Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined the effect of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, and N-(9-fluorenyl-methyloxycarbonyl)-L-leucine (F-L-Leu), a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, separately and combined, on the development of methylnitrosourea (MNU)-induced rat mammary gland carcinogenesis. Celecoxib and F-L-Leu significantly reduced tumor incidence and multiplicity (P < 0.05). Combining both agents exerted higher (synergistic) cancer inhibition than separate treatments (P < 0.05). The effects of the test drugs on COX-2 and PPAR gamma expression and on the synthesis of prostaglandin E(2) (PGE(2)) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) were examined in rat mammary normal (MNU-untreated), uninvolved, and tumor (MNU-treated) tissues. Celecoxib and F-L-Leu, separately, inhibited COX-2 and up-regulated PPAR gamma expression. These effects were paralleled by inhibition of PGE(2) synthesis and up-regulation of 15d-PGJ(2). Combined treatment resulted in higher alterations in COX-2 and PPAR gamma transcripts and PG synthesis compared with separate administrations. The effect of the test agents on Bcl(2), BAX, and protein kinase C alpha expression levels were examined in the rat mammary gland and the pro-(BAX:Bcl(2)) and anti-[PKC alpha*(Bcl(2)/BAX)] apoptotic ratios were evaluated. Each drug increased the proapoptotic ratio by 2- to 7-fold and reduced the antiapoptotic ratio by 2- to >8-fold in all tissues. Combined treatment, however, resulted in >9- to 14-fold up-regulation in the proapoptotic processes and 15- to >30-fold down-regulation in the antiapoptotic ones. Analyses were also carried out on the drug-induced modulation of cell cycle regulators and proliferation markers (cyclin-dependent kinase 1 and proliferating cell nuclear antigen). F-L-Leu and celecoxib each reduced the cyclin-dependent kinase 1 and proliferating cell nuclear antigen expression in the tumor. Higher down-regulation was attained in all tissues by combined treatment where cyclin-dependent kinase 1 and proliferating cell nuclear antigen almost retained the expression levels observed in the normal glands. In conclusion, simultaneous targeting of COX-2 and PPAR gamma may inhibit mammary cancer development more effectively than targeting each molecule alone. COX-2 inhibitors and PPAR gamma agonists coordinately mediate their anticancer effect via both COX-dependent (inhibition of COX-2, activation of PPAR gamma, and modulation PG synthesis) and COX-independent (induction of proapoptotic factors and inhibition of cell proliferation) pathways.
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PMID:Inhibition of rat mammary gland carcinogenesis by simultaneous targeting of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma. 1615 91

IL-1beta is known promote cyclooxygenase-2 (COX- 2) and matrix metalloproteinase-2 (MMP-2) expression. This study focuses on the characterization of the signaling cascade associated with IL-1beta-induced matrix metalloproteinase-2 (MMP-2) regulation in human chondrocytes. The decrease in collagen levels in the conditioned media was prevented by a broad spectrum MMP inhibitor, suggesting that IL-1beta promotes the proteolytic process leading to MMP-2 activation. IL-1beta-related MMP-2 expression was found to be dependent on prostaglandin E2 (PGE2) production. In addition, the induction of COX-2 and MMP-2 was inhibited by the pretreatment of chondrocytes with a SB203580 or Ro 31-8220, indicating the involvement of protein kinase C (PKC) or p38 mitogen-activated protein kinase (MAPK). However, there is no cross-talk between PKC and p38 MAPK in the IL-1beta-induced MMP-2 activation. Taken together, these results demonstrated that IL-1beta induces MMP-2 expression through the PGE2-dependent mechanism in human chondrocytes.
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PMID:Interleukin-1beta stimulates matrix metalloproteinase-2 expression via a prostaglandin E2-dependent mechanism in human chondrocytes. 1527 34

