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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progesterone priming of the ovariectomized rat, followed by a single injection of estradiol-17beta (10 mug) is followed by an increased uterine synthesis of both PGF and PGE. The administration of an estrogen antagonist (MER-25; 10 mg) concomitantly with estradiol had no effect on uterine prostaglandin synthesis. Similarly, the administration of either Actinomycin D or cycloheximide, antibiotics demonstrated to inhibit mRNA and protein synthesis, respectively, is without effect on estrogen-stimulated uterine prostaglandin synthesis. These results are considered with regard to the classic receptor theory of estrogen action and are a preliminary indication that estrogen-stimulated uterine prostaglandin synthesis may not require those receptor mediated events.
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PMID:Considerations into the mechanism of estrogen-stimulated uterine prostaglandin synthesis. 95 89

The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase-2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF(1alpha) also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.
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PMID:Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. 1151 32

Heme oxygenase-1 (HO-1) is induced as a beneficial and adaptive response in cells and tissues exposed to oxidative stress. Herein we examined how various eicosanoids affect the induction of HO-1, and the possible mechanism underlying 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2))-induced HO-1 expression. PGH(2), PGD(2) and its metabolites of the PGJ(2) series, and PGA(1) markedly induced the protein expression of HO-1. Arachidonic acid (AA), docosahexaenoic acid (DHA), PGE(2), PGF(2 alpha), and thromboxane B(2) (TXB(2)) were shown to have no effect on the induction of HO-1. 15d-PGJ(2) was the most potent activator achieving significance at 5 microM. Although 15d-PGJ(2) significantly activated the MAPKs of JNK and ERK, the activation of JNK and ERK did not contribute to the induction of HO-1 as determined using transfection of dominant-negative plasmids and MAPKs inhibitors. Additional experiment indicated that 15d-PGJ(2) induced HO-1 expression through peroxisome proliferator-activated receptor (PPAR)-independent pathway. 15d-PGJ(2) significantly decreased the intracellular level of reduced glutathione; and the thiol antioxidant, N-acetyl-L-cysteine (NAC), and the thiol-reducing agent, dithiothreitol (DTT), inhibited the induction of HO-1 by 15d-PGJ(2). Finally, NAC and DTT exhibited significant inhibition of HO-1 mRNA and HO-1 promoter reporter activity induced by 15d-PGJ(2). These results suggest that thiol antioxidant and reducing agents attenuate the expression of HO-1 induced by 15d-PGJ(2), and that the cellular thiol-disulfide redox status may be linked to HO-1 activation.
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PMID:Thiol antioxidant and thiol-reducing agents attenuate 15-deoxy-delta 12,14-prostaglandin J2-induced heme oxygenase-1 expression. 1499 22

VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT/beta-catenin signaling pathway. VEGFD, implicated in angiogenesis and lymphatic metastasis, is a pharmacogenomics target in the field of oncology.
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PMID:Comparative integromics on VEGF family members. 1668 60

Corpora lutea and blood samples were collected from superovulated ewes 0, 4, 8, 12 and 24 h after prostaglandin F(2alpha) (PGF) analog injection on day 10 of the estrous cycle. Changes in vascular cell and fibroblast composition, apoptosis and mRNA expression for several angiogenic factors in the corpus luteum (CL) were determined. While peripheral progesterone concentration decreased at 24 h after PGF injection, CL weight did not change. The area of positive BS-1 lectin staining (endothelial cell marker), smooth muscle cell actin (SMCA; pericyte and SMC marker), collagen type 1 (fibroblast marker), and the rate of cell death changed in luteal tissues after PGF treatment. In association with these cellular changes, mRNA for several angiogenic factors including vascular endothelial growth factor (VEGF) and receptors (Flt and KDR), basic fibroblast growth factor (FGF2) and receptor, angiopoietin (ANGPT) 1 and receptor Tie-2, endothelial nitric oxide synthase (NOS3), and angiotensin II receptor 1 (AT1) were altered. Changes in endothelial cell marker expression were positively correlated with changes in VEGF and NO systems. In addition, changes in mRNA expression for VEGF, Flt and KDR were positively correlated with changes in ANGPT2, Tie-2, and NOS3, indicating a functional relationship. This data demonstrates that after an initial increase, the endothelial component of the vascular bed decreases during PGF-induced luteal regression. However, SMCA expression remained high during luteal regression, potentially indicating a role of pericytes and vascular SMC in luteolysis, likely to regulate tissue remodeling and to maintain the integrity of larger blood vessels. Further, it appears that early regression may increase collagen type 1 production and/or expression by fibroblasts. Expression of angiogenic factors is influenced by PGF-induced luteolysis and may serve to maintain vascular structure in order to aid luteal regression.
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PMID:Vascular composition, apoptosis, and expression of angiogenic factors in the corpus luteum during prostaglandin F2alpha-induced regression in sheep. 1673 51

