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)

Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1beta (IL-1beta) which induces beta-cell apoptosis and exerts inhibitory actions on islet beta-cell insulin secretion. IL-1beta seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1beta and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect beta-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca(2+) influx through voltage-activated Ca(2+) channels (by K(+)-induced depolarization) was monitored in culture after treatment with IL-1beta or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1beta or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with gamma-tocopherol (but not alpha-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1beta effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2, 4]oxadiazolo[4,3-alpha]-quinoxaline-1-one) or blocking low voltage-activated Ca(2+) channels with NiCl(2) failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that gamma-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca(2+) channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the beta-cell, and the protection by gamma-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process.
 ...
PMID:gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. 1103 27

Vascular complications in diabetes mellitus are known to be associated with the activation of the protein kinase C (PKC) pathway through the de novo synthesis of diacylglycerol (DAG) from glycolytic intermediates. Specific PKC isoforms, mainly the beta- and delta-isoforms, have been shown to be persistently activated in diabetic mellitus. Multiple studies have reported that the activation of PKC leads to increased production of extracellular matrix and cytokines, enhances contractility, permeability and vascular cell proliferation, induces the activation of cytosolic phospholipase A2 and inhibits the activity of Na+-K+-ATPase. These events are not only frequently observed in diabetes mellitus but are also involved in the actions of vasoactive agents or oxidative stress. Inhibition of PKC by two different kinds of PKC inhibitors - LY333531, a selective PKC-beta-isoform inhibitor, and vitamin E, d-alpha-tocopheron - were able to prevent or reverse the various vascular dysfunctions in vitro and in vivo. Clinical studies using these compounds are now ongoing to evaluate the significance of DAG-PKC pathway activation in the development of vascular complications in diabetic patients.
 ...
PMID:Protein kinase C activation and its pharmacological inhibition in vascular disease. 1110

The scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesterol and cholesteryl ester (CE) from high density lipoprotein (HDL) into cells. The high expression in liver and steroidogenic tissues is compatible with a role of SR-BI in reverse cholesterol transport and steroid hormone synthesis. Ways of regulation thus far described include induction by trophic hormones via cAMP-activated protein kinase A (PKA) and the effects of cellular and plasma cholesterol. Here we show that vitamin E (vitE) has a major effect on the expression of SR-BI in rat liver and in a human hepatoma-derived cell line, HepG2. Feeding rats a vitE-depleted diet resulted in an 11-fold increase in the SR-BI protein level in liver tissue. This effect was readily reversed by feeding a vitE-enriched chow. In HepG2 cells, the expression of the human SR-BI homolog was reduced when the vitE content was increased by incubating the cells with vitE-loaded HDL or with phosphatidylcholine/vitE vesicles. The downregulation of human SR-BI (hSR-BI) was accompanied by a reduced level of protein kinase C (PKC) in the particulate cell fraction, and PKC inhibition decreased the expression of hSR-BI and the uptake of vitE and cholesterol from HDL. Our results are consistent with the view that the cellular level of vitE exerts a tight control over the expression of SR-BI. Furthermore, the inhibitory effect of vitE on PKC seems to be involved in the signaling pathway.
 ...
PMID:Regulation by vitamin E of the scavenger receptor BI in rat liver and HepG2 cells. 1110 34

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
 ...
PMID:Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. 1115 56

Vitamin E is the principal lipid-soluble antioxidant in human plasma, and some studies indicate that it may provide cardiovascular protection. To investigate putative mechanisms for vitamin E in this regard, the effect of vitamin E on vascular function and platelet aggregation was examined. In animal models of endothelial dysfunction, vitamin E improved the activity of endothelium-derived nitric oxide, and this effect was not dependent upon the antioxidant protection of LDL. In fact, vitamin E improved endothelial function in part due to the inhibition of protein kinase C (PKC) stimulation. This activity of vitamin E was examined in platelets, and vitamin E inhibited platelet aggregation in part through a mechanism that involves PKC. Moreover, the platelet inhibitory activity of vitamin E was independent of its antioxidant action because platelet inhibition was still observed with isoforms of vitamin E that were devoid of antioxidant activity.
 ...
PMID:Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. 1116 May 64

Atherosclerosis is the leading cause of morbidity and mortality in Westernized populations. The monocyte is a crucial cell in the genesis of the atherosclerotic lesion and is present during all stages of atherosclerosis. alpha-Tocopherol (AT) is the most active component of the vitamin E family and is the principal and most potent lipid-soluble antioxidant in plasma and LDL. With regard to monocyte function, AT supplementation (1200 IU/d) has been shown to decrease release of reactive oxygen species, lipid oxidation, release of cytokines such as interleukin-1ss (IL-1ss) and tumor necrosis factor-alpha (TNF-alpha) and decrease adhesion of monocytes to human endothelium. The mechanism of inhibition of superoxide and lipid oxidation by monocytes appears to be via inhibition of protein kinase C (PKC), the decrease in IL-1ss and TNF-alpha release by inhibition of 5-lipoxygenase and the inhibition of monocyte-endothelial cell adhesion via decrease in adhesion molecules on monocytes, CD11b and VLA-4 and by decreasing DNA-binding activity of nuclear transcription factor kappaB. Thus, in addition to the decrease in oxidative stress resulting from AT supplementation, as evidenced by decreased F(2)-isoprostanes and LDL oxidizability, AT is anti-inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes.
 ...
PMID:The effect of alpha-tocopherol on monocyte proatherogenic activity. 1116 May 67