A specific modulatory effect of PUFAs (polyunsaturated fatty acids) on gene expression of some cytokines involved in bone remodelling has been reported previously. In particular, although a direct action of AA (arachidonic acid) on bone cytokine gene expression has been shown in human osteoblastic cells, OA (oleic acid) and EPA (eicosapentaenoic acid) were ineffective. Since the NO (nitric oxide) system has also been shown to have an important modulatory activity on osteoblasts, osteoclasts and bone metabolism, in the present study we have investigated the effects of PUFAs on iNOS (inducible NO synthase) gene expression in a human osteoblast-like cell line. AA induced a significant increase in iNOS mRNA expression, whereas EPA and OA had no stimulatory effects but instead caused a significant inhibition of AA-induced iNOS gene expression. Blocking of the COX (cyclo-oxygenase) pathway did not inhibit AA-induced iNOS expression. AA action was inhibited instead by the addition of calphostin C and genistein, inhibitors of PKC (protein kinase C) and tyrosine kinases respectively. Experiments performed with specific anti-cytokine antibodies showed a significant decrease in iNOS expression in AA-treated osteoblastic cells, suggesting that both cytokine-dependent and -independent mechanisms account for the effects of AA on iNOS gene expression. In conclusion, our investigation clearly shows specific effects of PUFAs on iNOS expression in human osteoblast-like cells with a cytokine-dependent and -independent mechanism. These results might have clinical relevance and are of interest for understanding the reported beneficial effects of dietary PUFA manipulation on the prevention and/or treatment of primary and secondary bone disease.
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PMID:Specific effect of arachidonic acid on inducible nitric oxide synthase mRNA expression in human osteoblastic cells. 1580 9

Cardiovascular disease is the leading cause of morbidity in Westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. AT supplementation decreases interleukin 1 and 6 release from human monocytes. Thus, the aim of this study was to examine the effect of AT on an important proinflammatory cytokine, tumor necrosis factor-alpha (TNF) release from human monocytes. AT supplementation (1200 IU/day for 3 months) significantly decreased TNF release from activated human monocytes. Mechanisms that were examined included its effect as a general antioxidant, its inhibitory effect on protein kinase C (PKC), and the cycloxygenase-lipoxygenase pathway. While AT decreased TNF release from activated monocytes, other antioxidants had no effect on TNF release. Specific PKC inhibitors had no effect on TNF release from activated monocytes. The inhibition of TNF release by AT in activated monocytes was reversed by leukotriene B(4) (LTB(4)), a major product of the 5-lipoxygenase (5-LO) pathway. Similar observations were seen with inhibitors of 5-lipoxygenase. Indomethacin, a COX inhibitor, in the presence and absence of AT failed to affect TNF activity. These findings suggest that AT decreases TNF release from activated human monocytes via inhibition of 5-lipoxygenase. Also, AT as well as a 5-LO inhibitor significantly decreased TNF mRNA. Furthermore, AT and the 5-LO inhibitor decreased NFkappab-binding activity. Thus, in activated human monocytes, AT appears to inhibit TNF mRNA and protein by inhibition of 5-LO.
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PMID:Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. 1580 19

The barrier functions in epithelial and endothelial cells seem to be very important for maintaining normal biological homeostasis. However, it is unclear whether or how bile acids affect the epithelial barrier. We examined the bile acid-induced disruption of the epithelial barrier. We measured the transepithelial electrical resistance (TEER) of Caco-2 cells as a marker of disruption of the epithelial barrier. Reactive oxygen species (ROS) generation was also measured. Cholic acid (CA) decreased the TEER and increased intracellular ROS generation. PLA2 (phospholipase A2), COX (cyclooxygenase), PKC (protein kinase), ERK 1/2 (extracellular signal-regulated kinase 1/2), PI 3 K (phosphatidylinositol 3-kinase), p38 MAPK (p38 mitogen-activated protein kinase), MLCK (myosin light-chain kinase), NADH dehydrogenase, and XO (xanthine oxidase) inhibitors or ROS scavengers prevented the CA-induced TEER decrease. PLA2, COX, PKC, NADH dehydrogenase, and XO inhibitors prevented the CA-induced ROS generation but not ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors. If the cells were treated with ROS generators such as superoxide dismutase, the TEER decreased. ERK 1/2, PI 3 K, p38 MAPK, and MLCK inhibitors prevent these ROS generators from inducing the TEER decrease. These results suggest that ROS play an important role. In addition, PLA2, COX, PKC, NADH dehydrogenase, and XO are located upstream of the ROS generation, but ERK 1/2, PI 3 K, p38 MAPK, and MLCK are downstream during the signaling of CA-induced TEER alterations.
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PMID:Bile acid modulates transepithelial permeability via the generation of reactive oxygen species in the Caco-2 cell line. 1610 7

Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid beta peptide 25-35 (Abeta(25-35)) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E(2) (PGE(2)) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Abeta(25-35)-induced COX-2/PGE(2) synthesis. PKC-inhibitors prevent Abeta(25-35)-induced COX-2 and PGE(2) synthesis. Furthermore Abeta(25-35) rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms alpha and/or beta are most probably involved in Abeta(25-35)-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition.
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PMID:Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostaglandin E2 release in primary midbrain astrocytes. 1654 99

Previously we demonstrated that estrone non-genomically regulates rat aortic NOS and COX activity and that this effect depends on ovarian activity. The purpose of the present study was to characterize this effect and investigate the participation of phospholipase C and phophatidylinositol-3-kinase system in the intracellular transduction pathway involved in the response. Using aortic strips isolated from female fertile rats we showed that estrone stimulate nitric oxide synthase and cyclooxygenase in a short time interval (5-20 min), and that NO production was dependent in part on PGI2 production since 1 microM indomethacin significantly reduced this free radical production. Injection of 17-beta-estradiol to ovariectomized rats restored tissue capacity to rapidly increase NO production in response to "in vitro" treatment with 1 nM estrone. We also demonstrated that in aortic strips isolated from intact animals estrone elicited a rapid phospholipase C activation, inducing a biphasic increase in diacylglycerol generation (peaking at 45 s and 5 min). The presence of protein kinase C inhibitor chelerythrine did not prevent the increase of NO released in response to hormone treatment. We proved that PI3K-Akt system does not mediate NOS and COX activation. However, PLC activation was dependent on PI3K since presence of LY 294002 in the incubation medium abolished estrone-induced DAG increment. We concluded that, estrone rapid action on vascular tissue involves a cross talk between NOS and COX system, and the activation of PLC/DAG/PKC transduction pathways.
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PMID:Signal transduction pathways involved in non-genomic action of estrone on vascular tissue. 1686 Aug 31

We have studied the signaling pathways involved in pilocarpine-induced mucin release in rat submandibular slices. Pilocarpine produced a significant increment of PGE2 levels and a positive (r=0.8870) and significant (p=0.0077) correlation between PGE2 production and mucin released was determined. The participation of PGE2 was confirmed by the use of indomethacin (indo) and of acetyl salicylic acid (ASA), cyclooxygenase inhibitors, which inhibited pilocarpine-induced mucin release. The muscarinic receptors involved in the regulation of mucin release were identified as M1 and M4 by the use of the selective acetylcholine receptors (mAChR) antagonists, pirenzepine, AF-DX 116, 4-DAMP and tropicamide. The secretory process was dependent on both, intracellular and extracellular calcium pools since it was inhibited by thapsigargin and verapamil. Cyclic AMP, nitric oxide synthase and PKC also participated in pilocarpine-induced mucin release. It is concluded that pilocarpine, by activation the M1 and M4 mAChR subtypes induces an increase of intracellular Ca2+ concentration ([Ca2+]I) and elevates cAMP levels, which in turn stimulates COX, PKC and NOS and promotes mucin exocytosis. PGE2 released induces cAMP accumulation which, together with PKC are involved in the PGE2 increased Ca2+/cAMP-regulated exocytosis. Thus, cAMP accumulation induced by cholinergic stimulation is, in part, the result of PGE2 production.
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PMID:Signaling pathways involved in pilocarpine-induced mucin secretion in rat submandibular glands. 1713 4

