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)

Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). Cotreatment with ERK inhibitor PD98059 abrogated sildenafil-induced protection (31.8 +/- 4.4%). To further evaluate the role of ERK in delayed cardioprotection, mice were treated with sildenafil (ip) 24 h before global ischemia-reperfusion. PD98059 was administered (ip) 30 min before sildenafil treatment. Infarct size was reduced from 27.6 +/- 3.3% in controls to 7.1 +/- 1.5% in sildenafil-treated mice (P < 0.05). The delayed protective effect of sildenafil was also abolished by PD98059 (22.5 +/- 2.3%). Western blots revealed that sildenafil significantly increased phosphorylation of ERK1/2 and GSK-3beta and induced iNOS, eNOS, Bcl-2, and PKG activity in the heart 24 h after treatment. PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.
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PMID:ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. 1934 60

It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and non-operatively clinical uses. Nitric oxide (NO) is a crucial early mediator in mechanically induced bone formation. Here we found that US-mediated inducible nitric oxide synthase (iNOS) expression was attenuated by Ras inhibitor (manumycin A), Raf-1 inhibitor (GW5074), MEK inhibitor (PD98059), NF-kappaB inhibitor (PDTC), and IkappaB protease inhibitor (TPCK). US-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser(338) by US was inhibited by manumycin A and GW5074. US-induced MEK and ERK activation was inhibited by manumycin A, GW5074, and PD98059. Stimulation of preosteoblasts with US activated IkappaB kinase alpha/beta (IKK alpha/beta), IkappaBalpha phosphorylation, p65 phosphorylation at Ser(276), p65, and p50 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. US-mediated an increase of IKK alpha/beta, IkappaBalpha, and p65 phosphorylation, kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by manumycin A, GW5074, and PD98059. Our results suggest that US increased iNOS expression in preosteoblasts via the Ras/Raf-1/MEK/ERK/IKKalphabeta and NF-kappaB signaling pathways.
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PMID:Ultrasound stimulates NF-kappaB activation and iNOS expression via the Ras/Raf/MEK/ERK signaling pathway in cultured preosteoblasts. 1928 77

In our previous study, we reported the isolation of a novel humulene derivative, 5-hydroxyzerumbone, from Zingiber zerumbet and its inhibitory activity on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 mouse macrophage cells. This study was performed to examine its mechanism of action on the regulation of NO production. 5-Hydroxyzerumbone inhibited the expressions of iNOS mRNA and protein in a concentration-dependent manner. Treatment with 5-hydroxyzerumbone also induced the expression of heme oxygenase-1 (HO-1) in macrophage cells. In addition, 5-hydroxyzerumbone inhibited LPS-induced transcriptional activation of NF-kappaB, indicating that regulation of NF-kappaB activity might be involved in the inhibition of NO production by 5-hydroxyzerumbone. 5-Hydroxyzerumbone, however, did not affect the degradation of IkappaB-alpha and the activation of p38 and ERK in LPS-treated cells. Taken together, these results suggest that down-regulation of LPS-induced NO production by 5-hydroxyzerumbone is mediated by the suppression of iNOS expression through the modulation of NF-kappaB activation and HO-1 induction in macrophage cells.
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PMID:Suppression of lipopolysaccharide-stimulated inducible nitric oxide synthase (iNOS) expression by a novel humulene derivative in macrophage cells. 1929 70

Alpha-synuclein (Syn) is implicated in the pathogenesis of PD and related neurodegenerative disorders. Recent studies have also shown that alpha-synuclein can activate microglia and enhance dopaminergic neurodegeneration. The mechanisms of microglia activation by alpha-synuclein, however, are not well understood. In this study, we found that not only alpha-synuclein but also beta- and gamma-synucleins activated macrophages (RAW 264.7) in vitro. Macrophages treated with synuclein proteins secreted TNF-alpha in a dose-dependent manner. Synuclein family proteins also increased mRNA transcription of COX-2 and iNOS. Two alpha-synuclein deletion mutants, SynDeltaNAC and Syn61-140, activated macrophages, while deletion mutants Syn1-60 and Syn96-140 did not significantly activate them. Finally, we demonstrated that macrophage activation by alpha-synuclein was accompanied by phosphorylation of ERK. These results suggest that synuclein family proteins can activate macrophages, and that macrophage activation needs both the N-terminal and C-terminal domains of alpha-synuclein, but not the central NAC region.
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PMID:Identification of the amino acid sequence motif of alpha-synuclein responsible for macrophage activation. 1935 91

Chebulagic acid (CA), a natural anti-oxidant, showed potent anti-inflammatory effects in LPS-stimulated RAW 264.7, a mouse macrophage cell line. These effects were exerted via inhibition of NO and PGE2 production and down-regulation of iNOS, COX-2, 5-LOX, TNF-alpha and IL-6. CA inhibited NF-kappaB activation by LPS, and this was associated with the abrogation of IkappaB-alpha phosphorylation and subsequent decreases in nuclear p50 and p65 protein levels. Further, the phosphorylation of p38, ERK 1/2 and JNK in LPS-stimulated RAW 264.7 cells was suppressed by CA in a concentration-dependent manner. LPS-induced generation of reactive oxygen species (ROS) was also effectively inhibited by CA. These results suggest that CA exerts anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages by inhibition of NF-kappaB activation and MAP kinase phosphorylation.
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PMID:Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-kappaB and MAPK activation in RAW 264.7 macrophages. 1935 5

