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)

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
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PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 agonist, causes airway hyperreactivity through nuclear factor-kappaB (NF-kappaB). Because NF-kappaB induces cyclooxygenase-2 (COX-2) to increase synthesis of prostaglandins (PGs), including the potent airway anti-inflammatory and smooth muscle relaxant PGE(2), we investigated whether LPS causes short-term PGE(2)-dependent relaxation of mouse isolated trachea. In rings of trachea contracted submaximally with carbachol, LPS caused slowly developing, epithelium-dependent relaxations that reached a maximum within 60 min. Fluorescence immunohistochemistry revealed TLR4-like immunoreactivity localized predominantly to the epithelium. The LPS antagonist polymixin B; the nonselective COX inhibitor indomethacin; the selective COX-1 and COX-2 inhibitors 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560) and 4-[5-(4-chlorophenyl)-1-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide (SC236), respectively; the transcription inhibitor actinomycin D; the translation inhibitor cycloheximide; the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imadazole (SB203580); and a combination of the mixed DP/EP1/EP2 receptor antagonist 6-isopropoxy-9-xanthone-2-carboxylic acid (AH6809) and the EP4 receptor antagonist 4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1-5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide (L-161982) all abolished relaxation to LPS, giving instead slowly developing, small contractions over 60 min. The cytosolic phospholipase A(2) (cPLA(2)) inhibitor 1,1,1-trifluoro-6Z,9Z, 12Z,15Z-heneicosateraen-2-one significantly (p < 0.05) inhibited the relaxation to LPS, whereas the NF-kappaB proteasomal inhibitor Z-Leu-Leu-Leu-aldehyde (MG-132) had no affect on the relaxation in the first 20 min, after which it reversed the response to a contraction. In conclusion, our data indicate that LPS activates airway epithelial TLR4 to cause release of PGE(2) and subsequent EP2 and EP4 receptor-dependent smooth muscle relaxation. Activation of both COX-1 and COX-2 seems to be essential for this novel response to LPS, which also involves cPLA(2), p38 MAPK, NF-kappaB, and an unidentified NF-kappaB-independent, labile regulatory protein.
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PMID:Lipopolysaccharide induces epithelium- and prostaglandin E(2)-dependent relaxation of mouse isolated trachea through activation of cyclooxygenase (COX)-1 and COX-2. 1646 66

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various such electrophilic compounds. In this study, the regulatory effects of acrolein upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein induces the elevation of HO-1 protein levels, and subsequent enzyme activity, at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was also found to increase HO-1 expression and have less cytotoxicity than acrolein. Moreover, acrolein-mediated HO-1 induction is abrogated in the presence of actinomycin D and cycloheximide. Nrf2 is a transcription factor involved in the induction of HO-1 through an antioxidant response element (ARE) in the promoter region of the HO-1 gene. We show that acrolein induces Nrf2 translocation and ARE-luciferase reporter activity. Acrolein was also found to induce the production of both superoxide and H2O2 at levels greater than 100 microM. However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs. Our present findings suggest that reactive oxygen species (ROS) may not be a major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further enhanced the effects of acrolein. We also found that cellular GSH level was rapidly reduced after both 10 and 100 microM acrolein treatment. However, after 6 h of exposure to ECs, only 10 microM acrolein treatment increases GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had any significant inhibitory impact upon the upregulation of HO-1 by acrolein. Pretreatment with a range of other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show in our current experiments that a sublethal concentration of acrolein is in fact a novel HO-1 inducer, and we further identify the principal underlying mechanisms involved in this process.
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PMID:Upregulation of endothelial heme oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein. 1648 Jul 51

Aldehydes are widespread environmental and industrial compounds, which cause cytotoxicity, tissue damage, mutagenicity, and carcinogenicity leading to various disease conditions such as cardiovascular, bronchial, and visual complications. We have shown earlier that aldose reductase (AR) besides reducing glucose to sorbitol, efficiently reduces various toxic lipid-derived aldehydes, generated under oxidative stress, with K(m) in the physiological range. We have identified the role of AR in the prevention of various lipid aldehyde-induced cytotoxic signals leading to apoptosis in human lens epithelial cells (HLEC). HLEC were cultured without or with AR inhibitors followed by addition of various saturated and unsaturated lipid aldehydes with a carbon chain length varying from C3 to C10. The cell viability was assessed by cell counts and MTT assay, and apoptosis was measured by evaluating nucleosomal degradation and caspase-3 activation using specific ELISA kits. Although all the aldehydes caused apoptosis of HLEC, the unsaturated aldehydes were more toxic than saturated aldehydes. Inhibition of AR by sorbinil potentiated while the over-expression of AR prevented the apoptosis induced by various lipid aldehydes. AR over-expression also prevented the lipid aldehyde-induced activation of caspase-3, MAPK, JNK and the expression of Bcl-2 family of proteins in HLEC. The results indicate that the lipid aldehydes generated under oxidative stress are cytotoxic to HLEC leading to apoptosis and that the reduction of lipid aldehydes by AR would prevent it.
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PMID:Aldose reductase prevents aldehyde toxicity in cultured human lens epithelial cells. 1663 Nov 66

