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

---

Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In macrophages, nuclear factor kappa B (NF-kappaB) activation has important roles for the regulation of an inducible nitric oxide synthase (iNOS), several pro-inflammatory cytokines, and anti-apoptotic proteins. In order to analyze the transactivation process of NF-kappaB by lipopolysaccharide (LPS), we used the GAL4-NF-kappaB-p65 fusion protein. This chimeric NF-kappaB is activated transcriptionally only if NF-kappaB transactivation domain is active. With this system, we found that LPS can enhance the transactivation of GAL-NF-kappaB-p65 subunit independent of DNA binding ability and inhibitor of kappaB (IkappaB) regulation. Interestingly, this transactivation by LPS was eliminated with the treatment of U0126, specific inhibitor of mitogen-activated protein kinase (MAPK) kinases (MEKs) 1/2 which has little effect on NF-kappaB activation. We also investigated the effect of inhibitors of apoptosis (IAPs), which might be involved in LPS responses and c-Jun amino terminal kinase (JNKs) activation, on the transactivation of GAL-NF-kappaB-p65. The cIAP1, cIAP2 and XIAP could enhance the NF-kappaB transcription and the chimeric NF-kappaB-p65 transactivation. However, survivin decreased the NF-kappaB transcription and did not influence significantly the chimeric NF-kappaB-p65 transactivation. Taken together, LPS-dependent NF-kappaB transactivation may be involved in extracellular signal-regulated kinase (ERK) pathway and IAPs.
...
PMID:Modulation of the transactivation function of nuclear factor-kappaB by lipopolysaccharide in RAW264.7 macrophages. 1537 59

We previously reported that injury-induced medial vascular smooth muscle cell (VSMC) proliferation and neointima formation in carotid arteries of inducible nitric oxide synthase knockout (iNOS KO) mice were significantly reduced compared with wild type (WT). However, the molecular pathway underlying such differences is not known. In this in vitro study, we discovered that the AP-1/Ref-1/thioredoxin signaling pathway is altered in aortic VSMC from iNOS KO mice, which leads to reduced growth response when compared with aortic VSMC from WT mice. After equal initial seeding, the cell number after 7 days in serum medium was less in iNOS KO cells compared with WT VSMC (1.2 +/- 0.6 x 10(5) vs 3.2 +/- 1.1 x 10(5); p < 0.05). Significantly more iNOS KO cells remained in the G0/G1 phase compared with WT cells after 24-h serum treatment (82.6 +/- 13.7% vs 62.3 +/- 14.6%; p < 0.05) by cell-cycle analysis. Nuclear PCNA expression was also less in the iNOS KO cells, which was not affected by exogenous NO or superoxide. Superoxide generation after 24-h serum stimulation was less in the iNOS KO cells compared with WT cells. After 30-min serum stimulation, AP-1 DNA binding was reduced and a lack of increase in nuclear c-Jun protein was observed in iNOS KO VSMC. RT-PCR analysis confirmed a lack of inducible c-Jun mRNA after serum stimulation in the KO cells. In addition, KO cells had less nuclear reducing factor-1 (Ref-1) and serum-inducible thioredoxin protein expression. Reduced proliferative response of iNOS KO VSMC to serum treatment is associated with altered AP-1 /Ref-1 /thioredoxin pathway activation.
...
PMID:Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells. 1567 81

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-kappaB pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.
...
PMID:Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. 1581 1

We have reported recently that intrathecal (i.t.) injection of interleukin-1beta (IL-1beta), at a dose of 100 ng, induces inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in the spinal cord and results in thermal hyperalgesia in rats. This study further examines the role of mitogen-activated protein kinase (MAPK) in i.t. IL-1beta-mediated iNOS-NO cascade in spinal nociceptive signal transduction. All rats were implanted with an i.t. catheter either with or without an additional microdialysis probe. Paw withdrawal latency to radiant heat is used to assess thermal hyperalgesia. The iNOS and MAPK protein expression in the spinal cord dorsal horn were examined by western blot. The [NO] in CSF dialysates were also measured. Intrathecal IL-1beta leads to a time-dependent up-regulation of phosphorylated p38 (p-p38) MAPK protein expression in the spinal cord 30-240 min following IL-1beta injection (i.t.). However, neither the phosphorylated extracellular signal-regulated kinase (p-ERK) nor phosphorylated c-Jun NH2-terminal kinase (p-JNK) was affected. The total amount of p38, ERK, and JNK MAPK proteins were not affected following IL-1beta injection. Intrathecal administration of either selective p38 MAPK, or JNK, or ERK inhibitor alone did not affect the thermal nociceptive threshold or iNOS protein expression in the spinal cord. However, pretreatment with a p38 MAPK inhibitor significantly reduced the IL-1beta-induced p-p38 MAPK expression by 38-49%, and nearly completely blocked the subsequent iNOS expression (reduction by 86.6%), NO production, and thermal hyperalgesia. In contrast, both ERK and JNK inhibitor pretreatments only partially (approximately 50%) inhibited the IL-1beta-induced iNOS expression in the spinal cord. Our results suggest that p38 MAPK plays a pivotal role in i.t. IL-1beta-induced spinal sensitization and nociceptive signal transduction.
...
PMID:Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. 1603 22

