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)

AP-1 has been shown to behave as a redox-sensitive transcription factor that can be activated by both oxidant and antioxidant stimuli. However, the mechanisms involved in the activation of AP-1 by antioxidants are largely unknown. In this study we show that the structurally unrelated antioxidant agents pyrrolidine dithiocarbamate (PDTC), butylated hydroxyanisole, and Nacetylcysteine activated JNK (c-Jun NH2-terminal kinase) in Jurkat T cells. This activation differed substantially from that mediated by phorbol 12-myristate 13-acetate (PMA) and Ca2+ ionophore or produced by costimulation with antibodies against the T cell receptor-CD3 complex and to CD28. The activation of JNK by classical T cell stimuli was transient, whereas that mediated by PDTC and butylated hydroxyanisole (but not N-acetylcysteine) was sustained. The kinetics of JNK activation correlated with the expression of c-jun which was transient after stimulation with PMA plus ionophore and prolonged in response to PDTC, which also transiently induced c-fos. In addition, JNK activation by PMA plus ionophore was sensitive to inhibitors of signaling pathways involving Ca2+, protein kinase C, and tyrosine phosphorylation, which failed to inhibit the activation mediated by PDTC. Transfection of trans-dominant negative expression vectors of ras and raf, together with AP-1-dependent reporter constructs, as well as Western blot analysis using anti-ERK (extracellular signal-regulated kinase) antibodies, indicated that the Ras/Raf/ERK pathway did not appear to mediate the effect of the antioxidant. However, the combined treatment with PDTC and PMA, two agents that synergize on AP-1 activation, resulted in the persistent phosphorylation of ERK-2. In conclusion, our results identify JNK as a target of antioxidant agents which can be regulated differentially under oxidant and antioxidant conditions.
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PMID:JNK (c-Jun NH2-terminal kinase) is a target for antioxidants in T lymphocytes. 882 87

The nuclear factor kappaB (NF-kappaB) is involved in T cell activation and enhances HIV-1 gene expression. It is activated in response to numerous stimuli, including oxidative stress. Oxidative stress damages membrane lipids, proteins and nucleic acids. We have shown previously that oxidative DNA damage generated by photosensitization could trigger activation of NF-kappaB. We now show that a series of topoisomerase poisons (actinomycin D, camptothecin, daunomycin and etoposide) also activate NF-kappaB (NFKB1/RelA dimer) in ACH-2 and CEM cells. This activation is inhibited by pyrrolidine dithiocarbamate. In ACH-2 cells latently infected by HIV-1, camptothecin, daunomycin and etoposide are able to enhance virus production. Since topoisomerase poisons cause the formation of single- and double-strand breaks in DNA, these lesions might be capable of triggering NF-kappaB activation. Indeed, DNA damaging agents generating adducts (trans-platin and 4-nitroquinoline 1-oxide) and/or crosslinks in DNA (cisplatin and mitomycin C) do not or only weakly activate NF-kappaB in T cell lines.
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PMID:Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells. 893 79

N-(2-hydroxyethyl)-pyrrolidine (HEP, Epolamine) is a strong base used to salify organic acids of pharmaceutical interest in order to improve their solubility in water. Diclofenac-HEP (Flector) is the first example of an epolamine salt of a drug. In this study, [14C]-HEP was administered by oral route (300 mg, about 50 microCi/subject) to 3 volunteers with the aim to investigate its plasma profile and to calculate the relevant pharmacokinetic parameters. The experimental data correlated with a two-compartment pharmacokinetic model. Total radioactivity in urine and faeces was also measured. The radioactivity was excreted preferentially by the faecal route (about 65% of the dose administered in the 0-72 h collection interval). Urinary excretion accounted for about 30% of the dose and occurred very rapidly (about 22% of the dose was in the 0-8 h collection interval). Metabolic investigations were carried out on urine samples. TLC analysis with radioscan detector indicated a main radioactive zone, accounting for about 98% of the radioactivity in the plate. After scraping off and purification of the radioactive areas, the compound isolated (Met I) was analysed by gas chromatography-mass spectrometry with electron-impact ionization process. The structure of the metabolite was postulated to be pyrrolidine N-oxide.
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PMID:Pharmacokinetics and metabolism of N-(2-hydroxyethyl)-2,5-[14C]-pyrrolidine (HEP, Epolamine) in male healthy volunteers. 898 Sep 26

