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)

Isoprostanes are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonic acid. Isoprostanes evoke potent vascular effects but their actions in the neonatal vasculature are poorly known. We aimed to study the effects of 8-iso-PGE(1), 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) in pulmonary arteries (PA), pulmonary veins (PV), and mesenteric arteries (MA) from newborn and 2-wk-old piglets. Isoprostanes produced concentration-dependent contractions of PA, PV, and MA (magnitudes up to 1.5- to 2-fold greater than the responses to 62.5 mM KCl) but they were markedly less potent vasoconstrictors than the thromboxane A(2) (TXA(2)) mimetic U46619. Neonatal PA were more sensitive to 8-iso-PGF(1alpha), 8-iso-PGF(1beta), and 8-iso-PGF(2beta) than 2-wk-old PA. Neonatal PV were more sensitive to 8-iso-PGE(2) and 8-iso-PGF(1alpha), and neonatal MA were more sensitive to 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) than the corresponding 2-wk-old vessels. The sensitivity to U46619 decreased with postnatal age in MA but did not change in PA and PV. The contractile responses to all the isoprostanes and to U46619 were reverted by the TXA(2) receptor (TP) antagonist SQ 29,548. Moreover, isoprostane-evoked contractions in 2-wk-old PA were reduced by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and hydroxyfasudil) but not by inhibitors of protein kinase C (chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). In conclusion, isoprostanes produced compound-, tissue-, and age-dependent constriction of neonatal porcine pulmonary and mesenteric vascular smooth muscle. Isoprostane-evoked PA vasoconstriction involved TP receptors and activation of tyrosine kinases and Rho kinases.
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PMID:Age-related differences in vasoconstrictor responses to isoprostanes in piglet pulmonary and mesenteric vascular smooth muscle. 1584 38

We have previously reported that prostaglandin F2alpha (PGF2alpha) activates p44/p42 mitogen-activated protein (MAP) kinase through protein kinase C (PKC), resulting in the synthesis of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells, and that incadronate, a bisphosphonate, amplifies the VEGF synthesis. In the present study, we investigated the effects of tiludronate and etidronate, other bisphosphonates, on the PGF2alpha-stimulated VEGF synthesis in these cells. Tiludronate reduced the synthesis of VEGF induced by PGF2alpha. The PGF(2alpha)-stimulated phosphorylation of p44/p42 MAP kinase was suppressed by tiludronate. On the other hand, etidronate affected neither the VEGF synthesis nor the phosphorylation of p44/p42 MAP kinase elicited by PGF2alpha. Tiludronate attenuated the phosphorylation of both Raf-1 and MEK1/2 induced by PGF2alpha. The VEGF synthesis stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of PKC, was suppressed by tiludronate. The TPA-induced phosphorylations of Raf-1, MEK1/2 and p44/p42 MAP kinase were inhibited by tiludronate. These results strongly suggest that tiludronate but not etidronate suppresses the PGF2alpha-stimulated VEGF synthesis in osteoblasts, and that the effect of tiludronate is exerted at the point between PKC and Raf-1.
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PMID:Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1592 88

Aim of this study was to analyse the relationship between the plasma levels of polyphenols and the antioxidant activity of red and white wine. Twenty healthy subjects (HS) were randomly allocated to drink 300 ml of red (n = 10) or white n = 10 wine for 15 days. Ten HS who refrained from any alcohol beverage for 15 days were used as control. Urinary PGF-2alpha-III, a marker of oxidative stress and plasma levels of polyphenols were measured. Urinary PGF-2alpha-III significantly fell in subjects taking wine with a higher percentage decrease in subjects given red wine (-38.5 +/- 6%, p < 0.001) than in those given white wine (-23.1 +/- 6%). Subjects taking red wine had higher plasma polyphenols than those taking white wine (1.9 +/- 0.6 microM versus 1.5 +/- 0.33 microM, p < 0.001). Plasma polyphenols were inversely correlated with urinary PGF2alpha (r = 0.77, p < 0.001). No changes of urinary isoprostanes were observed in subjects who refrained from wine intake. In vitro study demonstrated that only a mixture of polyphenols, all in a range corresponding to that found in human circulation, inhibited LDL oxidation and PKC-mediated NADPH oxidase activation. Such inhibitory effects were more marked using the concentrations of polyphenols detected in human circulation after red wine intake. This study shows that red wine is more antioxidant than white wine in virtue of its higher content of polyphenols, an effect that may be dependent upon a synergism among polyphenols.
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PMID:Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine. 1631 Jan 97

