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)

The B vitamin nicotinamide (NIC), commonly known as niacin, is currently in trial as a potential means of preventing Type 1 diabetes in first-degree relatives of affected individuals. Sodium butyrate (BUT) a common dietary micronutrient has also been reported to have beneficial effects on the differentiation and function of pancreatic beta cells. Cultured rat insulin-secreting BRIN-BD11 cells were used to investigate the effects of 3 days exposure to NIC (10 mM) and BUT (1 mM) both alone and in combination on beta cell function. Culture with NIC and/or BUT resulted in reduction of growth, insulin content and basal insulin secretion. BUT additionally decreased cell viability whilst NIC had no significant effect. Treatment with either agent abolished beta cell glucose sensitivity but insulin secretory responsiveness to a wide range of beta cell stimulators, including a depolarizing concentration of K+, elevation of Ca2+ and activation of adenylate cyclase and protein kinase C, were enhanced. These data illustrate that long term exposure to NIC and BUT has both positive and negative effects on the function of insulin-secreting cells.
 ...
PMID:Effects of long-term exposure to nicotinamide and sodium butyrate on growth, viability, and the function of clonal insulin secreting cells. 1509 20

A novel isoform of the NOX-2 subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has been identified using expressed sequence tag (EST) database mining. The novel isoform, NOX-2S, is a splice variant of NOX-2 and includes a previously unidentified exon, mapped 6.4 kb downstream of exon III, and encodes an in-frame stop codon generating a predicted truncated protein of approximately 12.7 kDa, the smallest reported member of the NOX family. Thus, NOX-2S is predicted to have only two transmembrane domains, however, the new C-terminal sequence includes two new potential protein kinase C (PKC) phosphorylation sites. Expression of NOX-2S mRNA was detected in many mouse tissues, and several human cell lines including the myeloid cell line HL-60, and the B cell line Ramos, indicating that the splice variant is conserved in mouse and man. NOX-2S is found co-expressed together with NOX-2 in all of the tissues and cells under investigation, both nonphagocytic and phagocytic. Induction of the myeloid cell line HL-60 into the neutrophil phagocytic lineage by dimethyl sulphoxide (DMSO), led to a marked increase in NOX-2S and NOX-2 expression in the myelocyte rather than promyelocyte stages of differentiation. Furthermore, in the B-cell line Ramos, differentiated with the cytokine interferon-gamma (IFN-gamma), splicing was altered to increase NOX-2S mRNA generation over NOX-2. Here we have identified NOX-2S, the first reported normally occurring splice variant of NOX-2. The sequence identity between mouse and human NOX-2S strongly implies conservation in function and possibly a role for NOX-2S in the regulation of NADPH oxidase activity.
 ...
PMID:NOX-2S is a new member of the NOX family of NADPH oxidases. 1519 96

Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
 ...
PMID:Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. 1553 8

Phosphorylation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components p67phox and p47phox accompanies the assembly and activation of this enzyme complex. We have previously reported that activation of human monocytes with opsonized zymosan (ZOP), a potent stimulator of NADPH oxidase activity, results in the phosphorylation of p67phox and p47phox. In this study, we investigated the regulation of p67phox phosphorylation. Although protein kinase C (PKC)alpha has previously been shown to regulate NADPH oxidase activity, we found that inhibition of PKCalpha had no effect on p67phox phosphorylation. Our studies demonstrate that pretreatment of monocytes with antisense oligodeoxyribonucleotides specific for PKCdelta or rottlerin, a selective inhibitor for PKCdelta, inhibited the phosphorylation of p67phox in monocytes, and Go6976, a specific inhibitor for conventional PKCs, PKCalpha and PKCbeta, had no such inhibitory effect. Additional studies indicate that ZOP stimulation of monocytes induces PKCdelta and p67phox to form a complex. We also demonstrate that lysates from activated monocytes as well as PKCdelta immunoprecipitates from activated monocytes can phosphorylate p67phox in vitro and that pretreatment of monocytes with rottlerin blocked the phosphorylation in each case. We further show that recombinant PKCdelta can phosphorylate p67phox in vitro. Finally, we show that PKCdelta-deficient monocytes produce significantly less superoxide anion in response to ZOP stimulation, thus emphasizing the functional significance of the PKCdelta regulation of p67phox phosphorylation. Taken together, this is the first report to describe the requirement of PKCdelta in regulating the phosphorylation of p67phox and the related NADPH oxidase activity in primary human monocytes.
 ...
PMID:Protein kinase Cdelta regulates p67phox phosphorylation in human monocytes. 1559 Nov 24

