Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel alpha-iso-cubebenol, which has anti-inflammatory effects in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, was isolated from the fruits of Schisandra chinensis. alpha-iso-cubebenolinhibited LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production. Consistent with these findings, alpha-iso-cubebenol also reduced the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 at the protein and mRNA levels in a concentration-dependent manner. alpha-iso-cubebenol also inhibited LPS-induced nuclear translocation of the NF-kappaB p65 subunit. Furthermore, alpha-iso-cubebenol suppressed the phosphorylation of ERK, JNK, and p38 kinase induced by LPS. Since the novel alpha-iso-cubebenol blocked the production of several pro-inflammatory mediators induced by LPS in macrophages, the molecule can be useful material for the development of anti-inflammatory agents against bacterial infections or endotoxin.
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PMID:Identification of a novel compound that inhibits iNOS and COX-2 expression in LPS-stimulated macrophages from Schisandra chinensis. 2004 Mar 59

Coffee is a popular beverage worldwide with various nutritional benefits. Diterpene cafestol, one of the major components of coffee, contributes to its beneficial effects through various biological activities such as chemopreventive, antitumorigenic, hepatoprotective, antioxidative and antiinflammatory effects. In this study, we examined the precise molecular mechanism of the antiinflammatory activity of cafestol in terms of prostaglandin E(2) (PGE(2)) production, a critical factor involved in inflammatory responses. Cafestol inhibited both PGE(2) production and the mRNA expression of cyclooxygenase (COX)-2 from lipopolysaccharide (LPS)-treated RAW264.7 cells. Interestingly, this compound strongly decreased the translocation of c-Jun into the nucleus and AP-1 mediated luciferase activity. In kinase assays using purified extracellular signal-regulated kinase 2 (ERK2) or immunoprecipitated ERK prepared from LPS-treated cells in the presence or absence of cafestol, it was found that this compound can act as an inhibitor of ERK2 but not of ERK1 and mitogen-activated protein kinase kinase 1 (MEK 1). Therefore our data suggest that cafestol may be a novel ERK inhibitor with AP-1-targeted inhibitory activity against PGE(2) production in LPS-activated RAW264.7 cells.
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PMID:Cafestol, a coffee-specific diterpene, is a novel extracellular signal-regulated kinase inhibitor with AP-1-targeted inhibition of prostaglandin E2 production in lipopolysaccharide-activated macrophages. 2004 50

Glehnia littoralis (Umbelliferae) has been used traditionally in Korean, Japanese, and Chinese medicine for the treatment of immune-related diseases; however, its anti-inflammatory activity and underlying mechanism remain to be defined. We investigated the anti-inflammatory effect and inhibitory mechanism on inflammation by the methylene chloride fraction from Glehnia littoralis extract (MCF-GLE), which was more effective than Glehnia littoralis extract (GLE). MCF-GLE inhibited 12-O-Tetradecanoyl-phorbol-13-acetate (TPA)-induced inflammation in an inflammatory edema mouse model. Also, MCF-GLE strongly inhibited the releases of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) and significantly suppressed the mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-stimulated RAW 264.7 macrophage cells in a dose-dependent manner. Furthermore, MCF-GLE suppressed NF-kappaB activation and IkappaB-alpha degradation. MCF-GLE also attenuated the activation of ERK and JNK in a dose-dependent manner. These results indicate that MCF-GLE has an inhibitory effect on the in vivo and in vitro inflammatory reaction and is a possible therapeutic agent. Our results suggest that the anti-inflammatory properties of MCF-GLE may result from the inhibition of pro-inflammatory mediators, such as NO, PGE(2), TNF-alpha, and IL-1beta via suppression of NF-kappaB- and mitogen-activated protein kinases-dependent pathways.
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PMID:Anti-inflammatory activity of methylene chloride fraction from Glehnia littoralis extract via suppression of NF-kappa B and mitogen-activated protein kinase activity. 2009 88