The role of pro-inflammatory cytokines and prostaglandins in human labour is well established. Many of the mRNAs stabilised by the MAPK pathway encode inflammatory mediators, suggesting that this kinase pathway plays a major role in the regulation of inflammation. The aim of this study was to determine if the MAPK pathway regulates the inflammatory response in human gestational tissues. Placenta and fetal membranes (n=5) obtained from pregnant women undergoing Caesarean section before the onset of labour were exposed to LPS, and co-incubated in the absence or presence of 12.5, 25 and 50 microM U0126 (ERK 1/2 inhibitor), SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). After 18 h incubation, tissues were collected and ERK 1/2, p38 MAPK, and JNK total and phosphorylated protein expression was assessed by ELISA and/or Western blotting. The incubation medium was collected and TNF-alpha, IL-1beta, IL-6, IL-8, PGE(2) and PGF(2alpha) release was quantified by ELISA. Treatment of placenta and fetal membranes with LPS activated all three MAPK proteins. Co-incubation with U0126, SP600125 and SB202190 significantly suppressed LPS-stimulated activation of ERK 1/2, JNK, and p38 MAPK, respectively. All cytokine and prostaglandin release was significantly suppressed by all concentrations of U0126. LPS-stimulated IL-6, TNF-alpha, PGE(2) and PGF(2alpha) release was significantly suppressed by treatment with all concentrations of SB202190, whereas ILS-stimulated IL-1beta release was only significantly inhibited in the presence of 50 microM SB202190 and there was no effect of SB202190 on LPS-stimulated IL-8 release. SP600125 significantly repressed LPS-stimulated release of IL-1beta and TNF-alpha at all concentrations, whereas LPS-stimulated IL-6, PGE(2) and PGF(2alpha) release were inhibited at 25 and 50 microM. In conclusion, the MAPK inhibitors used in this study demonstrated differential activity against a range of sequelae commonly associated with inflammation, supporting the therapeutic potential of MAPK inhibitors in pregnancy complications associated with an aberrant inflammatory response.
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PMID:Mitogen-activated protein kinase proteins regulate LPS-stimulated release of pro-inflammatory cytokines and prostaglandins from human gestational tissues. 1743 32

Processes of human labour include increased oxidative stress, formation of inflammatory mediators (e.g. cytokines) and uterotonic phospholipid metabolites (e.g. prostaglandins). In non-gestational tissues, advanced glycation endproducts (AGE) induce the expression of pro-inflammatory molecules through mitogen-activated protein kinase and nuclear factor kappaB (NF-kappaB)-dependent pathways. Thus, the aim of this study was to investigate the effects of AGE on 8-isoprostane (a marker of oxidative stress), pro-inflammatory cytokine and prostaglandin release in human gestational tissues, and to define the signalling pathways involved. Human placenta and gestational membranes (amnion and choriodecidua combined; n=5) were incubated in the absence or presence of AGE-BSA (0.25, 0.5, 1 and 2 mg/ml) for 18 h. AGE significantly increased in vitro release of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, prostaglandin (PG)E(2), PGF(2alpha) and 8-isoprostane from human placenta and gestational membranes. This was associated with a concomitant increase in NF-kappaB p65 activation and ERK 1/2 phosphorylation. AGE-stimulated 8-isoprostane, cytokine and prostaglandin production was significantly suppressed by the ERK 1/2 inhibitor U0126 and the NF-kappaB inhibitor BAY 11-7082. In conclusion, AGE mediates inflammatory actions in human gestational tissues. Protein kinases and the NF-kappaB pathway play an essential role in AGE signalling in human gestational tissues.
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PMID:Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-kappaB and extracellular signal-regulated kinase 1/2. 1747 May 18