In Sertoli epithelial cells, the IL-1beta induces prostaglandins (PG) PGE(2), PGF(2alpha) and PGI(2) (7-, 11-, and 2-fold, respectively), but not PGD(2), production. Cyclohexamide pretreatment inhibiting protein synthesis prevents IL-1beta increases in PG levels, indicating that induction requires de novo protein synthesis. IL-1beta-regulated PGE(2) and PGF(2alpha) production and cytokine expression require activation of cyclooxygenase-2 (COX-2) and c-Jun NH(2)-terminal kinase, as shown using specific enzyme inhibition. PGE(2) and PGF(2alpha) stimulate expression of IL-1alpha, -1beta, and -6, findings consistent with PG involvement in IL signaling within the seminiferous tubule. PGE(2) and PGF(2alpha) reverse COX-2-mediated inhibition of IL-1beta induction of cytokine expression and PG production. Sertoli PG receptor expression was determined; four known E-prostanoid receptor (EP) subtypes (1-4) and the F-prostanoid and prostacyclin prostanoid receptors were demonstrated using RNA and protein analyses. Pharmacological characterization of Sertoli PG receptors associated with cytokine regulation was ascertained by quantitative real-time RT-PCR analyses. IL-1beta regulates both EP(2) mRNA and protein levels, data consistent with a regulatory feedback loop. Butaprost (EP(2) agonist) and 11-deoxy PGE(1) (EP(2) and EP(4) agonist) treatments show that EP(2) receptor activation stimulates Sertoli cytokine expression. Consistent with EP(2)-cAMP signaling, protein kinase A inhibition blocks both IL-1beta- and PGE(2)-induced cytokines. Together, the data indicate an autocrine-amplifying loop involving IL-1beta-regulated Sertoli function mediated by COX-2-induced PGE(2) and PGF(2alpha) production. PGE(2) activates EP(2) and/or EP(4) receptor(s) and the protein kinase A-cAMP pathway; PGF(2alpha) activates F-prostanoid receptor-protein kinase C signaling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into physiological events as well as proinflammatory-mediated pathogenesis in the testis.
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PMID:A multistep kinase-based sertoli cell autocrine-amplifying loop regulates prostaglandins, their receptors, and cytokines. 1642 68

To better understand the process of slow luteal regression of the nonpregnant cycle in dogs and the acute luteolysis that occurs prepartum, the present study investigated in vitro PGF2alpha production by the endometrium, corpus luteum and placental explants obtained at known times of the cycle from pregnant bitches (days 63, 64 and immediately postpartum; day 0 = estimated day of the ovulatory LH surge) and from nonpregnant diestrus bitches (approximately days 65, 75 and 85). Both basal PGF2alpha production and its production in the presence of the protein kinase C (PKC) stimulator 12,13-phorbol dibutyrate (PDBu) were determined. For PDBu-supplemented incubations, mean PGF2alpha production (pg/mL/mg/6 h) by endometrium explants of the nonpregnant bitches in late diestrus was highest on day 65 (205 +/- 87) and reduced to low levels (38 +/- 17 and 11 +/- 11) on days 75 and 85, respectively. The production by corpus luteum explants from these bitches was significantly less on day 65 (46 +/- 14) than that of the day 65 endometrium explants, and was slightly increased on day 85 (103 +/- 52). The corresponding mean PGF2alpha production by the endometrium explants of pregnant bitches was on average much greater (i.e., two to three-fold) compared to nonpregnant bitches (P < 0.01) and involved high concentrations at day 64 (1523 +/- 467) and postpartum, compared to somewhat lower levels on day 63 (830+/-65); luteal PGF production (165 +/- 4) was also higher than in nonpregnant bitches around day 65. For pregnant bitches, PGF production per gram of tissue in the endometrium explants was greater than for the CL or placenta explants (180 +/- 37). Therefore, the endometrium of the pregnant bitch has an increased capability to produce PGF2alpha immediately prepartum, which on a tissue weight basis, exceeds that of either corpora lutea or the placenta. However, assuming a larger mass of placental tissue in vivo, we inferred that the placenta may contribute substantially to peripheral PGF concentrations.
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PMID:In vitro PGF2alpha production by endometrium and corpus luteum explants from pregnant and nonpregnant diestrus bitches and placental explants from pregnant bitches. 1646 69