Bisphenol A (4,4'-dihydroxy-2,2-diphenylpropane; BPA) is an endocrine disruptor that affects the reproductive health of wildlife and possibly of humans. Evidence suggests that BPA interrupts ovarian steroidogenesis by altering steroidogenic enzymes. We evaluated the effect of BPA on aromatase expression in rat testicular Leydig cells. In addition, we investigated whether cyclooxygenase-2 (COX-2) was involved in BPA-induced aromatase expression. BPA induced a time- and concentration-dependent increase in aromatase protein expression in rat testicular Leydig R2C cells. It also increased aromatase gene expression and its enzyme and promoter activity, but reduced testosterone synthesis; increased COX-2 mRNA expression and promoter activity, the production of prostaglandin E(2) (PGE(2)), and the gene expression of PGE(2) (EP2 and EP4) receptors; induced the activation of cyclic adenosine monophosphate (cAMP) response element (CRE) and CREB binding; and increased the phosphorylation of protein kinase A (PKA), Akt, and mitogen-activated protein (MAP) kinase signaling pathways. BPA activation of aromatase was reversed by various inhibitors (COX-2, PKA, Akt, ERK, JNK, and p38). Taken together, these results suggest that BPA increases aromatase activity, which is correlated with COX-2 up-regulation mediated by the CRE, PKA, Akt, and MAP kinase signaling pathways in rat testicular Leydig cells.
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PMID:Bisphenol A-induced aromatase activation is mediated by cyclooxygenase-2 up-regulation in rat testicular Leydig cells. 2009 55

Lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated signaling pathways have caught the attention of strategies designed for rheumatoid arthritis (RA). In this study, we identified that cPLA(2)alpha acted as a modulator of LPS-induced VCAM-1 expression and THP-1 (human acute monocytic leukemia cell line) adherence. Treatment of RA synovial fibroblasts (RASFs) with LPS, a TLR4 agonist, promoted the VCAM-1 expression and THP-1 adherence which were decreased by pretreatment with a selective cytosolic phospholipase A(2) (cPLA(2)) inhibitor (AACOCF(3)), implying the involvement of cPLA(2)alpha in these responses. This notion was further confirmed by knockdown of cPLA(2)alpha expression by transfection with cPLA(2)alpha small interfering RNA (siRNA) leading to a decrease in VCAM-1 expression and THP-1 adherence induced by LPS. Subsequently, the LPS-stimulated cPLA(2)alpha phosphorylation was attenuated by pretreatment with a MEK1/2 inhibitor (U0126), suggesting that LPS-stimulated cPLA(2)alpha phosphorylation and activity are mediated through an ERK-dependent mechanism. Moreover, COX-2-derived PGE(2) production appeared to involve in LPS-induced VCAM-1 expression which was attenuated by pretreatment with selective COX-2 inhibitors (NS-398 and celecoxib), transfection with COX-2 siRNA, or PGE(2) receptor antagonists. In addition, pretreatment with ecosapentaenoic acid (EPA), a substrate competitor of arachidonic acid (AA), also blocked LPS-induced VCAM-1 mRNA and protein expression, and THP-1 adherence. Collectively, these results suggest that LPS-induced VCAM-1 expression and adhesion of THP-1 cells are mediated through the TLR4/ERK/cPLA(2)alpha phosphorylation and COX-2 expression/PGE(2) synthesis in RASFs.
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PMID:TLR4-dependent induction of vascular adhesion molecule-1 in rheumatoid arthritis synovial fibroblasts: Roles of cytosolic phospholipase A(2)alpha/cyclooxygenase-2. 2011 84

