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)

Campylobacter jejuni is the leading cause of food-borne illness in the USA and one of the most common causes of diarrhoea worldwide. Central to its pathogenicity is its ability to induce the production of proinflammatory cytokines such as interleukin (IL)-8 in intestinal epithelial cells. Here, we demonstrated that C. jejuni infection of intestinal epithelial cells results in the activation of the ERK and p38 mitogen-activated protein kinases and that the ERK kinase pathway is essential for IL-8 production. We found that MAP kinase stimulation leading to IL-8 secretion requires C. jejuni gene products whose production is stimulated upon contact with epithelial cells. We also found that C. jejuni flagellin is a very poor stimulator of Toll-like receptor (TLR)-5 and therefore does not play a significant role in the stimulation of cytokine production.
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PMID:Signal transduction in Campylobacter jejuni-induced cytokine production. 1583 95

Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.
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PMID:Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. 1657 47

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), produce excessive amounts of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), which play key roles in the processes of inflammation. Andrographis paniculata Nees is a traditional Chinese herb commonly used for treatment of infection, inflammation, and diarrhea. However, the mechanism of its therapeutic function is not well known. In the present study, the effect of neoandrographolide, one of bioactive components in A. paniculata, on iNOS-mediated NO production and COX-2-mediated PGE(2) in bacterial lipopolysaccharide (LPS) stimulated-murine macrophages was investigated. Neoandrographolide at concentrations (30-90 microM) significantly (p<0.05) inhibited the productions of NO and PGE(2) in LPS stimulated macrophages without inducing cytotoxicity. The effect of neoandrographolide also has been investigated on iNOS and COX-2 expression in activated macrophage by using RT-PCR and immunoblotting. The inhibition of NO release by neoandrographolide can be attributed to the block of iNOS mRNA transcription followed by inhibiting protein expression. However, neoandrographolide inhibited COX-2 protein expression only but without inhibiting COX-2 mRNA expression, which was involved in the inhibitory activity against the PGE(2 )overproduction. This suggests that the effect of neoandrographolide on iNOS expression may occur at the transcriptional level and the inhibition of COX-2 expression occurs at the translational level. Furthermore, we have found that the addition of neoandrographolide inhibited the activation of p38 mitogen-activated protein kinase (MAPKs) instead of JNK, ERK1/2, or NF-kappaB. These results indicated that the anti-inflammatory properties of neoandrographolide might result from the inhibition of iNOS and COX-2 expression through inhibiting p38 MAPKs activation. Therefore, neoandrographolide isolated from A. paniculata could be offered as a leading compound for anti-inflammation.
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PMID:Inhibitory effects of neoandrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage. 1710 78

Enteropathogenic Escherichia coli (EPEC) is a major cause of infantile diarrhea. In this work we investigated the effect of outer membrane proteins (OMP) of EPEC on barrier integrity and the role of actin, junctional adhesion molecule (JAM) and signaling pathways contributing to these changes. Barrier function was assessed by transepithelial electrical resistance (TER). OMP of wild type EPEC, eaeA and maltoporin mutants decreased TER levels of Caco-2 cells. The OMP of espB mutant was deficient in decreasing TER of Caco-2 cells. The proteinase K-digested wild type OMP and EAF mutant OMP did not cause any change in barrier function. Our previous studies have demonstrated that EPEC OMP induced changes in cadherin junctions of Caco-2 cells. Immunofluorescence revealed disruption in actin cytoskeleton by EPEC OMP. However, no change in expression of junctional adhesion molecule-1 was observed. NF-kappaB inhibitor slightly blocked the decrease in TER and protected against actin disruption while ERK1/2 inhibitor had no effect in blocking these changes. In conclusion, our data suggest that the OMP of EPEC alter intestinal barrier function by disrupting actin cytoskeleton and signaling pathways like NF-kappaB may have a role in regulating barrier changes.
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PMID:Modulation of tight junction barrier function by outer membrane proteins of enteropathogenic Escherichia coli: role of F-actin and junctional adhesion molecule-1. 1738 65