Prostaglandin (PG) F(2alpha) is a potent bioactive lipid in the female reproductive tract, and exerts its function after coupling with its heptahelical G-protein-coupled receptor [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of fibroblast growth factor (FGF) 2, FGF receptor 1 (FGFR1), and FP receptor, colocalized within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF(2alpha)-FP receptor interaction in modulating FGF2 expression and signaling using an endometrial adenocarcinoma cell line stably expressing the FP receptor to the levels detected in endometrial adenocarcinomas (FPS cells) and endometrial adenocarcinoma tissue explants. PGF(2alpha)-FP receptor activation rapidly induced FGF2 mRNA expression, and elevated FGF2 protein expression and secretion into the culture medium in FPS cells and endometrial adenocarcinoma explants. The effect of PGF(2alpha) on the expression and secretion of FGF2 could be abolished by treatment of FPS cells and endometrial tissues with an FP receptor antagonist (AL8810) and inhibitor of ERK (PD98059). Furthermore, we have shown that FGF2 can promote the expression of FGF2 and cyclooxygenase-2, and enhance proliferation of endometrial adenocarcinoma cells via the FGFR1 and ERK pathways, thereby establishing a positive feedback loop to regulate neoplastic epithelial cell function in endometrial adenocarcinomas.
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PMID:F-prostanoid receptor regulation of fibroblast growth factor 2 signaling in endometrial adenocarcinoma cells. 1747 53

Communication between endothelial and bone cells is crucial for controlling vascular supply during bone growth, remodeling, and repair but the molecular mechanisms coordinating this intercellular crosstalk remain ill-defined. We have used primary human and rat long bone-derived osteoblast-like cells (HOB and LOB) and human umbilical vein endothelial cells (HUVEC) to interrogate the potential autocrine/paracrine role of vascular endothelial cell growth factor (VEGF) in osteoblast:endothelial cell (OB:EC) communication and examined whether prostaglandins (PG), known modulators of both OB and EC behavior, modify VEGF production. We found that the stable metabolite of PGI2, 6-keto-PGF(1alpha) and PGE2, induced a concentration-dependent increase in VEGF release by HOBs but not ECs. In ECs, VEGF promoted early ERK1/2 activation, late cyclooxygenase-2 (COX-2) protein induction, and release of 6-keto-PGF1alpha. In marked contrast, no significant modulation of these events was observed in HOBs exposed to VEGF, but LOBs clearly exhibited COX-dependent prostanoid release (10-fold less than EC) following VEGF treatment. A low level of osteoblast-like cell responsiveness to exogenous VEGF was supported by VEGFR2/Flk-1 immunolabelling and by blockade of VEGF-mediated prostanoid generation by a VEGFR tyrosine kinase inhibitor (TKI). HOB alkaline phosphatase (ALP) activity was increased following long-term non-contact co-culture with ECs and exposure of ECs to VEGF in this system further increased OB-like cell differentiation and markedly enhanced prostanoid release. Our studies confirm a paracrine EC-mediated effect of VEGF on OB-like cell behavior and are the first supporting a model in which prostanoids may facilitate this unidirectional VEGF-driven OB:EC communication. These findings may offer novel regimes for modulating pathological bone remodeling anomalies through the control of the closely coupled vascular supply.
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PMID:Evaluation of VEGF-mediated signaling in primary human cells reveals a paracrine action for VEGF in osteoblast-mediated crosstalk to endothelial cells. 1768 28

Endothelial dysfunction is associated with endothelial cell activation, i.e., up-regulation of surface cell adhesion molecules and the release of proinflammatory cytokines. 20-Hydroxyeicosatetraenoic acid (HETE), a major vasoactive eicosanoid in the microcirculation, has been implicated in the regulation of endothelial cell function through its angiogenic and pro-oxidative properties. We examined the effects of 20-HETE on endothelial cell activation in vitro. Cells transduced with adenovirus containing either CYP4A1 or CYP4A2 produced higher levels of 20-HETE, and they demonstrated increased expression levels of the adhesion molecule intercellular adhesion molecule (ICAM) (4-7-fold) and the oxidative stress marker 3-nitrotyrosine (2-3-fold) compared with cells transduced with control adenovirus. Treatment of cells with 20-HETE markedly increased levels of prostaglandin (PG) E(2) and 8-epi-isoprostane PGF(2alpha), commonly used markers of activation and oxidative stress, and most prominently, interleukin-8, a potent neutrophil chemotactic factor whose overproduction by the endothelium is a key feature of vascular injury. 20-HETE at nanomolar concentrations increased inhibitor of nuclear factor-kappaB phosphorylation by 2 to 5-fold within 5 min, which was followed with increased nuclear translocation of nuclear factor-kappaB (NF-kappaB). Likewise, 20-HETE activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway by stimulating phosphorylation of ERK1/2. Inhibition of NF-kappaB activation and inhibition of ERK1/2 phosphorylation inhibited 20-HETE-induced ICAM expression. It seems that 20-HETE triggers NF-kappaB and MAPK/ERK activation and that both signaling pathways participate in the cellular mechanisms by which 20-HETE activates vascular endothelial cells.
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PMID:20-Hydroxyeicosatetraenoic acid stimulates nuclear factor-kappaB activation and the production of inflammatory cytokines in human endothelial cells. 1794 96


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