Reactive oxygen species (ROS) such as hydrogen peroxide serve as second messengers in the induction of the transcription factor NF-kappaB, and hence in the activation and replication of human immunodeficiency virus type 1 (HIV-1) in human cells. During inflammatory reactions, many oxidative species are produced, one of which is hypochlorous acid (HOCl), which is responsible for the microbicidal effects of activated human polymorphonuclear leukocytes. Treatment of a T-lymphocytic cell line with micromolar concentrations of HOCl promoted the appearance of transcription factor NF-kappaB (the heterodimer p50/p65) in the nucleus of the cells, even in the absence of de novo protein synthesis. Western blot analysis of the NF-kappaB inhibitory subunits (IkappaB) demonstrated that both IkappaB-alpha proteolysis and p105 processing were induced by the treatment. NF-kappaB activation was very effective when cells were subjected to hyperthermia before being treated with HOCl. Various antioxidants, such as pyrrolidine dithiocarbamate, p-bromophenacyl-bromide and nordihydroguaiaretic acid could strongly reduce NF-kappaB translocation, demonstrating the importance of oxidative species in the transduction mechanism. Moreover, ACH-2 cells treated with HOCl or H2O2 released tumour necrosis factor-alpha (TNF-alpha) in the supernatants. The importance of TNF-alpha release in NF-kappaB induction by HOCl or H2O2 was demonstrated by the fact that: (1) the nuclear appearance of NF-kappaB was promoted in untreated cells; and (2) synergism between TNF-alpha and HOCl was detected. Collectively, these results suggest that HOCl should be considered as an oxidative species capable of inducing NF-kappaB in a T-lymphocytic cell line through a transduction mechanism involving ROS, and having a long-distance effect through subsequent TNF-alpha release.
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PMID:Activation of the NF-kappaB transcription factor in a T-lymphocytic cell line by hypochlorous acid. 903 66

Interleukin-10 (IL-10) is elevated in HIV-1-infected individuals and has been implicated in disease progression. We previously reported that IL-10 cooperates with tumor necrosis factor-alpha (TNF-alpha) to activate HIV-1 expression synergistically in acutely infected monocyte-derived macrophages and the chronically infected U1 promonocytic cell line. To determine whether IL-10 also cooperates with TNF-alpha to activate latent HIV-I expression in lymphocytes, we examined the effects of IL-10 on proviral expression in the chronically infected T-cell line, ACH-2. Although IL-10 inhibited HIV-1 expression acting alone, in combination with suboptimal concentrations of TNF-alpha, IL-10 increased HIV-1 steady-state mRNA expression and p24 core antigen production in ACH-2 cells. Interestingly, IL-10 concentrations that synergistically induced virus also maximally stimulated endogenous TNF-alpha expression, suggesting that cell-derived TNF-alpha may contribute to cytokine synergy. Transfection studies in ACH-2 cells indicated that IL-10 combined with TNF-alpha to activate the HIV-1 long terminal repeat (LTR). IL-10 also cooperated with TNF-alpha to activate HIV-1 LTR in 1G5 cells, a Jurkat T-cell line stably transfected with an LTR-dependent luciferase reporter gene. Pyrrolidine dithiocarbamate, a potent transcriptional inhibitor of the viral LTR, abrogated the cytokine responses in both U1 and ACH-2 cells, suggesting a common TNF-alpha-mediated transcriptional mechanism in these cell types despite their different modes of provirus latency. Taken collectively, these data suggest that IL-10 enhances suboptimal TNF-alpha activation of HIV-1 transcription in chronically infected T-cells at least in part through induction of endogenous TNF-alpha expression.
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PMID:Interleukin-10 enhances tumor necrosis factor-alpha activation of HIV-1 transcription in latently infected T cells. 983 40

