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)

We investigate whether temperature preconditioning (TP), induced by short-term hypothermic perfusion and rewarming, may protect hearts against ischaemic/reperfusion injury like ischaemic preconditioning (IP). Isolated rat hearts were perfused for 40 min, followed by 25 min global ischaemia and 60 min reperfusion (37 degrees C). During pre-ischaemia, IP hearts underwent three cycles of 2 min global ischaemia and 3 min reperfusion at 37 degrees C, whereas TP hearts received three cycles of 2 min hypothermic perfusion (26 degrees C) interspersed by 3 min normothermic perfusion. Other hearts received a single 6 min hypothermic perfusion (SHP) before ischaemia. Both IP and TP protocols increased levels of high energy phosphates in the pre-ischaemic heart. During reperfusion, TP improved haemodynamic recovery, decreased arrhythmias and reduced necrotic damage (lactate dehydrogenase release) more than IP or SHP. Measurements of tissue NAD+ levels and calcium-induced swelling of mitochondria isolated at 3 min reperfusion were consistent with greater inhibition of the mitochondrial permeability transition at reperfusion by TP than IP; this correlated with decreased protein carbonylation, a surrogate marker for oxidative stress. TP increased protein kinase Cepsilon (PKCepsilon) translocation to the particulate fraction and pretreatment with chelerythrine (PKC inhibitor) blocked the protective effect of TP. TP also increased phosphorylation of AMP-activated protein kinase (AMPK) after 5 min index ischaemia, but not before ischaemia. Compound C (AMPK inhibitor) partially blocked cardioprotection by TP, suggesting that both PKC and AMPK may mediate the effects of TP. The presence of N-(2-mercaptopropionyl) glycine during TP also abolished cardioprotection, indicating an involvement of free radicals in the signalling mechanism.
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PMID:Temperature preconditioning of isolated rat hearts--a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore. 1796 21

Electrophile and free radical detoxifying enzymes including NAD(P)H:quinine oxidoreductase 1 (Nqo1) play an important role in the defense system by enhancing cellular antioxidant capacity. Chemopreventive efficacy of 3H-1,2-dithiole-3-thione (D3T) is mediated through activation of the transcription factor Nrf2 and subsequent elevation of detoxifying enzymes. In the present study, we have investigated the potential role of extracellular signal-regulated kinase (ERK) in regulation of D3T-induced and Nrf2-dependent gene expression in murine keratinocytes. Expression levels of Nqo1 were highly inducible by D3T treatment and increased nuclear levels of Nrf2 were observed in these cells. Treatment with pharmacological inhibitor of ERK1/2 largely blocked nuclear accumulation of Nrf2, ARE-driven reporter gene expression, and induction of Nqo1, as well as other phase 2 genes. Activation of ERK1/2 has been demonstrated following treatment with D3T. While, inhibitors of p38, PKC and PI3K did not affect ARE-driven gene expression. Involvement of the ERK1/2 cascade in inducible ARE-transcription activities was also observed in cells treated with other types of inducers oltipraz, sulforaphane and hydrogen peroxide. Collectively, current study suggests that phosphorylation cascade via ERK1/2 is associated with the activation process of Nrf2 and subsequent transactivation of its target gene Nqo1 following treatment with dithiolethione in murine keratinocyte.
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PMID:Induction of Nrf2-regulated genes by 3H-1, 2-dithiole-3-thione through the ERK signaling pathway in murine keratinocytes. 1785 98

The induction of NF-E2-related factor-2 (Nrf2)-mediated detoxifying/antioxidant enzymes is recognized as an effective strategy for cancer chemoprevention. Here, we report that 3-morpholinopropyl isothiocyanate (3MP-ITC) is an exceptionally strong chemical inducer of these enzymes. Exposure of 3MP-ITC in HepG2C8 cells not only induced endogenous Nrf2 protein but also suppressed endogenous Kelch-like ECH-associated protein 1, resulting in an increased nuclear accumulation of Nrf2. Using chemical inhibitors of protein synthesis (cycloheximide) and 26S proteosomal degradation (MG-132), we observed that the induction of Nrf2 protein by 3MP-ITC appeared to be post-translationally regulated. 3MP-ITC activated ERK1/2 and JNK1/2 and the activation of antioxidant response element (ARE) by 3MP-ITC was significantly attenuated by chemical inhibition of PKC and PI3K signaling pathways in HepG2C8 cells. Treatment with 3MP-ITC significantly depleted the intracellular level of glutathione (GSH) in HepG2C8 cells and oral administration of 3MP-ITC increased the protein expression of hepatic NAD[P]H:quinone oxidoreductase-1 and Nrf2 in Nrf2 (+/+) but not in Nrf2 (-/-) mice, whereas UDP-glucuronosyl transferase 1A1 was induced in both genotypes. Our results indicate that 3MP-ITC is a novel ITC that strongly induces Nrf2-dependent ARE-mediated detoxifying/antioxidant enzymes in vitro and in vivo via the Nrf2 signaling pathway coupled with GSH depletion and activation of multiple signaling kinase pathways, which could be potentially useful agent for cancer chemoprevention.
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PMID:3-Morpholinopropyl isothiocyanate is a novel synthetic isothiocyanate that strongly induces the antioxidant response element-dependent Nrf2-mediated detoxifying/antioxidant enzymes in vitro and in vivo. 1791 1

Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous pulmonary diseases. Various mainly membrane-bound ROS-generating processes exist in alveolar cells. Vitamin E (vit. E) is the most important lipophilic antioxidant. However, the significance of vit. E levels in alveolar cells for the regulation of ROS generation has not been investigated so far. We demonstrated here that feeding rats with vit. E-depleted nourishment for 5 weeks reduced the concentration of vit. E in alveolar type II cell preparations to one-fifth the amount of control animals. This reduction of vit. E levels was associated with an approximately threefold increase in ROS generation in type II pneumocytes, lymphocytes, and macrophages. The contribution of individual processes of ROS formation in control animals differed strongly among these three cell types. However, vit. E deficiency induced predominantly nonmitochondrial ROS formation in alveolar cells. Expression and NAD(P)H-oxidase activity in alveolar type II cell preparations was not affected by vit. E deficiency. Moreover, protein kinase C (PKC) also did not seem to be responsible for vit. E deficiency-induced ROS generation in alveolar cells. Alimentary vit. E supplementation for 2 days corrected the cellular vit. E concentration but failed to normalize ROS generation in alveolar cells. These data let us assume that alimentary vit. E deficiency caused a preferentially nonmitochondria-mediated increase of ROS formation in type II pneumocytes, macrophages, and lymphocytes. However, the short-term supplementation of vit. E does not reverse these effects.
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PMID:Formation of reactive oxygen species in lung alveolar cells: effect of vitamin E deficiency. 1831 37

The purpose of this study was to investigate the role of the oestrogen receptor subtypes ERalpha and ERbeta in mediating the non-genomic effects of 17-beta-estradiol (E(2)) in two human endometrial cancer cell lines (RL95-2 and HEC-1A) expressing different levels of these receptor subtypes. Western blotting analysis using phosphorylation site-specific antibodies showed that physiological concentrations of E(2) rapidly (<20 min) activated PKCalpha, but not PKCdelta in the RL95-2 cell line. E(2) had no effect on PKCalpha or PKCdelta activity in the HEC-1A cell line and suppressed basal levels of PKA activity in both cell lines. PKCalpha activation coincided with its membrane translocation. ERalpha was detected in the RL95-2 cell line by Western blotting and RT-PCR but not in the HEC-1A cells, which did express ERbeta. A selective ERalpha agonist PPT had the same effect as E(2) on PKCalpha activation in the RL95-2 cells, but the selective ERbeta agonist DPN had no such effect. A 46kDa variant of ERalpha increased in abundance in the cell membrane within 20 min of E(2) treatment suggesting that ERalpha mediated the E(2) non-genomic effects on PKCalpha through the formation of a membrane associated signalling complex.
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PMID:Membrane ERalpha-dependent activation of PKCalpha in endometrial cancer cells by estradiol. 1853 51

Sulfonylureas are considered to cause beta-cell apoptosis. However, it is unclear how this occurs and whether there is a difference in such effects among various sulfonylureas. Here, we examined the effects of various sulfonylureas and a short-acting insulin secretagogue, nateglinide, on oxidative stress and apoptosis using the beta-cell line MIN6. After cultured MIN6 cells were exposed to various concentrations of sulfonylureas (glibenclamide, glimepiride, and gliclazide) or nateglinide, intracellular production of reactive oxygen species (ROS) was evaluated by staining with 2',7'-dichlorofluorescein diacetate. The effect of these agents on apoptosis was also evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling technique. Exposure of beta-cells to glibenclamide, glimepiride, and nateglinide significantly increased intracellular ROS production in a concentration-dependent manner (0.1-10 micromol/L). These effects were completely blocked by nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitors (diphenylene iodonium or apocynin) or a protein kinase C inhibitor (calphostin C). After exposure to these agents for 48 hours, the numbers of apoptotic cells were also significantly increased. These effects were significantly blocked by apocynin and antioxidant N-acetyl-L-cysteine. In contrast, exposure to any concentrations of gliclazide did not affect either intracellular ROS production or the numbers of apoptotic cells. Sulfonylureas (glibenclamide and glimepiride, but not gliclazide) and nateglinide stimulated ROS production via protein kinase C-dependent activation of NAD(P)H oxidase and consequently caused beta-cell apoptosis in vitro. Because of the lack of such adverse effects, gliclazide may have a benefit in the preservation of functional beta-cell mass.
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PMID:Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. 1864 Mar 79