In our previous study, we showed that prostaglandin F2alpha (PGF2alpha) stimulates vascular endothelial growth factor (VEGF) synthesis via activation of p44/p42 mitogen-activated protein (MAP) kinase via protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In addition, we demonstrated that incadronate amplified, and tiludronate suppressed PGF2alpha-induced VEGF synthesis among bisphosphonates, while alendronate or etidronate had no effect. In the present study, we investigated the effects of minodronate, a newly developed bisphosphonate, on PGF (2alpha)-induced VEGF synthesis in MC3T3-E1 cells. Minodronate significantly reduced VEGF synthesis induced by PGF2alpha dose-dependently at levels between 3 and 100 microM. PGF2alpha-stimulated phosphorylation of Raf-1, MEK1/2 and p44/p42 MAP kinase were suppressed by minodronate. 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator VEGF synthesis induced by PKC, was inhibited by minodronate. Minodronate inhibited Raf-1, MEK1/2 and p44/p42 MAP kinase phosphorylation induced by TPA. Mevalonate failed to affect the suppressive effect of minodronate on PGF2alpha-induced VEGF synthesis. Taken together, these results indicate that minodronate suppresses PGF2alpha-stimulated VEGF synthesis at the point between PKC and Raf-1 in osteoblasts.
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PMID:Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1667 5

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction.
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PMID:Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity. 1688 82

The asynchronous secretion of gonadotrope LH and FSH under the control of GnRH is crucial for ovarian cyclicity but the underlying mechanism is not fully resolved. Because prostaglandins (PG) are autocrine regulators in many tissues, we determined whether they have this role in gonadotropes. We first demonstrated that GnRH stimulates PG synthesis by induction of cyclooxygenase-2, via the protein kinase C/c-Src/phosphatidylinositol 3'-kinase/MAPK pathway in the LbetaT2 gonadotrope cell line. We then demonstrated that PGF(2alpha) and PGI2, but not PGE2 inhibited GnRH receptor expression by inhibition of phosphoinositide turnover. PGF(2alpha), but not PGI2 or PGE2, reduced GnRH-induction of LHbeta gene expression, but not the alpha-gonadotropin subunit or the FSHbeta subunit genes. The prostanoid receptors EP1, EP2, FP, and IP were expressed in rat gonadotropes. Incubations of rat pituitaries with PGF(2alpha), but not PGI2 or PGE2, inhibited GnRH-induced LH secretion, whereas the cyclooxygenase inhibitor, indomethacin, stimulated GnRH-induced LH secretion. None of these treatments had any effect on GnRH-induced FSH secretion. The findings have thus elaborated a novel GnRH signaling pathway mediated by PGF(2alpha)-FP and PGI2-IP, which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and differentially inhibit LH and FSH release. These findings provide a mechanism for asynchronous LH and FSH secretions and suggest the use of combination therapies of GnRH and prostanoid analogs to treat infertility, diseases with unbalanced LH and FSH secretion and in hormone-dependent diseases such as prostatic cancer.
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PMID:Reciprocal cross talk between gonadotropin-releasing hormone (GnRH) and prostaglandin receptors regulates GnRH receptor expression and differential gonadotropin secretion. 1713 45