In vivo expression of cell survival factors protein kinase C (PKC), nuclear factor kappaB (NFkappaB), and extracellular signal-regulated kinase (Erk), which may contribute to the development of radioresistance following radiotherapy, was looked for. Their modulation with natural compounds (curcumin, rutin or nicotinamide) was attempted in mice bearing a serially transplanted fibrosarcoma. Expression of protein kinase C was isoform specific. No translocation of any of the isozymes was noticed following gamma-irradiation as has been reported elsewhere. None of the isoforms could be significantly inhibited by the modulators. However, significant inhibition of radiation-induced ERK and NFkappaB was observed with both curcumin and nicotinamide. Therefore we conclude that use of inhibitors of MAP kinases or NFkappaB may be a more promising strategy to enhance tumour cell killing or to prevent the development of radioresistance during radiotherapy.
 ...
PMID:In vivo modulation of signaling factors involved in cell survival. 1563 57

Leukotrienes (LTs) are lipid mediators that participate in inflammatory diseases and innate immune function. We sought to investigate the importance of LTs in regulating the microbicidal activity of alveolar macrophages (AMs) and the molecular mechanisms by which this occurs. The role of LTs in enhancing AM microbicidal activity was evaluated pharmacologically and genetically using in vitro challenge with Klebsiella pneumoniae. Exogenous LTs increased AM microbicidal activity in a dose- and receptor-dependent manner, and endogenous production of LTs was necessary for optimal killing. Leukotriene B4 (LTB4) was more potent than cysteinyl LTs. An important role for nicotinamide adenine dinucleotide (NADPH) oxidase in LT-induced microbicidal activity was indicated by the fact that bacterial killing was abrogated by the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10 microM) and in AMs derived from gp91phox-deficient mice. By contrast, LT-induced microbicidal activity was independent of the generation of nitric oxide. LTs increased H2O2 production, and LTB4 was again the more potent agonist. Both classes of LTs elicited translocation of p47phox to the cell membrane, and LTB4 induced phosphorylation of p47phox in a manner dependent on protein kinase C-delta (PKC-delta) activity. In addition, the enhancement of microbicidal activity by LTs was also dependent on PKC-delta activity. Our results demonstrate that LTs, especially LTB4, enhanceAM microbicidal activity through the PKC-delta-dependent activation of NADPH oxidase.
 ...
PMID:Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase. 1571 14