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.
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PMID:Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes. 1094 Nov 51

Reactive oxygen species (ROS) generated during inflammation and aging contribute to the resorption of articular cartilage. Low antioxidant levels are a risk factor for arthritis because they protect cartilage from ROS. N-Acetylcysteine (NAC) is a ROS scavenger and, depending upon the concentration, an anti-inflammatory or prooxidant agent. Mechanisms of action for NAC were studied in primary human and bovine chondrocytes. NAC dose-dependently activated phosphorylation of extracellular signal-regulated kinases-mitogen-acivated protein kinases (ERK-MAPK). ERK activation peaked within 15 min and declined afterward up to 180 min. This activation was inhibited by the MAPKK inhibitor, PD098059. The induction was mimicked by other thiols, l-cysteine, reduced glutathione, and pyrrolidine dithiocarbamate (PDTC) but not by a nonthiol, N-acetylalanine. The total nonphosphorylated ERKs levels remained unaffected by these treatments. Activation of the ERK-MAPK pathway provides a mechanism for the reported promotion of chondrocyte survival by thiol antioxidants.
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PMID:Thiol antioxidant, N-acetylcysteine, activates extracellular signal-regulated kinase signaling pathway in articular chondrocytes. 1097

Genes encoding the catalytic (GCS(h)) and regulatory (GCS(l)) subunits of human gamma-glutamylcysteine synthetase (gammaGCS), which catalyzes the rate limiting step in glutathione synthesis, are up-regulated in response to xenobiotics through Electrophile Response Elements (EpREs). Exposure of HepG2 cells to the GCS-inducing agent, Pyrrolidine dithiocarbamate (PDTC), results in ERK and p38 MAP kinase activation. Inhibition of ERK or p38 kinases by PD98059 or SB202190, respectively, results in approximately 50% reduction in GCS gene induction, while simultaneous inhibition completely eliminates induction. Induction of GCS expression is associated with an increase in Nrf2 and JunD binding to GCS EpREs. Pretreatment with the MAPK inhibitors significantly reduces binding of both transcription factors. These studies indicate that ERK and p38 contribute to the transcriptional up-regulation of the GCS subunit genes following PDTC treatment. Furthermore, supershift analyses suggest that binding of Nrf2 and JunD to the EpRE is a downstream consequence of ERK and p38 phosphorylation events.
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PMID:Inhibition of ERK and p38 MAP kinases inhibits binding of Nrf2 and induction of GCS genes. 1109 62

Effects of endothelin-1 (ET-1) on glial cell line-derived neurotrophic factor (GDNF) production in cultured astrocytes were examined. Treatment of cultured astrocytes with ET-1 (100 nM) increased mRNA levels of GDNF in 1-6h. The effect of ET-1 was inhibited by BQ788, an ET(B) receptor antagonist, but not by FR139317, an ET(A) receptor antagonist. ET-1 stimulated release of GDNF into culture medium. Dexamethasone (1 microM) and pyrrolidine dithiocarbamate (PDTC, 100 microM), which inhibit activation of NFkappaB, prevented the increases in GDNF mRNA by H(2)O(2). In contrast, the effect of ET-1 was not affected by dexamethasone and PDTC. The increase of astrocytic GDNF mRNA by ET-1 was inhibited by BAPTA/AM (30 microM) and PD98059 (50 microM), but not by calphostin C, staurosporine, and cyclosporine A. These results suggest that ET-1 stimulated expression of astrocytic GDNF through ET(B) receptor-mediated increases in cytosolic Ca(2+) and ERK activation.
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PMID:Endothelin-1 stimulates glial cell line-derived neurotrophic factor expression in cultured rat astrocytes. 1268 49


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