Arachidonic acid is a potential paracrine agent released by the uterine endometrial epithelium to induce PTGS2 [PG (prostaglandin)-endoperoxide synthase 2] in the stroma. In the present study, bovine endometrial stromal cells were used to determine whether PTGS2 is induced by arachidonic acid in stromal cells, and to investigate the potential role of PPARs (peroxisome-proliferator-activated receptors) in this effect. Arachidonic acid increased PTGS2 levels up to 7.5-fold within 6 h. The cells expressed PPARalpha and PPARdelta (also known as PPARbeta) (but not PPARgamma). PTGS2 protein level was increased by PPAR agonists, including polyunsaturated fatty acids, synthetic PPAR ligands, PGA1 and NSAIDs (non-steroidal anti-inflammatory drugs) with a time course resembling that of arachidonic acid. Use of agonists and antagonists indicated PPARalpha (but not PPARdelta or PPARgamma) was responsible for PTGS2 induction. PTGS2 induction by arachidonic acid did not require PG synthesis. PTGS2 levels were increased by the PKC (protein kinase C) activators 4beta-PMA and PGF(2alpha), and the effects of arachidonic acid, NSAIDs, synthetic PPAR ligands and 4beta-PMA were blocked by PKC inhibitors. This is consistent with PPAR phosphorylation by PKC. Induction of PTGS2 protein by 4beta-PMA in the absence of a PPAR ligand was decreased by the NF-kappaB (nuclear factor kappaB) inhibitors MG132 and parthenolide, suggesting that PKC acted through NF-kappaB in addition to PPAR phosphorylation. Use of NF-kappaB inhibitors allowed the action of arachidonic acid as a PPAR agonist to be dissociated from an effect through PKC. The results are consistent with the hypothesis that arachidonic acid acts via PPARalpha to increase PTGS2 levels in bovine endometrial stromal cells.
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PMID:Peroxisome-proliferator-activated receptors and the control of levels of prostaglandin-endoperoxide synthase 2 by arachidonic acid in the bovine uterus. 1751 15

Mouse NIH3T3 fibroblast cells overexpressing phosphatidylinositol transfer protein beta (PI-TPbeta, SPIbeta cells) demonstrate a low rate of proliferation and a high sensitivity towards UV-induced apoptosis when compared with wtNIH3T3 cells. In contrast, SPIbetaS262A cells overexpressing a mutant PI-TPbeta that lacks the protein kinase C-dependent phosphorylation site Ser-262, demonstrate a phenotype comparable with wtNIH3T3 cells. This suggests that the phosphorylation of Ser-262 in PI-TPbeta is involved in the regulation of apoptosis. Conditioned medium (CM) from wtNIH3T3 cells contains bioactive factors, presumably arachidonic acid metabolites [H. Bunte, et al., 2006; M. Schenning, et al., 2004] that are able to protect SPIbeta cells against UV-induced apoptosis. CM from SPIbeta cells lacks this protective activity. However, after heat denaturation CM from SPIbeta cells regains a protective activity comparable with that of wtNIH3T3 cells. This indicates that CM from SPIbeta cells contains an antagonistic factor interfering with the anti-apoptotic activity present. SPIbetaS262A cells do not produce the antagonist suggesting that phosphorylation of Ser-262 is required. Moreover, in line with the apparent lack of anti-apoptotic activity, CM from SPIbeta cells does not induce the expression of COX-2 or the activation of p42/p44 MAP kinase in SPIbeta cells. In contrast, CM from wtNIH3T3 and SPIbetaS262A cells or heat-treated CM from SPIbeta cells does induce these anti-apoptotic markers. Since we have previously shown that some of the arachidonic acid metabolites present in CM from wtNIH3T3 cells are prostaglandin (PG) E(2) and PGF(2alpha), we investigated the effect of these PGs on cell survival. Although PGE(2) and PGF(2alpha) were found to protect wtNIH3T3 and SPIbetaS262A cells against UV-induced apoptosis, these PGs failed to rescue SPIbeta cells. The fact that the concentrations of PGE(2) and PGF(2alpha) in the CM from SPIbeta cells and wtNIH3T3 cells were found to be comparable suggests that the failure of these PGs to protect SPIbeta cells could render these cells more apoptosis sensitive. Concomitantly, upon incubation with PGE(2) and PGF(2alpha), an increased expression of COX-2 and activation of p42/p44 MAP kinase were observed in wtNIH3T3 and SPIbetaS262A cells but not in SPIbeta cells. Hence, it appears that specific mechanisms of cell survival are impaired in SPIbeta cells.
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PMID:The anti-apoptotic MAP kinase pathway is inhibited in NIH3T3 fibroblasts with increased expression of phosphatidylinositol transfer protein beta. 1768 9


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