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)

In the present study, we report the inhibitory effect of equol on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression in murine macrophages. In vivo administration of equol (i.p.) attenuated NO production by peritoneal adherent cells isolated from lipopolysaccharide (LPS)-treated mice. Equol dose-dependently inhibited the LPS-induced production of NO in isolated peritoneal adherent cells and RAW 264.7 cells. The mRNA expression of iNOS was also blocked by equol in LPS-stimulated RAW 264.7 cells. Further study demonstrated that the LPS-induced activation of Akt was suppressed by equol in RAW 264.7 cells while the activation of ERK, SAPK/JNK and p38 MAP kinase was not affected. Equol also blocked LPS-induced NF-kappaB activation. Moreover, the LPS-induced NO production and NF-kappaB activation was inhibited by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase/Akt pathway, in RAW 264.7 cells. These results suggest that equol might inhibit NO production and iNOS gene expression, at least in part, by blocking Akt activation and subsequent down-regulation of NF-kappaB activity.
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PMID:Equol inhibits nitric oxide production and inducible nitric oxide synthase gene expression through down-regulating the activation of Akt. 1732 72

Alpha-galactosylceramide (alpha-GalCer), a bioactive glycolipid isolated from the marine sponge Agelas mauritianus, is a potent immunomodulator with therapeutic potential for the treatment of autoimmune diseases and cancer. The Toll-like receptor 4 (TLR4), one of the promising molecular targets for immune-modulating drugs, is commonly expressed in innate immune cells especially macrophages and dendritic cells. Currently, whether alpha-GalCer can activate TLR4 signaling pathways remains unreported. In this study, we examined the effects of alpha-GalCer and its various structural analogs, CCL-1 approximately 47, on TLR4 activation. We found that one alpha-GalCer analog (CCL-34), but not alpha-GalCer itself, strongly stimulated NF-kappaB activity in RAW 264.7 cells. CCL-34 activated NF-kappaB in a TLR4-dependent manner and stimulated TNF-alpha production in bone marrow cells of TLR4-functional C3H/HeN mice but not in those of TLR4-defective C3H/HeJ mice. Furthermore, CCL-34 treatment stimulated NF-kappaB activation and IL-8 production in a 293 cell line constitutively expressing human TLR4, MD-2 and CD14. Treatment of RAW 264.7 cells with CCL-34 also activated TLR4-downstream mitogen-activated protein kinases (ERK, JNK and p38), induced expression of TLR4-downstream genes (TNF-alpha, IL-6, IL-1beta and iNOS) and promoted production of cytokines characteristic of activated macrophages. CCL-34-treated RAW 264.7 cells acquired a distinct morphology similar to that of LPS-activated macrophages and exhibited higher phagocytotic activity. Moreover, treatment with a TLR4-neutalizing antibody inhibited the CCL-34-induced morphological alteration. In summary, we identify a novel synthetic compound CCL-34 that can activate macrophages via TLR4-dependent signaling pathways. Our results suggest that CCL-34 is an immune modulator and may serve as a potential drug lead for immunotherapy.
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PMID:A synthetic analog of alpha-galactosylceramide induces macrophage activation via the TLR4-signaling pathways. 1744 76

Redox sensitive, pro-inflammatory nuclear transcription factor NF-kappaB plays a key role in both inflammation and aging processes. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-kappaB through diverse kinases. Thus, the search and characterization of new substances that modulate NF-kappaB are of recent research interest. Cinnamaldehyde (CNA) is the major component of cinnamon bark oil, which has been widely used as a flavoring agent in foodstuffs such as beverages and ice cream. In the present study, CNA was examined for its molecular modulation of inflammatory NF-kappaB activation via the redox-related NIK/IKK and MAPK pathways through the reduction of oxidative stress. Results show that age-related NF-kappaB activation upregulated NF-kappaB targeting genes, inflammatory iNOS, and COX-2, all of which were inhibited effectively by CNA. Our study further shows that CNA inhibited the activation of NF-kappaB via three signal transduction pathways, NIK/IKK, ERK, and p38 MAPK. Our results indicate that CNA's antioxidative effect and the restoration of redox balance were responsible for its anti-inflammatory action. Thus, the significance of the current study is the new information revealing the anti-inflammatory properties of CNA and the role it plays in the regulation of age-related alterations in signal transduction pathways.
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PMID:Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. 1748 22

Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P(2)) has been known to serve as a substrate for phosphatidylinositol 3-kinase (PI(3)K) and phosphoinositide-specific phospholipase C (PI-PLC), which can produce PtdIns(3,4,5)P(3) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) and diacylglycerol (DAG), respectively. In this study, we elucidated the role of PI-PLC during the LPS-activated mouse macrophages RAW264.7 treated with PI(3)K inhibitor wortmannin. First, wortmannin treatment enhanced Ins(1,4,5)P(3) production and iNOS expression in LPS-activated macrophages. Inhibition of PI(3)K by p85 siRNA also showed an enhancement of iNOS expression. On the other hand, overexpression of PI(3)K by ras-p110 expression plasmid significantly decreased iNOS expression in LPS-activated macrophages. In addition, overexpression of wild-type or dominant-negative Akt expression plasmid did not affect the iNOS expression in LPS-activated macrophages. Second, treatment of PI-PLC inhibitor U73122 reversed the enhancement of iNOS expression, the increase of phosphorylation level of ERK, JNK and p38, and the increase of AP-1-dependent gene expression in wortmannin-treated and LPS-activated macrophages. However, NF-kappaB activity determined by EMSA assay and reporter plasmid assay did not change during LPS-activated macrophages with or without wortmannin. We propose that the inhibition of PI(3)K by wortmannin in mouse macrophages enhances the PI-PLC downstream signals, and subsequently increases the LPS induction of iNOS expression independently of Akt pathway.
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PMID:Switch activation of PI-PLC downstream signals in activated macrophages with wortmannin. 1748 50

