Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.
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PMID:Modulation of human lymphocyte proliferative response with aging. 1177 24

Vitamin E-succinate (VES) induced monocvtic differentiation of HL-60 human leukemia cells. Treatment with VES increased the nitroblue tetrazolium reduction activity, and the expression of monocyte specific cell surface antigen, CD14 and c-fms. During the monocytic differentiation of HL-60 cells that were induced by VES, the phosphorylation of extracellular signal-regulated protein kinase (ERK) was increased by 12 h and then gradually decreased to a level that was similar to that of the control. However, the phosphorylation levels of p38 and JNK, as well as the expression levels of ERK, p38, and JNK, were unchanged by the VES treatment. Treatment with VES also induced hypophosphorylation of the retinoblastoma protein and an increase of the p21WAF1 protein level. VES-induced ERK phosphorylation was abolished by the ERK inhibitor, PD98059, which resulted in a remarkable prevention of VES-induced monocytic differentiation. Inhibition of the ERK activity by PD98059 also diminished the VES-induced p21WAF1 protein expression, but did not change the phosphorylation state of the retinoblastoma protein. Collectively, these data suggest that the ERK signaling pathway mediates the up-regulation of the p21xWAF1 expression that is induced by VES, which is required for monocytic differentiation of HL 60 cells.
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PMID:Expression of p21WAF1 is dependent on the activation of ERK during vitamin E-succinate-induced monocytic differentiation. 1191 63

Cyclooxygenase-2 (COX-2) appears to play an important role in inflammation and carcinogenesis, and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a hydrophilic azo compound known to generate free radicals. Because reactive oxygen species (ROS) are known to elevate COX-2 expression, we evaluated the effect of AAPH on the expression of COX-2 in a human keratinocyte cell line, HaCaT. When cells were exposed to AAPH, marked COX-2 induction was observed. To clarify the signaling mechanism involved, we next investigated the effects of AAPH upon three major subfamilies of the mitogen-activated protein kinases (MAPKs). AAPH caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase (JNK). Furthermore, we found that PD98059, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished AAPH-induced COX-2 expression and PGE(2) production, whereas JNK inhibitor did not suppress COX-2 expression or PGE(2) production by AAPH. These findings suggest that the ERK and p38 MAPK pathways, but not the JNK pathway, are involved in AAPH-induced inflammatory progression. In addition, we found that both the water-soluble Vitamin E derivative, Trolox, and the green tea constituent, (-)-epigallocatechin gallate (EGCG), diminished AAPH-induced COX-2 expression and p38 activation.
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PMID:Involvement of ERK AND p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells. 1499 26

Vitamin E derivative, RRR-alpha-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring form of vitamin E, delta-tocotrienol, and a novel vitamin E analog, alpha-tocopherol ether acetic acid analog [alpha-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, alpha-TEA and delta-tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no or lower levels of apoptosis in normal human mammary epithelial cells and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct alpha-TEA and delta-tocotrienol were identical to those previously reported for VES, that is, alpha-TEA- and delta-tocotrienol-induced apoptosis involved up-regulation of TGF-beta receptor II expression and TGF-beta-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (delta-tocotrienol) and a novel nonhydrolyzable vitamin E analog (alpha-TEA).
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PMID:Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. 1520 83