6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is an active ingredient of Wasabi (Wasabia japonica (Miq.) Matsumura), which is a very popular pungent spice in Japan. To clarify the cellular signaling mechanism underlying the anti-inflammatory action of 6-MITC, we investigated the effects of 6-MITC on the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. 6-MITC showed a dose-dependent inhibition of LPS-induced nitric oxide (NO), iNOS mRNA and protein. LPS caused the c-Jun phosphorylation (a major component of AP-1) and IkappaB-alpha degradation. 6-MITC suppressed LPS-induced c-Jun phosphorylation, but did not inhibit IkappaB-alpha degradation. Cellular signaling analysis using MAPK-(U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) and Jak2-specific (AG490) inhibitors demonstrated that LPS stimulated iNOS expression via activating Jak2-mediated JNK, but not ERK and p38, pathway. 6-MITC suppressed iNOS expression through the inhibition of Jak2-mediated JNK signaling cascade with the attendant to AP-1 activation. In addition, the structure-activity study revealed that the inhibitory potency of methylsulfinyl isothiocyanates (MITCs) depended on the methyl chain length. These findings provide the molecular basis for the first time that 6-MITC is an effective agent to attenuate iNOS production.
...
PMID:6-(Methylsulfinyl)hexyl isothiocyanate suppresses inducible nitric oxide synthase expression through the inhibition of Janus kinase 2-mediated JNK pathway in lipopolysaccharide-activated murine macrophages. 1613 49

In response to endogenous and exogenous stimuli, macrophages are activated to produce a cocktail of proinflammatory and anti-apoptotic mediators, thereby participating in the processes of inflammation-associated oncogenesis. Cereals, including corn and rice, have biological potentials to synthesize self-protective chemicals in order to repel the invasion of microorganisms and insects. We examined the suppressive effects of several fatty acids, including a new class of lipoxygenase metabolites of linoleic acid (LA) found in cereals, namely (+/-)-9-hydroxy-trans,cis-10,12-octadecadienoic acid (9-HOA from rice), (+/-)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA from corn), and (+/-)-10-oxo-trans-11-octadecen-13-olide (10-ODO from corn), on lipopolysaccharide (LPS)-induced mRNA expression of proinflammatory mediators in RAW264.7 murine macrophages. Each metabolite exhibited a suppressive activity toward nitrite production than LA, octadeca-9Z,11E-dienoic acid (a conjugated LA), and 13S-hydroxyoctadeca-9Z,11E-dienoic acid. LPS-up-regulated mRNA expression of inducible nitric oxide synthase, cyclooxygenase (COX)-2, interleukin-6, and toll-like receptor-2, -4, and -9 was also markedly attenuated without affecting the expression levels of several constitutive genes, including COX-1, as detected by reverse transcription-polymerase chain reactions. In addition, Western blot and luciferase reporter assay results showed that 13-HOA suppressed the phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinasel/2, c-Jun N-terminal kinasel/2, p38 mitogen-activated protein kinase), and Akt (Ser473), and also attenuated degradation of inhibitor kappaB, nuclear translocation of nuclear factor kappaB (NFkappaB), and the transcriptional activities of NFkappaB and activator protein-1, both of which have essential roles in the transcription of numerous proinflammatory and oncogenic genes. In contrast, 13-HOA did not serve as a ligand for peroxisome proliferator-activated receptor-gamma. Based on our findings, we propose that 13-HOA, a functionally novel LA-derivative, is a promising agent for anti-inflammatory and chemopreventive strategies with reasonable molecular mechanisms.
...
PMID:New class of linoleic acid metabolites biosynthesized by corn and rice lipoxygenases: suppression of proinflammatory mediator expression via attenuation of MAPK- and Akt-, but not PPARgamma-, dependent pathways in stimulated macrophages. 1614 12