We have demonstrated that LPA (lysophosphatidic acid)-induced IL (interleukin)-8 secretion was partly mediated via transactivation of EGFR [EGF (epidermal growth factor) receptor] in HBEpCs (human bronchial epithelial primary cells). The present study provides evidence that LPA-induced transactivation of EGFR regulates COX (cyclo-oxygenase)-2 expression and PGE(2) [PG (prostaglandin) E(2)] release through the transcriptional factor, C/EBPbeta (CCAAT/enhancer-binding protein beta), in HBEpCs. Treatment with LPA (1 microM) stimulated COX-2 mRNA and protein expression and PGE(2) release via G(alphai)-coupled LPARs (LPA receptors). Pretreatment with inhibitors of NF-kappaB (nuclear factor-kappaB), JNK (Jun N-terminal kinase), or down-regulation of c-Jun or C/EBPbeta with specific siRNA (small interference RNA) attenuated LPA-induced COX-2 expression. Downregulation of EGFR by siRNA or pretreatment with the EGFR tyrosine kinase inhibitor, AG1478, partly attenuated LPA-induced COX-2 expression and phosphorylation of C/EBPbeta; however, neither of these factors had an effect on the NF-kappaB and JNK pathways. Furthermore, LPA-induced EGFR transactivation, phosphorylation of C/EBPbeta and COX-2 expression were attenuated by overexpression of a catalytically inactive mutant of PLD2 [PLD (phospholipase D) 2], PLD2-K758R, or by addition of myristoylated PKCzeta [PKC (protein kinase C) zeta] peptide pseudosubstrate. Overexpression of the PLD2-K758R mutant also attenuated LPA-induced phosphorylation and activation of PKCzeta. These results demonstrate that LPA induces COX-2 expression and PGE(2) production through EGFR transactivation-independent activation of transcriptional factors NF-kappaB and c-Jun, and EGFR transactivation-dependent activation of C/EBPbeta in HBEpCs. Since COX-2 and PGE(2) have been shown to be anti-inflammatory in airway inflammation, the present data suggest a modulating and protective role of LPA in regulating innate immunity and remodelling of the airways.
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PMID:Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E(2) release via C/EBPbeta in human bronchial epithelial cells. 1829 42

Spurred by the paradoxical anti-inflammatory activity of some aminoacylphorbol derivatives, the naturally occurring and epimeric N,N-dimethylvalinoyl-4alpha-4-deoxyphorbol derivatives 3b and 3d have been prepared from 4alpha-4-deoxyphorbol (3e), a byproduct of the isolation of phorbol from Croton oil and a phorboid polyol so far largely overlooked in terms of biological activity. The configuration of the side chain stereocenter was confirmed for both natural products, and to investigate the side chain structure-activity relationships within this class of compounds, their corresponding N,N-dimethylglycinate (3g) and nor (3h) and di-nor derivatives (3i, 3j) were also prepared. By using a PKC-sensitive model of HIV-1 latency (activation of HIV- gene expression in Jurkat-LAT-GFP cells), it was found that both 3b and 3d can activate PKC-dependent responses, while a series of experiments with isoform-specific PKC inhibitors showed that these compounds target PKCalpha and -delta. Both N,N-dimethylation and the presence of side chain alpha-substitution were critical for activity. Selective PKC binding, rather than COX inhibition, might explain the paradoxical anti-inflammatory activity of extracts containing aminoacylphorboids in the mouse ear edema assay.
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PMID:Synthesis and biological evaluation of 12-aminoacylphorboids. 2012 Dec 37


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