In the present study, the chemical constituents of Artemisia fukudo essential oil (AFE) were investigated using GC-MS. The major constituents were alpha-thujone (48.28%), beta-thujone (12.69%), camphor (6.95%) and caryophyllene (6.01%). We also examined the effects of AFE on the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Western blotting and RT-PCR tests indicated that AFE has potent dose-dependent inhibitory effects on pro-inflammatory cytokines and mediators. We investigated the mechanism by which AFE inhibits NO and PGE(2) by examining the level of nuclear factor-kappaB (NF-kappaB) activation within the mitogen-activated protein kinase (MAPK) pathway, which is an inflammation-induced signal pathway in RAW 264.7 cells. AFE inhibited LPS-induced ERK, JNK, and p38 phosphorylation. Furthermore, AFE inhibited the LPS-induced phosphorylation and degradation of Ikappa-B-alpha, which is required for the nuclear translocations of the p50 and p65 NF-kappaB subunits in RAW 264.7 cells. Our results suggest that AFE might exert an anti-inflammatory effect by inhibiting the expression of pro-inflammatory cytokines. Such an effect is mediated by a blocking of NF-kappaB activation which consequently inhibits the generation of inflammatory mediators in RAW264.7 cells. AFE may be useful for treating inflammatory diseases.
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PMID:Artemisia fukudo essential oil attenuates LPS-induced inflammation by suppressing NF-kappaB and MAPK activation in RAW 264.7 macrophages. 2015 20

In addition to their microbiocidal properties, human beta-defensins (hBDs) and cathelicidin LL-37 stimulate a number of mammalian cell activities, including migration, proliferation, and cytokine/chemokine production. Because hBDs and LL-37 cause mast cells to release pruritogens such as histamine and PGs, we hypothesized that these peptides would stimulate the secretion of a novel pruritogenic mediator IL-31, predominantly produced by T cells. hBDs and LL-37 enhanced IL-31 gene expression and IL-31 protein production and release in the human mast cell line LAD2, as well as in peripheral blood-derived cultured mast cells, suggesting that mast cells are another source of IL-31. Moreover, the expression of IL-31 was elevated in psoriatic skin mast cells, and hBD-2-4 and LL-37, but not hBD-1, enhanced its expression in vivo in rat skin mast cells. hBDs and LL-37 also induced the release of other pruritogenic mediators, including IL-2, IL-4, IL-6, GM-CSF, nerve growth factor, PGE(2), and leukotriene C(4), and increased mRNA expression of substance P. hBD- and LL-37-mediated IL-31 production/release was markedly reduced by pertussis toxin and wortmannin, inhibitors of G-protein and PI3K, respectively. As evidenced by the inhibitory effects of MAPK-specific inhibitors, hBD-2-4 and LL-37 activated the phosphorylation of MAPKs p38, ERK, and JNK that were required for IL-31 production and release. The ability of hBDs and LL-37 to stimulate the production and release of IL-31 by human mast cells provides a novel mechanism by which skin-derived antimicrobial peptides/proteins may contribute to inflammatory reactions and suggests a central role of these peptides in the pathogenesis of skin disorders.
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PMID:Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. 2019 Jan 40

Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)-2 served as a major neurotoxic factor in CNS injury. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown. Therefore, we investigated the mechanisms underlying EV71-induced COX-2 expression and prostaglandin E(2) (PGE(2)) production in rat brain astrocytes (RBA)-1, determined by Western blotting, RT-PCR, and promoter assay. Here, we reported that EV71-induced COX-2 expression and PGE(2) production were attenuated by pretreatment with the inhibitors of c-Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF-kappaB (helenalin), and AP-1 (Tanshinone) and transfection with shRNA or siRNA of c-Src, PDGFR, p85, c-Jun, c-Fos, ERK1, or ERK2. We further observed that EV71-induced activation of Akt and p42/p44 MAPK were mediated via c-Src and PDGFR. Pretreatment with PP1 attenuated EV71-stimulated phosphorylation of Src, PDGFR, Akt, and p42/p44 MAPK. Inhibition of PI3K by Wortmannin attenuated EV71-induced Akt and p42/p44 MAPK phosphorylation, but had no effect on PDGFR phosphorylation, suggesting that PDGFR is an upstream and p42/p44 MAPK is a downstream component of PI3K/Akt in these responses. EV71-stimulated NF-kappaB translocation from the cytoplasm to the nucleus, IkappaBalpha degradation and NF-kappaB promoter activity were attenuated by pretreatment with helenalin, but not AG1296, Wortmannin, and PD98059. EV71-induced c-Jun mRNA expression was attenuated by pretreatment with PD98059, AG1296, or Wortmannin. These results demonstrate that in RBA-1 cells, EV71-induced COX-2 expression associated with PGE(2) production is mediated through activation of c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP-1.
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PMID:EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. 2033 48