Basic calcium phosphate (BCP) crystals, including hydroxyapatite, octacalcium phosphate (OCP) and carbonate-apatite, have been associated with severe osteoarthritis and several degenerative arthropathies. Most studies have considered the chondrocyte to be a bystander in the pathogenesis of calcium crystal deposition disease, assuming that synovial cell cytokines were the only triggers of chondrocyte activation. In the present study we identified direct activation of articular chondrocytes by OCP crystals, which are the BCP crystals with the greatest potential for inducing inflammation. OCP crystals induced nitric oxide (NO) production and inducible nitric oxide synthase (NOS) mRNA expression by isolated articular chondrocytes and cartilage fragments, in a dose-dependent manner and with variations over time. OCP crystals also induced IL-1beta mRNA expression. Using pharmacological and cytokine inhibitors, we observed that OCP crystals induced NO production and inducible NOS mRNA activation were regulated at both the transcriptional and the translational levels; were independent from IL-1beta gene activation; and involved p38 and c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, as further confirmed by OCP crystal-induced p38 and JNK MAPK phosphorylation. Taken together, our data suggest that the transcriptional inducible NOS response to OCP crystals involved both the p38 and the JNK MAPK pathways, probably under the control of activator protein-1. NO, a major mediator of cartilage degradation, can be directly produced by BCP crystals in chondrocytes. Together with synovial activation, this direct mechanism may be important in the pathogenesis of destructive arthropathies triggered by microcrystals.
...
PMID:Octacalcium phosphate crystals directly stimulate expression of inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in articular chondrocytes. 1620 33

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH(2)-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-alpha, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-gamma and IFN-beta were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-alpha and IL-1beta also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.
...
PMID:The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury. 1641 Mar 67

Inflammatory responses stimulated by bacterial endotoxin LPS involve Ca2+-mediated signaling, yet the cellular sensors that determine cell fate in response to LPS remain poorly understood. We report that exposure of RAW 264.7 macrophage-like cells to LPS induces a rapid increase in CaM abundance, which is associated with the modulation of the inflammatory response. Increases in CaM abundance precede nuclear localization of key transcription factors (i.e., NF-kappaB p65 subunit, phospho-c-Jun, Sp1) and subsequent increases in the proinflammatory cytokine TNF-alpha and inducible nitric oxide synthase (iNOS). Cellular apoptosis after LPS challenge is blocked upon inhibition of iNOS activity using the pharmacological inhibitor 1400W. LPS-mediated iNOS expression and apoptosis also were inhibited by siRNA-mediated silencing of TNF induction, indicating TNF induction both precedes and is necessary for subsequent regulation of iNOS expression. Increasing the level of cellular CaM by stable transfection results in reductions in LPS-induced expression of TNF and iNOS, along with reduced activation of their transcriptional regulators and concomitant protection against apoptosis. Thus the level of CaM available for Ca2+-dependent signaling regulation plays a key role in determining the expression of the proinflammatory and proapoptotic cascade during cellular activation by LPS. These results indicate a previously unrecognized central role for CaM in maintaining cellular homeostasis in response to LPS such that, under resting conditions, cellular concentrations of CaM are sufficient to inhibit the biosynthesis of proinflammatory mediators associated with macrophage activation. Although CaM and iNOS protein levels are coordinately increased as part of the oxidative burst, limiting cellular concentrations of CaM due to association with iNOS (and other high-affinity binders) commit the cell to an unchecked inflammatory cascade leading to apoptosis.
...
PMID:Functional link between TNF biosynthesis and CaM-dependent activation of inducible nitric oxide synthase in RAW 264.7 macrophages. 1642 Dec 3

This work aimed to elucidate the anti-inflammatory mechanism of the n-BuOH subfraction (PL) prepared from fruiting bodies of Phellinus linteus. PL induced heme oxygenase-1 (HO-1) of the RAW264.7 macrophages in concentration- and time-dependent manner. It suppressed induction of inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO) through down-regulation of iNOS promoter activity in lipopolysaccharide (LPS)-stimulated macrophages. Zn(II) protoporphyrin IX (ZnPP), a specific inhibitor of HO-1, partly blocked suppression by PL on iNOS promoter activity and NO production, which were elevated in LPS-stimulated macrophages. LPS was able to enhance NO production via reactive oxygen species (ROS) generation, c-Jun NH(2)-terminal kinase (JNK) and c-Jun induction. ZnPP prevented PL from down-regulating ROS generation and JNK activation in LPS-stimulated macrophages. Taken together, PL shows its anti-inflammatory activity via mediation of HO-1 in an in vitro inflammation model.
...
PMID:Heme oxygenase-1 mediates the anti-inflammatory effect of mushroom Phellinus linteus in LPS-stimulated RAW264.7 macrophages. 1648 96


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---