in Ins2(Akita) diabetic mice.
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PMID:Increased superoxide contributes to enhancement of vascular contraction in Ins2(Akita) diabetic mice, an autosomal dominant mutant model. 1878 99

Micro- and macrovascular complications are major causes of disability and death in patients with diabetes mellitus. Functional impairment of endothelial activity precedes the development of morphological alterations during the progression of diabetes. This endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO), mainly due to accelerated NO degradation by reactive oxygen species (ROS). Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via several distinct mechanisms, increased oxidative stress seems to be the first alteration triggering several others. Mechanisms proposed to explain glucose- and lipid-induced vascular alterations in diabetes include accelerated formation of advanced glycation end-products (AGEs), protein kinase C activation, inflammatory signaling and oxidative stress. Insulin resistance with impaired PI 3-kinase effects decreases insulin mediated production of NO and reduces vasodilation, capillary recruitment and antioxidant properties of endothelium. Compensatory hyperinsulinemia enhances activation of intact MAP-kinase pathways and contributes to pro-atherogenic events by increasing secretion of endothelin-1 (ET-1), stimulating expression of adhesion molecules such as VCAM-1 and E-selectin, and inducing production of ROS. Conventional therapies to reduce hyperglycemia, dyslipidemia and insulin resistance may effectively improve endothelial function and delay the onset of vascular complications. Novel therapeutic approaches designed to inhibit AGEs formation, reduce PKC activation, decrease inflammatory signals and restore the ox/redox balance of endothelium may be predicted to ameliorate vascular function in diabetic state. This review summarizes the current knowledge on the most important mechanisms involved in endothelial dysfunction during diabetes. In addition, novel therapeutic strategies that may result from recently identified targets are also described.
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PMID:Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. 1914 64

Tumor cells have evolved effective strategies to escape the host immune response. The objective of this study was to determine whether tumor cells can condition endothelial cells in a specific manner to prevent subsequent adhesion of polymorphonuclear neutrophils (PMNs) and/or peripheral blood lymphocytes (PBLs). Human umbilical vein endothelial cells (HUVECs) and UKF-NB-4 neuroblastoma tumor cells were established in coculture on opposite sides of porous transwell filters. After 24 hours with and without HUVEC conditioning, PMNs or PBLs were added to the HUVEC monolayer. Adhesion to conditioned HUVEC versus adhesion to nonconditioned HUVEC was compared. Effects on endothelial CD44v4, CD44v5, CD44v7, intercellular adhesion molecule 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule 1 (VCAM-1) adhesion receptor expression were analyzed by flow cytometry, intracellular signaling proteins of the mitogen-activated protein kinase pathway and protein kinase C (PKC) subtypes quantified by Western blot analysis. Endothelial conditioning led to a distinct reduction in PMN but not in PBL adhesion to HUVEC. CD44 was significantly reduced, whereas ICAM-1, E-selectin, and VCAM-1 were not altered during HUVEC conditioning. Antibody blockade against CD44v4, CD44v5, and CD44v7 inhibited PMN but not PBL binding. The observed effects were caused by direct tumor cell-HUVEC contact because addition of isolated tumor cell membrane fragments but not of soluble cell culture supernatant to HUVEC induced the CD44 receptor loss. PKCalpha activity was strongly enhanced in conditioned HUVEC. Blocking PKC prevented the reduction in PMN binding, indicating that this protein is involved in PMN adhesion regulation. A novel tumor escape strategy is presented here. Cell contact-dependent adhesion of tumor cells to the vascular wall promotes down-regulation of endothelial CD44 receptor expression, impairing an effective neutrophil attack.
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PMID:Tumor-endothelium cross talk blocks recruitment of neutrophils to endothelial cells: a novel mechanism of endothelial cell anergy. 1979 64


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