Pancreatic stellate cells (PSC) are now recognized as the key mediators of pancreatic fibrosis, a characteristic feature of chronic pancreatitis. The role of PSC in alcoholic pancreatic fibrosis has been examined in vivo (using pancreatic tissue from patients with alcohol-induced chronic pancreatitis and from animal models of experimental pancreatitis) and in vitro (using PSC in culture). These studies indicate that PSC are activated early in the course of pancreatic injury and are the predominant source of collagen in the fibrotic pancreas. The factors responsible for mediating PSC activation during chronic alcohol exposure include ethanol, its metabolite acetaldehyde, oxidant stress and cytokines (released during episodes of alcohol-induced pancreatic necroinflammation). Most recently, the intracellular signaling mechanisms regulating ethanol-induced PSC activation have been identified and include the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), and the transcription factor activator protein-1 (AP-1).
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PMID:Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. 1695 84

To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral density, induction of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression, and enhanced bone resorption, all of which were prevented by treatment with 17beta-estradiol (E(2)). The addition of progesterone did not enhance the beneficial effect of E(2) alone. Consistent with our in vivo findings, EtOH stimulated RANKL mRNA expression in cultured primary osteoblasts, and this expression was blocked by 4-methylpyrazole. Acetaldehyde also induced RANKL expression. Class 1 alcohol dehydrogenase was found to be expressed and EtOH-inducible in cultured osteoblasts, whereas CYP2E1 was undetectable. We found that EtOH induced phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3). E(2) and the mitogenactivated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked ERK and STAT3 phosphorylation and blocked RANKL induction. Moreover, E(2) completely blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor coculture system. The E(2) effects were estrogen receptor-mediated. Therefore, E(2) prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.
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PMID:Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaB ligand in osteoblasts. 1697 3

4-hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues and was recently identified as a potent catabolic factor in OA cartilage. In this study, we provide additional evidence that HNE acts as an inflammatory mediator by elucidating the signaling cascades targeted in OA chondrocytes leading to cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression. HNE induced COX-2 protein and mRNA levels with accompanying increases in prostaglandin E2 (PGE(2)) production. In contrast, HNE had no effect on basal iNOS expression or nitric oxide (NO) release. However, HNE strongly inhibited IL-1beta-induced iNOS or NO production. Transient transfection experiments revealed that the ATF/CRE site (-58/-53) is essential for HNE-induced COX-2 promoter activation and indeed HNE induced ATF-2 and CREB-1 phosphorylation as well as ATF/CRE binding activity. Overexpression of p38 MAPK enhanced the HNE-induced ATF/CRE luciferase reporter plasmid activation, COX-2 synthesis and promoter activity. HNE abrogated IL-1beta-induced iNOS expression and promoter activity mainly through NF-kappaB site (-5,817/-5,808) possibly via suppression of IKKalpha-induced IkappaBalpha phosphorylation and NF-kappaB/p65 nuclear translocation. Upon examination of upstream signaling components, we found that IKKalpha was inactivated through HNE/IKKalpha adduct formation. Taken together, these findings illustrate the central role played by HNE in the regulation of COX-2 and iNOS in OA. The aldehyde induced selectively COX-2 expression via ATF/CRE activation and inhibited iNOS via IKKalpha inactivation.
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PMID:Differential regulation of cyclooxygenase-2 and inducible nitric oxide synthase by 4-hydroxynonenal in human osteoarthritic chondrocytes through ATF-2/CREB-1 transactivation and concomitant inhibition of NF-kappaB signaling cascade. 1703 50

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.
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PMID:P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. 1719 91

The aldehyde 4-hydroxy-2-nonenal (HNE) is an end-product of polyunsaturated fatty acid oxidation. HNE is involved in the pathogenesis of coronary artery disease and is present in oxidatively modified low density lipoproteins and in atherosclerotic plaques in humans. HNE enhances chronic inflammation within the vessel wall by activating macrophages, stimulates smooth muscle cell proliferation and fibrosis and contributes to endothelial cell dysfunction. Endogenous adaptive antioxidant pathways are activated in response to oxidative injury elicited by 4-HNE. The induction of antioxidant genes such as heme oxygenase-1 (HO-1) is co-ordinated by activation of mitogen-activated protein kinase pathways, leading to nuclear translocation of the transcription factor Nrf2 and subsequent transactivation of an antioxidant response element in the promoter regions of these genes. We here review the evidence that HNE activates Nrf2 and antioxidant gene expression in vascular and other cells types, highlighting the potential of targeting the Nrf2 as a therapeutic strategy for the prevention of vascular diseases characterised by oxidative injury and diminished antioxidant defence.
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PMID:Modulation of antioxidant gene expression by 4-hydroxynonenal: atheroprotective role of the Nrf2/ARE transcription pathway. 1726 1

4-Hydroxynonenal (HNE) is one of the most abundant aldehyde components of ox-LDL and it exerts various effects on intracellular and extracellular signaling cascades. In this mini-review, a brief synopsis of HNE-modulated signaling pathways will be presented mainly focused on cell death, including recent studies from our laboratory. The results of a number of studies demonstrate the ability of HNE to induce apoptosis and ROS formation in a dose-dependent manner. Several signaling pathways have been shown to be modulated by HNE, including MAP kinases, PKC isoforms, cell-cycle regulators, receptor tyrosine kinases and caspases. In order to get insight into the mechanisms of apoptotic response by HNE, MAP kinase and caspase activation pathways have been studied in 3T3 fibroblasts; HNE induced early activation of JNK and p38 proteins but down-regulated the basal activity of ERK-1/2. We have shown that HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with certain molecules such as resveratrol. Additionally, overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicated a role for JNK-c-Jun/AP-1 pathway. JNK-dependent induction of c-Jun/AP-1 activation data in the literature indicates a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation.
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PMID:Apoptosis signalling by 4-hydroxynonenal: a role for JNK-c-Jun/AP-1 pathway. 1726 5


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