We recently described a novel GnRH receptor signaling pathway mediated by the prostaglandins (PGs) F(2alpha) and PGI(2), which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and inhibit LH but not FSH release. Here we further explore the cross talk between GnRH and the PG receptors. GnRH stimulates arachidonic acid (AA) release from LbetaT2 gonadotrope cells via the Ca(2+)-independent phospholipase A(2) (iPLA(2)) and not via the more common Ca(2+)-dependent cytosolic phospholipase A(2)alpha (cPLA(2)alpha). AA release was followed by a marked induction of cyclooxygenase (COX)-1 and COX-2 by GnRH via the protein kinase C/c-Src/phosphatidylinositol 3-kinase/MAPK pathway. COX-2 transcription by GnRH is mediated by the two nuclear factor-kappaB sites and the CCAAT/enhancer-binding protein site within its promoter. Indeed, GnRH stimulates p65/RelA phosphorylation (22-fold) in LbetaT2 cells and the two nuclear factor-kappaB sites apparently act as a composite response element. Although GnRH stimulates cAMP formation in LbetaT2 cells, we found no role for cAMP acting via the cAMP response element site in the COX-2 promoter. PGF(2alpha), PGI(2), or PGE(2) had no effect on GnRH-stimulated ERK, c-Jun N-terminal kinase, and p38MAPK activation or on GnRH- and high K(+)-stimulated intracellular Ca(2+) elevation in LbetaT2 and gonadotropes in primary culture. Although, PGF(2alpha), PGI(2), and PGE(2) reduced GnRH-stimulated cAMP formation, we could not correlate it to the inhibition of GnRH receptor expression, which is exerted only by PGF(2alpha) and PGI(2.) Hence, the inhibition by PGF(2alpha) and PGI(2) of the autoregulation of GnRH receptor expression is most likely mediated via inhibition of GnRH-stimulated phosphoinositide turnover and not by inhibition of Ca(2+) elevation and MAPK activation.
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PMID:Elucidation of mechanisms of the reciprocal cross talk between gonadotropin-releasing hormone and prostaglandin receptors. 2039 30

Mesoporous silica xerogels with various amount of calcium (0, 5, 10 and 15%, named m-SXC0, m-SXC5, m-SXC10 and m-SXC15, respectively) were synthesized by template sol-gel methods, and cell responses to m-SXCs were studied using murine pre-osteoblast MC3T3-E1 in vitro. The results showed that cell morphology was not affected by m-SXCs indicating good biocompatibility. Furthermore, cell proliferation ratio on the m-SXCs increased over time, among which m-SXC10 was highest. NO production obviously rose with the increase of Ca content in m-SXCs. ALP activity and PGE(2) level on m-SXC5 significantly improved compared with m-SXC0 while decreased with the increase of Ca content for m-SXC10 and m-SXC15. No obvious discrepancy on osteopontin mRNA expressions was observed among m-SXCs. The collagen I and osteocalcin mRNA expression on m-SXC5 were up-regulated, while decreased on m-SXC15 evidently. The phosphorylation level of ERK 1/2 for the m-SXC10 was highest after 7 days. In conclusion, calcium in m-SXCs plays an important role in osteoblast activity, which indicates mesoporous silica xerogel containing appropriate calcium could stimulate osteoblast proliferation, differentiation, gene expression via the activation of ERK 1/2 signaling pathway, and shows great prospects in bone regeneration field using as a drug controlled release filler.
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PMID:The bio-functional role of calcium in mesoporous silica xerogels on the responses of osteoblasts in vitro. 2041 7


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