Stimulated production of reactive oxygen species (ROS) by plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidases (Nox) in non-phagocytic cells regulates a number of biological processes including growth, vessel tone, and oxygen sensing. The purpose of this study was to investigate H(2)O(2)-stimulated ROS production in primary adult cardiac fibroblasts (CF). Results demonstrate that CF express an H(2)O(2)-inducible oxidant generating system that is inhibitable by diphenylene iodonium (DPI) and sensitive to antioxidants. In addition to H(2)O(2), generation of ROS was stimulated potently by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and arachidonic acid (AA) in a protein kinase C-independent manner. Pretreatment with arachidonyl trifluoromethyl ketone was nearly as effective as DPI at reducing H(2)O(2)- and OAG-stimulated oxidant generation indicating a central role for phospholipase A(2) (PLA(2)) in this signaling pathway. Co-stimulation with H(2)O(2) and OAG did not increase ROS generation as compared to OAG alone suggesting both agonists signal through a shared, rate-limited enzymatic pathway involving PLA(2). Co-stimulation with H(2)O(2) and AA had additive effects indicating these two agonists stimulate oxidant production through a parallel activation pathway. Reverse transcriptase-coupled polymerase chain reaction and Western blotting demonstrate primary cardiac fibroblasts express transcripts and protein for Nox4, p22, p47, and p67 phox. Transfections with Nox4 small inhibitory ribonucleic acid oligonucleotides or p22 phox antisense oligonucleotides significantly downregulated stimulated Nox activity. Inhibitors of nitric oxide synthases were without effect. We conclude adult CF express Nox4/p22 phox-containing oxidant generating complex activated by H(2)O(2), OAG, and AA through a pathway that requires activation of PLA(2).
 ...
PMID:H2O2 activates Nox4 through PLA2-dependent arachidonic acid production in adult cardiac fibroblasts. 1584

Vitamin B(1) (thiamine) is an essential nutrient for humans. Vitamin B(1) deficiency causes beriberi, which disturbs the central nervous and circulatory systems. In countries in which rice (Oryza sativa) is a major food, thiamine deficiency is prevalent because polishing of rice removes most of the thiamine in the grain. We demonstrate here that thiamine, in addition to its nutritional value, induces systemic acquired resistance (SAR) in plants. Thiamine-treated rice, Arabidopsis (Arabidopsis thaliana), and vegetable crop plants showed resistance to fungal, bacterial, and viral infections. Thiamine treatment induces the transient expression of pathogenesis-related (PR) genes in rice and other plants. In addition, thiamine treatment potentiates stronger and more rapid PR gene expression and the up-regulation of protein kinase C activity. The effects of thiamine on disease resistance and defense-related gene expression mobilize systemically throughout the plant and last for more than 15 d after treatment. Treatment of Arabidopsis ecotype Columbia-0 plants with thiamine resulted in the activation of PR-1 but not PDF1.2. Furthermore, thiamine prevented bacterial infection in Arabidopsis mutants insensitive to jasmonic acid or ethylene but not in mutants impaired in the SAR transduction pathway. These results clearly demonstrate that thiamine induces SAR in plants through the salicylic acid and Ca(2+)-related signaling pathways. The findings provide a novel paradigm for developing alternative strategies for the control of plant diseases.
 ...
PMID:Vitamin B1 functions as an activator of plant disease resistance. 1598 Feb 1

Hyperglycemia is the major causal factor in the development of endothelial dysfunction in patients with diabetes mellitus. Although the mechanisms underlying this phenomenon are likely to be multifactorial, recent in vivo and in vitro studies have indicated a crucial role of the diacylglycerol (DAG)-protein kinase C (PKC) pathway in mediating this phenomenon. PKC may have multiple adverse effects on vascular function, including the activation of superoxide-producing enzymes such as the nicotinamide adenine dinicleotide phosphate (NADPH) oxidase as well as increased expression of a dysfunctional, superoxide-producing, uncoupled endothelial nitric oxide synthase (NOS III). PKC-mediated superoxide production may inactivate nitric oxide (NO) derived from endothelial NOS III, but also may inhibit the activity and/or expression of the NO downstream target, the soluble guanylyl cyclase. Among the different isoforms of PKC, mainly the beta-isoforms have been shown to be activated. Recent studies with selective (isoform-specific) and non-selective PKC inhibitors show that they are able to beneficially influence glucose-induced endothelial dysfunction in experimental animal models as well as in patients, pointing to the therapeutic potential of these compounds in the prevention and treatment of vascular complications of diabetes.
 ...
PMID:Mechanisms underlying endothelial dysfunction in diabetes mellitus: therapeutic implications. 1598 46

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
 ...
PMID:Vitamin E, oxidative stress, and inflammation. 1601 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>