The underlying pathogenesis of stroke is mediated by a variety of environmental risk factors as well as genetic ones. Thus, we have to evaluate the environmental factors precisely to identify the stroke-related gene polymorphisms. The Hisayama study, an epidemiological study of cardiovascular diseases, was established in 1961 in Hisayama, Japan. In 2002, a screening survey for the genetic study was performed in Hisayama. The Fukuoka Stroke Registry (FSR) is a hospital-based registration of stroke patients. Stroke specialists from eight medical centers in southern Japan have participated in FSR. In the present study, control and case subjects were recruited from the Hisayama study and FSR, respectively. We performed a genome-wide case-control study and found that a nonsynonymous SNP in PRKCH encoding a member of protein kinase C (PKCC eta) was significantly associated with brain infarction. As a candidate gene analysis, we investigated the role of NAD (P) H oxidase C242T polymorphism in the development of brain infarction. The C242T polymorphism was not associated with lacunar and atherothrombotic infarction; however, the presence of T-allele may have a protective role in the occurrence of atrial fibrillation and cardioembolic brain infarction. These studies may provide important information for the development of the therapeutic strategies against stroke.
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PMID:[Molecular epidemiology of cerebrovascular diseases; the Hisayama study and the Fukuoka Stroke Registry (FSR)]. 1919 8

Overactivation of poly(adenosine diphosphate-ribose) polymerase (PARP), an enzyme involved in cellular response to DNA injury resulting from oxidative and nitrosative stress, is considered to play a key role in the pathogenesis of diabetes complications by promoting numerous vascular dysfunctions. In this study, we examined the ability of metformin, which was reported to possess intrinsic vasculoprotective properties independently of its antihyperglycemic effects, to inhibit PARP activation induced by high glucose concentrations in bovine aortic endothelial cells; and we investigated the potential mechanisms involved in this inhibition. The PARP activity was measured by cellular enzyme-linked immuno-specific assay (CELISA) method; cell poly(ribosyl)ated protein polymer accumulation was evaluated by immunofluorescence. Peroxynitrite anion productions were determined using dihydrorhodamine 123 fluoroprobe; and expression of p47phox subunit of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase was analyzed by Western blot in the absence and presence of protein kinase C and NAD(P)H oxidase inhibitors (calphostin and diphenyleneiodonium chloride, respectively). Our data showed that a therapeutically relevant concentration of metformin (5.10(-5) mol/L) was able to abolish PARP activation, to reduce poly(ribosyl)ated protein polymer accumulation, to decrease intracellular peroxynitrite anion level, and to reverse the overexpression of p47phox in bovine aortic endothelial cells stimulated by 25 mmol/L glucose in a similar manner to that of calphostin or diphenyleneiodonium chloride. Taken together, these results suggest that metformin could inhibit glucose-induced PARP activation through blockade of a protein kinase C-dependent NAD(P)H oxidase activation pathway. We propose that some of the beneficial effects of metformin on vascular endothelial cell functions in diabetes may be related to its inhibitory effect on PARP overactivation and its deleterious consequences.
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PMID:Metformin suppresses high glucose-induced poly(adenosine diphosphate-ribose) polymerase overactivation in aortic endothelial cells. 1930 74

Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE(2) are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE(2) synthesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE(2), has been linked to colorectal carcinogenesis. In this study, we determined whether bile acids altered the expression of 15-PGDH in human colon cancer cell lines. Treatment with unconjugated bile acids (chenodeoxycholate and deoxycholate) suppressed the transcription of 15-PGDH, resulting in reduced amounts of 15-PGDH mRNA, protein, and enzyme activity. Conjugated bile acids were less potent suppressors of 15-PGDH expression than unconjugated bile acids. Treatment with chenodeoxycholate activated protein kinase C (PKC), leading in turn to increased extracellular signal-regulated kinase (ERK) 1/2 activity. Small molecules that inhibited bile acid-mediated activation of PKC and ERK1/2 also blocked the downregulation of 15-PGDH. Bile acids induced early growth response factor-1 (Egr-1) and Snail, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Egr-1 or Snail blocked chenodeoxycholate-mediated downregulation of 15-PGDH. Together, these data indicate that bile acids activate the signal transduction pathway PKC --> ERK1/2 --> Egr-1 --> Snail and thereby suppress 15-PGDH transcription. Bile acids appear to increase the release of PGs from cells by downregulating catabolism in addition to stimulating synthesis. These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis.
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PMID:Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes. 1960 33

Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2)--antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.
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PMID:Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. 2017 24


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