Activation of microglia has been increasingly associated with the pathogenesis of several neurodegenerative disorders including Parkinson's and Alzheimer's diseases, and the suppression of microglial activation may lead to alleviation of the progression of neurodegeneration in these diseases. We sought to investigate whether Phellodendri cortex (PC) that has been used for centuries in Chinese traditional medicine for the treatment of various inflammatory conditions, inhibits production of anti-inflammatory cytokines and nitric oxide (NO) in microglia, and further studied the molecular and cellular mechanisms that govern these anti-inflammatory effects. The methanol extract of PC (PC extract) attenuated LPS-stimulated increase in production of TNF-alpha, IL-1beta, and NO in BV2 cells, a mouse microglia cell line, as well as in primary mouse microglia. The RNase protection assay and RT-PCR revealed that the PC extracts inhibited increases in mRNAs of these cytokines and iNOS in LPS-stimulated BV2 cells. The PC extracts significantly decreased release of these cytokines and NO from LPS-stimulated microglia in a dose-dependent manner. Molecular mechanisms that govern attenuation of the levels of mRNAs and proteins of these cytokines and iNOS revealed that the PC extract inhibited LPS-stimulated phosphorylation of ERK and activation of NF-kappaB. The studies demonstrate that the PC extract effectively inhibits microglial production and release of inflammatory cytokines and NO, and could be a candidate agent for anti-inflammation in neurodegenerative human brain diseases.
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PMID:Inhibition of gene expression and production of iNOS and TNF-alpha in LPS-stimulated microglia by methanol extract of Phellodendri cortex. 1749 98

LCY-2-CHO has anti-inflammatory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of anti-inflammatory and inflammatory proteins in cultured rat aortic vascular smooth muscle cells (VSMC). LCY-2-CHO is able to induce heme oxygenase-1 (HO-1) protein expression through a transcriptional action. The HO-1 inducting effect of LCY-2-CHO was inhibited by SB203580, N(G)-nitro-l-arginine methylester (l-NAME), and wortmannin, but was not affected by U0126 or SP600125. In accordance LCY-2-CHO increased protein phosphorylation of p38, Akt, and eNOS. Nrf2 is a transcription factor essential for HO-1 gene induction and we showed that LCY-2-CHO is able to cause Nrf2 nuclear translocation and this action depends on p38, Akt and eNOS. In addition to induce anti-inflammatory HO-1, LCY-2-CHO reduced interleukin-1beta (IL-1beta)-induced inflammatory mediators, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), growth-related oncogene protein-alpha (GRO-alpha), and interleukin-8 (IL-8). Inhibitory effect on IL-1beta-mediated NF-kappaB activation was evidenced by the diminishment of IkappaB kinase (IKK) phosphorylation and IkappaBalpha degradation. In contrast, IL-1beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1beta and LCY-2-CHO displayed the non-additivity. Taken together, given the overall anti-inflammatory properties of LCY-2-CHO in VSMC, in terms to induce HO-1 gene expression and inhibit inflammatory gene expression, these results highlight the therapeutic potential of LCY-2-CHO in atherosclerosis.
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PMID:The anti-inflammatory actions of LCY-2-CHO, a carbazole analogue, in vascular smooth muscle cells. 1749 20

Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
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PMID:Molecular targets of curcumin. 1756 14

Recent studies suggest AMP-activated protein kinase (AMPK), an enzyme involved in energy homeostasis, might be a novel signaling pathway in regulating inflammatory response, but the precise intracellular mechanisms are not fully understood. In this study, we have demonstrated that 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, inhibited lipopolysaccharide (LPS)-induced protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in macrophages and microglial cells at the gene transcription level. Data obtained from electrophoretic mobility shift assay (EMSA) and promoter activity assay have further confirmed the ability of AICAR to block LPS-mediated NF-kappaB, AP-1, CREB, and C/EBPbeta activation. However, AICAR did not affect LPS-mediated IKK, ERK, and p38 activation. Regardless of the ability of AICAR to activate AMPK, the inhibitory effects of AICAR on iNOS and COX-2 expression were not associated with AMPK. An adenosine kinase inhibitor 5'-iodotubercidin, which effectively abolished AMPK activation caused by AICAR, did not reverse the anti-inflammatory effect of AICAR. Moreover, another AMPK activator metformin was not able to mimic the effects of AICAR. Direct addition of AICAR in EMSA assay interrupted binding of NF-kappaB, CREB, and C/EBPbeta to specific DNA elements. Taken together, this study demonstrates that the anti-inflammatory effects of AICAR against LPS-induced iNOS and COX-2 gene transcription are not associated with AMPK activation, but might be resulting from the direct interference with DNA binding to transcription factors.
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PMID:Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. 1761 55

Hypothermic perfusion is a standard method for neuroprotection during cardiac surgery in children. However, the cellular responses underlying these mechanisms have not been clearly elucidated. In the present study we demonstrated that the inflammatory response of stimulated microglial cells is significantly reduced after moderate hypothermia. Continuous hypothermia caused a diminished NO release. Moderate hypothermia and rewarming caused a downregulation of phosphorylated MEK, ERK and iNOS-expression, diminished cytokine release and reduced CD-11a and ICAM-1 expression. Thus, neuroprotection offered by hypothermia could be attributed to reduced cytotoxic products released from stimulated microglial cells mediated by the MEK/ERK signal transduction pathway.
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PMID:Hypothermia suppresses inflammation via ERK signaling pathway in stimulated microglial cells. 1765 18

Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-alpha and Il-1beta) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries.
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PMID:Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries. 1782 93


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