Infection of mucosal epithelial cells by Shigella species leads to an intense and acute inflammatory bowel disease that is characterized by watery diarrhea and purulent discharge. Mucin production is a common defense mechanism to protect the underlying mucosa against pathogens. The molecular mechanism(s) underlying mucin induction is unknown in Shigellosis. In this study, we have evaluated the relationship between Shigella infection, the expression of MUC2 and MUC5AC and the participation of signaling molecules TNF-alpha, PKC and ERK1/2. Shigella infection up-regulated MUC2 and MUC5AC expression in 6-8 h, through activation of TNF-alpha, PKC and ERK1/2. These results confirm that, in response to Shigella infection, the normal expression pattern of MUC-2 and MUC-5AC is altered. This in vivo study brings new insights into the molecular pathogenesis of Shigellosis and new potential therapeutic targets for Shigellosis.
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PMID:Altered expression of MUC2 and MUC5AC in response to Shigella infection, an in vivo study. 1739 79

Zinc deficiency enhances infectious diarrhea whereas probiotics may inhibit pathogen enterocyte invasion. The effect of probiotics on zinc-deficient versus normal human intestinal epithelium (Caco-2 and T-84) with regard to invasion and subsequent inflammatory response by Salmonella typhimurium was determined. Cells were infected with pathogens and preincubated with media conditioned by several lactobacilli or Bifidobacterium bifidum 12. Pathogen invasion was quantified, inflammation was determined by IL-8 secretion, and MAP kinase activation in the epithelium was analyzed. Probiotic inhibiting factors were partially characterized based on physicochemical properties. Zinc deficiency allowed for greater pathogen invasion and enhanced IL-8 secretion. Probiotic conditioned media reduced activation of proinflammatory signaling via the ERK and p38 pathway. Probiotic factors reverse increased susceptibility of zinc-deficient enterocytes to S. typhimurium invasion, suggesting an additive protective effect of probiotics in zinc deficiency. Probiotic conditioned media but not bacteria inhibited pathogen invasion and IL-8 production in zinc deficient enterocytes. Probiotic inhibitory factors are stable to treatment with proteases, deoxyribonucleases (DNAses), ribonucleases (RNAse), strong acid, and heat.
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PMID:Secreted probiotic factors ameliorate enteropathogenic infection in zinc-deficient human Caco-2 and T84 cell lines. 1759 54

It was reported earlier that Escherichia coli heat stable enterotoxin (STa), a major causative agent of secretory diarrhea, can also inhibit the proliferation of colon carcinoma cells with the involvement of cGMP mediated calcium influx. In the present study it is shown that E. coli STa inhibits cell proliferation in the colonic carcinoma cell line COLO-205 by the PKG-ERK44/42 mediated signaling pathway. This enterotoxin negatively regulates cell proliferation by downregulating the activity of ERK44/42(MAPK) and subsequently the activity of a transcription regulatory protein cMyc. The antiproliferative effect of STa was reversed by LY83583, a guanylate cyclase (GC) inhibitor and KT5823, a PKG inhibitor. Thus suggesting the involvement of cGMP dependent protein kinase (PKG) in the downregulation of ERK44/42 and subsequent inactivation of cMyc activity. Moreover, it has been shown that a specific ERK44/42 inhibitor, PD98059, also inhibits cMyc activation and cell proliferation, which further confirms the involvement of ERK44/42 in the activation of cMyc. It is also shown that E. coli STa significantly inhibits the vascular endothelial growth factor (VEGF, a potent angiogenic factor) expression in COLO-205 cells and also downregulates vascular cell adhesion molecule-1 (VCAM-1, a potent metastatic factor) expression on the COLO-205 cell surface. So it is reported for the first time that E. coli STa inhibits the proliferation of the colonic carcinoma cell line COLO-205 by the PKG-ERK44/42 mediated pathway and it may have a role against the development of colon carcinoma.
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PMID:Downregulation of human colon carcinoma cell (COLO-205) proliferation through PKG-MAP kinase mediated signaling cascade by E. coli heat stable enterotoxin (STa), a potent anti-angiogenic and anti-metastatic molecule. 1782 4