We investigated whether lipid peroxidation might influence activation of the mitogen activated protein kinase (MAPK) extracellular regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) in neointimal hyperplasia induced by flow interruption of carotid artery in mice. C57/BL6 mice were subjected to a complete ligation of the left common carotid artery or to a sham ligation. Animals were randomized to receive either IRFI-042, a Vitamin E-like inhibitor of lipid peroxidation (20 mg/kg/i.p., immediately after artery occlusion) or its vehicle (1 ml/kg of a NaCl-DMSO solution). The extent of lipid peroxidation (investigated by the means of conjugated dienes levels) and JNK and ERK activation were evaluated by Western blot analysis after blood flow interruption. ICAM-1 expression in injured arteries was investigated 4 days after artery ligation by the means of reverse transcriptase polymerase chain reaction (RT-PCR) and quantification of the ICAM-1 protein levels. Morphometric analysis of the structural alteration caused by the disruption of the arterial blood flow was performed 4 weeks after surgery. Flow interruption in the carotid artery resulted at 10 min, following occlusion in a marked increase in conjugated dienes tissue levels (5.8+/-0.44 DeltaABS/mg protein), caused at 30 min after occlusion peak increase in both ERK1/2 (45+/-8 integrated intensity) and JNK (38+/-6 integrated intensity) activities, enhanced ICAM-1 expression (1.5+/-0.45 relative amount of ICAM-1 mRNA) and ICAM-1 protein levels (55+/-12 pg/mg protein) and produced a marked neointimal hyperplasia (mean intimal area=101+/-14 microm2). Injured arteries harvested from IRFI-042-treated mice had reduced conjugated dienes tissue levels (2.9+/-0.5 DeltaABS/mg protein), attenuated ERK1/2 (19+/-6 integrated intensity) and JNK (2.9+/-0.5 integrated intensity) activities, blunted ICAM-1 expression (0.38+/-0.1 relative amount of ICAM-1 mRNA) and protein levels (26+/-8 pg/mg protein) and decreased neointimal hyperplasia (mean intimal area=4.5+/-1.5 microm2). Our data indicate that ERK1/2 and JNK kinases play a crucial role in neointimal hyperplasia induced by flow cessation in the mouse carotid artery. Furthermore, the present data suggest that lipid peroxidation triggers ERK and JNK activation.
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PMID:Lipid peroxidation triggers both c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) activation and neointimal hyperplasia induced by cessation of blood flow in the mouse carotid artery. 1569 37

(+/-)-2-Chloropropionic acid (2-CPA) is a neurotoxic compound which kills cerebellar granule cells in vivo, and makes cerebellar granule cells in vitro produce reactive oxygen species (ROS). We have studied the effect of 2-CPA on ROS formation in human neutrophil granulocytes in vitro. We found an increased formation of ROS after 2-CPA exposure using three different methods; the fluorescent probe DCFH-DA and the chemiluminescent probes lucigenin and luminol. Four different inhibitors of ROS formation were tested on the cells in combination with 2-CPA to characterize the signalling pathways. The spin-trap s-PBN, the ERK1/2 inhibitor U0126 and the antioxidant Vitamin E inhibited the 2-CPA-induced ROS formation completely, while the mitochondrial transition permeability pore blocker cyclosporine A inhibited the ROS formation partly. We also found that 2-CPA induced an increased nitric oxide production in the cells by using the Griess reagent. The level of reduced glutathione, measured with the DTNB assay, was decreased after exposure to high concentrations of 2-CPA. Western blotting analysis showed that 2-CPA exposure led to an elevated phosphorylation of ERK MAP kinase. This phosphorylation was inhibited by U0126. Based on these experiments it seems like the mechanisms for 2-CPA induced toxicity involves ROS formation and is similar in neutrophil granulocytes as earlier shown in cerebellar granule cells. This also implies that 2-CPA may be immunotoxic.
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PMID:(+/-)-2-Chloropropionic acid elevates reactive oxygen species formation in human neutrophil granulocytes. 1700 89

An altered vascular reactivity is an important manifestation of the hemodynamic and renal dysfunction during liver cirrhosis. Oxidative stress-derived substances and nitric oxide (NO) have been shown to be involved in those alterations. In fact, both can affect vascular contractile function, directly or by influencing intracellular signaling pathways. Nevertheless, it is unknown whether oxidative stress contributes to the impaired systemic and renal vascular reactivity observed in cirrhosis. To test this, we evaluated the effect of vitamin E supplementation (5,000 IU/kg diet) on the vasoconstrictor and vasodilator responses of isolated perfused kidneys and aortic rings of rats with cirrhosis induced by bile duct ligation (BDL), and on the expression of renal and aortic phospho-extracellular regulated kinase 1/2 (p-ERK1/2). BDL induced a blunted renal vascular response to phenylephrine and ACh, while BDL aortic rings responded less to phenylephrine but normally to ACh. Cirrhotic rats had higher levels of oxidative stress-derived substances [measured as thiobarbituric acid-reactive substances (TBARS)] and NO (measured as urinary nitrite excretion) than controls. Vitamin E supplementation normalized the renal hyporesponse to phenylephrine and ACh in BDL, although failed to modify it in aortic rings. Furthermore, vitamin E decreased levels of TBARS, increased levels of NO, and normalized the increased kidney expression of p-ERK1/2 of the BDL rats. In conclusion, BDL rats showed a blunted vascular reactivity to phenylephrine and ACh, more pronounced in the kidney and reversed by vitamin E pretreatment, suggesting a role for oxidative stress in those abnormalities.
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PMID:Vitamin E supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats. 1715 69