The hypothesis that oxidative stress has a role in atherosclerosis rests on a large body of experimental work carried out in animal models of heart disease. The situation is more complex in humans, in that the results from vitamin E supplementation trials have been conflicting. Nonetheless, there is emerging information that alpha-tocopherol may play a critical role in maintaining the function of key cellular components in the atherosclerotic process through its ability to inhibit the activity of protein kinase C, a key player in many signal transduction pathways. alpha-Tocopherol modulates pathways of platelet aggregation, endothelial cell nitric oxide production, monocyte/macrophage superoxide production and smooth muscle cell proliferation. Regulation of adhesion molecule expression and inflammatory cell cytokine production by alpha-tocopherol has also been reported. More studies are required to relate alpha-tocopherol intakes to optimal tissue responses in humans.
 ...
PMID:Does vitamin E decrease heart attack risk? summary and implications with respect to dietary recommendations. 1116 May 68

Since recent reports have suggested that alpha-synuclein might play a role in neuronal plasticity, the main objective of this study was to determine the effects of alpha-synuclein on neuritic outgrowth. We stably transfected either human (h) alpha- or beta-synuclein cDNA in B103 rat neuronal cells. Expression of h(alpha)-synuclein resulted in reduced neurite extension and weak adhesion compared to vector-transfected and h(beta)-synuclein expressing cells. To investigate the potential pathways involved, we studied the effects of reagents known to modulate B103 proliferation and differentiation. Neither phorbol 12-myristate 13-acetate nor forskolin or antioxidants (catalase, superoxide dismutase, or vitamin E) were able to restore the reduced length of neurites in h(alpha)-synuclein-expressing cells. These results suggest that reduced neuritic activity in the h(alpha)-synuclein-expressing cells might be due, in part, to alterations in cell adhesion capacity. This might be attributed to alpha-synuclein affecting a signal transduction pathway distinct from protein kinase C and protein kinase A.
 ...
PMID:Reduced neuritic outgrowth and cell adhesion in neuronal cells transfected with human alpha-synuclein. 1116 75

Leukocyte-endothelial cell interactions are mediated by adhesion molecules, expression of which is modulated by cytokines and chemical mediators in the early phase of inflammatory and immunologic reactions, including the development of atherosclerosis. Vitamin E is a lipid-soluble antioxidant that is present in all cell membranes at a low concentration and is reported to be an anti-atherogenic agent. Recently, it was reported that vitamin E inhibits the activation of protein kinase C and nuclear factor-kappa B (NF-kappa B). We demonstrated that vitamin E can prevent leukocyte-endothelial cell adhesion by inhibiting signal transduction involved in the surface expression of adhesion molecules by leukocytes and endothelial cells. These results suggest that vitamin E may have a protective effect against the progression of inflammation and atherosclerosis.
 ...
PMID:Vitamin E and leukocyte-endothelial cell interactions. 1121 86

Nutritional status directly affects immune competence; therefore, dietary supplements can be beneficial. Vitamin A, a fat-soluble nutrient obtained exogenously from animal protein or synthesized endogenously from carotenoids, is important in vision, epithelial tissue maintenance, reproduction, and growth. It is also an antioxidant, and can interfere with HIV-related oxidative destruction. Vitamin C, a water-soluble antioxidant important in hydroxylation reactions and required by erythrocytes for retrieving stored iron, can suppress HIV in vitro. However, this requires long-term administration, and its effect ceases upon termination of treatment. Vitamin E, fat-soluble tocopherols, can be found in plants, vegetable oils, milk, eggs, fish, meats, and cereals. A potent antioxidant because of its electron-donating ability, vitamin E reduces HIV replication. Deficiency reduces inhibition of tumor necrosis factor alpha (TNF-a) and protein kinase C, therefore limiting immunocompetence. Additionally, damaging side effects of AZT, normally reversed or minimized by vitamin E, may induce low leukocyte counts and anemia. Vitamin E acts synergistically with selenium, another antioxidant, to block the rate of lipid peroxidation. Its administration may reduce diarrhea, cramping, and weight loss, and may improve epithelial conditions and reduce the frequency of illness. N-acetylcysteine (NAC), a sulfur-containing amino acid, inhibits HIV replication by raising serum glutathione levels through inhibition of TNF-a. Finally, HIV-infected patients should consider gluten-free diets during times of acute gastric distress.
 ...
PMID:Nutrition and HIV. 1136 99


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