Methylglyoxal profoundly stimulates host's immune response against tumor cell by producing reactive oxygen intermediates (ROI's) and reactive nitrogen intermediates (RNI's) [Bhattacharyya, N., Pal, A., Patra, S., Haldar, A.K., Roy, S., Ray, M., 2008. Activation of macrophages and lymphocytes by methylglyoxal against tumor cells in the host. Int. Immunophar. 8 (11), 1503-1512]. Present study indicated that methylglyoxal stimulates iNOS activation by p38 MAPK-NF-kappa beta dependent pathway and ROS production by ERK and JNK activation in sarcoma-180 tumor bearing mice. Proinflammatory cytokines, for macrophage activation, IL-6 and IL-1 beta were also increased. Production of TLR 4 and TLR 9, which acts through the same signaling pathway, were also upregulated. Hence, concluded that methylglyoxal augmented the IL-6 and IL-1 beta, expression of TLR 4 and TLR 9 and produced MAPKs, important regulators of ROIs and RNIs. Methylglyoxal treatment also increased M-CSF, an upregulator of macrophage production. CD8 and CD4 molecules, associated with T(C) and T(H) cells respectively, were also increased. Overall methylglyoxal treatment is important for enhancement of macrophages and lymphocyte activation or immunomodulation against sarcoma-180 tumor.
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PMID:Methylglyoxal induced activation of murine peritoneal macrophages and surface markers of T lymphocytes in sarcoma-180 bearing mice: involvement of MAP kinase, NF-kappa beta signal transduction pathway. 1937 2

Ureteral obstruction leads to increased pressure and inducible nitric oxide synthase (iNOS) expression. This study examined the involvement of epidermal growth factor (EGF) receptor (EGFR), nuclear factor-kappaB (NFkappaB), and signal transducers and activators of transcription 3 (STAT3) in iNOS induction in human proximal tubule (HKC-8) cells in response to pressure or EGF. HKC-8 cells were subjected to 60 mmHg pressure or treated with EGF for 0-36 h. iNOS was more rapidly induced in response to EGF than pressure. The addition of EGFR, NFkappaB, and STAT3 inhibitors significantly suppressed pressure- or EGF-stimulated iNOS mRNA and protein expression. Analysis of the activated states of EGFR, NFkappaB p65, and STAT3 after exposure to both stimuli demonstrated phosphorylation within 2.5 min. Anti-EGF antibody inhibited iNOS induction in pressurized HKC-8 cells, providing evidence that endogenous EGF mediates the response to pressure. In ureteral obstruction, when pressure is elevated, phosphorylated EGFR was detected in the apical surface of the renal tubules, validating the in vitro findings. These data indicate that EGFR, NFkappaB, and STAT3 are required for human iNOS gene induction in response to pressure or EGF, indicating a similar mechanism of activation.
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PMID:Pressure activates epidermal growth factor receptor leading to the induction of iNOS via NFkappaB and STAT3 in human proximal tubule cells. 1940 42

The skin is the largest organ in the body and one of its main functions is to protect the body from environmental and endogenous noxious conditions, such as injury, infection and inflammation. The inducible nitric oxide synthase (iNOS) has been implicated as a key component in the inflammatory response. In the present study, we assessed the role of iNOS in the skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice deficient in iNOS had reduced edema and cellular infiltration in the skin following topical TPA application. Moreover, the genetic blockage of iNOS signaling inhibited the TPA-induced ERK and p38 activation resulting in reduced COX-2 upregulation. Finally, immunohistochemical studies revealed that iNOS knockout mice exhibited marked inhibition of AP-1, CREB and NF-kappaB transcriptional factors activation. Together, these results indicate that TPA induces the activation of several iNOS-dependent intracellular signaling pathways that have a key role in the control of inflammatory response in the skin. Therefore, selective iNOS inhibitors may be potentially relevant tools for cutaneous skin disease drug development.
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PMID:Reduced skin inflammatory response in mice lacking inducible nitric oxide synthase. 1940 74

Clinical and basic science data support an integral role of calcitonin gene-related peptide (CGRP) in the pathophysiology of temporomandibular joint disorders. Recently, we have shown that CGRP can stimulate the synthesis and release of nitric oxide (NO) from trigeminal ganglion glial cells. The goal of this study was to determine the role of mitogen-activated protein kinase (MAPK) signaling pathways in CGRP regulation of iNOS expression and NO release from cultured trigeminal ganglion glial cells from Sprague-Dawley rats. CGRP treatment for 2 h significantly increased activity of the MAPK reporter genes, Elk, ATF-2, and CHOP. In addition, CGRP increased nuclear staining for the active forms of the MAPKs: extracellular signal-regulated kinase, c-Jun amino-terminal kinase, and p38. This stimulatory event was not observed in cultures pre-treated with the CGRP receptor antagonist peptide CGRP(8-37). Similarly, pre-treatment with selective MAPK inhibitors repressed increases in reporter gene activity as well as CGRP-induced increases in iNOS expression and NO release mediated by MAPKs. In addition, over-expression of MAPK kinase 1 (MEK1), MEK3, MEK6, and MEK kinase significantly increased iNOS expression and NO production in glial cells. Results from our study provide evidence that CGRP binding to its receptor can stimulate iNOS gene expression via activation of MAPK pathways in trigeminal ganglion glial cells.
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PMID:CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involves mitogen-activated protein kinase pathways. 1945 95

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
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PMID:Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. 1947 86


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