Andrographolide (Andro) is a potentially anti-inflammatory diterpenoid lactone isolated from the traditional herbal medicine ANDROGRAPHIS PANICULATA, which has been effectively used for the treatment of infection, inflammation, cold, fever and diarrhea in China for centuries. In the current study, we found that Andro significantly decreased the number of surviving hepatoma-derived Hep3B cells in the MTT assay and induced cell apoptosis. Further study showed that Andro induced activation of mitogen-activated protein kinases (MAPKs) including p38 kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-related kinases (ERK1/2), but had no significant effect on caspase-3, Bcl-xL and Bcl-2, which are apoptosis-related proteins. Moreover, inhibition of JNK activation partially rescued the toxic effect of Andro on Hep3B cells. Therefore, our results indicate that the JNK signaling pathway plays an important role in the toxic effect of Andro on Hep3B cells.
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PMID:Andrographolide inhibits human hepatoma-derived Hep3B cell growth through the activation of c-Jun N-terminal kinase. 1791 40

Reactive oxygen species (ROS) are key mediators in a number of inflammatory conditions, including inflammatory bowel disease (IBD). ROS, including hydrogen peroxide (H(2)O(2)), modulate intestinal epithelial ion transport and are believed to contribute to IBD-associated diarrhea. Intestinal crypt fluid secretion, driven by electrogenic Cl(-) secretion, hydrates and sterilizes the crypt, thus reducing bacterial adherence. Here, we show that pathophysiological concentrations of H(2)O(2) inhibit Ca(2+)-dependent Cl(-) secretion across T(84) colonic epithelial cells by elevating cytosolic Ca(2+), which contributes to activation of two distinct signaling pathways. One involves recruitment of the Ca(2+)-responsive kinases, Src and Pyk-2, as well as extracellular signal-regulated kinase (ERK). A separate pathway recruits p38 MAP kinase and phosphoinositide 3-kinase (PI3-K) signaling. The ion transport response to Ca(2+)-dependent stimuli is mediated in part by K(+) efflux through basolateral K(+) channels and Cl(-) uptake by the Na(+)-K(+)-2Cl(-) cotransporter, NKCC1. We demonstrate that H(2)O(2) inhibits Ca(2+)-dependent basolateral K(+) efflux and also inhibits NKCC1 activity independently of inhibitory effects on apical Cl(-) conductance. Thus, we have demonstrated that H(2)O(2) inhibits Ca(2+)-dependent Cl(-) secretion through multiple negative regulatory signaling pathways and inhibition of specific ion transporters. These findings increase our understanding of mechanisms by which inflammation disturbs intestinal epithelial function and contributes to intestinal pathophysiology.
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PMID:Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins. 1821 55

Probiotics promote intestinal epithelial integrity and reduce infection and diarrhea. We evaluated the effect of Lactobacillus rhamnosus GG-produced soluble proteins (p40 and p75) on the hydrogen peroxide-induced disruption of tight junctions and barrier function in Caco-2 cell monolayers. Pretreatment of cell monolayers with p40 or p75 attenuated the hydrogen peroxide-induced decrease in transepithelial resistance and increase in inulin permeability in a time- and dose-dependent manner. p40 and p75 also prevented hydrogen peroxide-induced redistribution of occludin, ZO-1, E-cadherin, and beta-catenin from the intercellular junctions and their dissociation from the detergent-insoluble fractions. Both p40 and p75 induced a rapid increase in the membrane translocation of PKCbetaI and PKCepsilon. The attenuation of hydrogen peroxide-induced inulin permeability and redistribution of tight junction proteins by p40 and p75 was abrogated by Ro-32-0432, a PKC inhibitor. p40 and p75 also rapidly increased the levels of phospho-ERK1/2 in the detergent-insoluble fractions. U0126 (a MAP kinase inhibitor) attenuated the p40- and p75-mediated reduction of hydrogen peroxide-induced tight junction disruption and inulin permeability. These studies demonstrate that probiotic-secretory proteins protect the intestinal epithelial tight junctions and the barrier function from hydrogen peroxide-induced insult by a PKC- and MAP kinase-dependent mechanism.
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PMID:Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. 1829 83


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