Carbon tetrachloride (1 ml/kg body weight as a 1:1 mixture of CCl(4) and mineral oil) was orally administered to rats. After 12 h, the activity of plasma ALT (alanine aminotransferase) was significantly higher than that of the control group, and plasma ALT and AST (aspartate aminotransferase) activities significantly increased 24 h after CCl(4) administration. These results indicated that the necrotic process had initiated at about 12 h and developed thereafter. After 6-24 h of CCl(4) administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after CCl(4) intoxication and thereafter. Oral administration of vitamin E (1 ml/kg body weight as a 1:1 mixture of alpha-tocopherol and mineral oil) 12 h before CCl(4) administration caused a significant elevation of liver vitamin E level and ameliorated liver necrosis 24 h after CCl(4) intoxication based on plasma AST and ALT. Vitamin E also significantly restored the hepatic vitamin C concentration 12 and 24 h after CCl(4) intoxication, demonstrating that vitamin E functioned as an antioxidant. The liver vitamin E concentration was not changed by vitamin E supplementation to rats that did not receive CCl(4). This result indicated that vitamin E accumulated in the damaged liver. The activation of JNK, ERK1/2 and p38 MAPK took place 1.5 h after CCl(4) administration. Co-administration of alpha-tocopherol with CCl(4) did not affect these early changes in MAPKs.
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PMID:Effect of alpha-tocopherol on carbon tetrachloride intoxication in the rat liver. 1906 52

Cypermethrin (CYP), an insecticide, has deleterious effects on male reproductive function. The objective was to identify whether the effects of beta-CYP on male reproductive organs were associated with oxidative stress. Three doses of beta-CYP (1, 10, and 20mg/kg) were administered to male mice for 35 d, with or without vitamin E (20mg/kg). The moderate (10mg/kg) and high (20mg/kg) doses of beta-CYP not only decreased body weight and the weight of the testes, epididymides, seminal vesicles, and prostate (P<0.05) but also reduced serum testosterone concentration and the expression of steroidogenic acute regulatory protein (P<0.05), in addition to damaging the seminiferous tubules and sperm development. Furthermore, moderate and high doses of beta-CYP administration decreased sperm number, sperm motility, and intact acrosome rate (P<0.05). Based on ultrastructural analyses, high doses of beta-CYP produced swelling and degeneration of mitochondria and the smooth endoplasmic reticulum of Leydig cells and caused the formation of concentric circles. These toxic effects of beta-CYP may be mediated by increasing oxidative stress, as the moderate and high doses of this compound increased malondialdehyde and nitric oxide in testes (P<0.05); reduced the activity of catalase, glutathione peroxidase (GSH-Px), and superoxide dismutase (P<0.05); and activated ERK1/2 (P<0.05). Vitamin E reversed the effects of beta-CYP on testosterone production and testis damage (P<0.05 vs. the high-dose group). Therefore, we inferred that beta-CYP damaged the structure of testes and decreased sperm output by inducing oxidative stress.
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PMID:Beta-cypermethrin impairs reproductive function in male mice by inducing oxidative stress. 1950 Aug 28

Vitamin E succinate (RRR-alpha-tocopheryl succinate, VES), an efficient inducer of apoptosis, acts as a potent agent for cancer therapy. However, the mechanism by which VES mediates the effects are not yet fully understood. Here we studied the effect of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) on VES-induced apoptosis of SGC-7901 human gastric cancer cells. VES caused cytological changes typical of apoptosis, increased ER dilation and cytosolic Ca(2+) concentration. And endogenous ER stress markers, GRP78 and GRP94 were transcriptionally and translationally altered. In response to VES, induction of CHOP, activation of caspase-4 and JNK were observed. Furthermore, VES also triggered activation of UPR components, including RNA-dependent protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6), X-box-binding protein 1 (XBP1), and ATF4 in a concentration- and time-dependent manner. Consequently, our results suggest that VES-induced apoptosis is coupled to ER stress and UPR activation in SGC-7901 human gastric cancer cells.
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PMID:Endoplasmic reticulum stress contributes to vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. 2043 8


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