Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
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PMID:New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase. 1645 63

Advancing knowledge regarding the cellular mechanisms of intestinal inflammation has led to a better understanding of the disease pathology in patients with chronic disorders of the gut including inflammatory bowel disease, coeliac disease, lymphocytic colitis and irritable bowel syndrome. An emerging new paradigm suggests that changes in the homeostasis of bacteria- and host-derived signal transduction at the epithelial cell level may lead to functional and immune disturbances of the intestinal epithelium. It has become clear from numerous studies that enteric bacteria are a critical component in the development and prevention/treatment of chronic intestinal inflammation. Signal-specific activation of mitogen-activated protein kinases (MAPK), interferon-regulated factors (IRF) and the transcription factor NF-kappaB through pattern recognition receptor signalling effectively induce inflammatory defence mechanisms. Unbalanced activation of these innate signalling pathways because of host genetic predispositions and/or the lack of adequate anti-inflammatory feedback mechanisms may turn a physiological response into a pathological situation including failure of bacterial clearance and development of chronic inflammation. Host-derived regulators from the immune and enteric nerve system crosstalk to the innate signalling network of the intestinal epithelium in order to shape the extent and duration of inflammatory processes.
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PMID:Intestinal epithelial cell signalling and host-derived negative regulators under chronic inflammation: to be or not to be activated determines the balance towards commensal bacteria. 1648 9

Involvement of mitogen-activated protein (MAPK) in inflammatory bowel disease (IBD) remains enigmatic. We sought to evaluate the expression and activity of p38 and JNK MAPK in IBD and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis; and the effects of a p38 inhibitor, SB203580, in TNBS colitis. P38 and JNK were quantified in colonic mucosa of 28 IBD patients and 19 controls and in 77 TNBS or control mice treated or not with SB203580. Colitis severity was assessed by survival, macroscopic and microscopic scoring, and molecular markers. Expression and activity of p38 and JNK were similar in IBD patients and controls and not modified by inflammation. In mice, p38 and JNK expression or activity did not increase following the induction of colitis. SB203580 decreased the p38 activity but displayed no clinical nor biological therapeutic effect. In conclusion, these results minimize the role of p38 and JNK in inflammatory colitis and the interest of p38 as a therapeutic target in IBD.
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PMID:No evidence for an involvement of the p38 and JNK mitogen-activated protein in inflammatory bowel diseases. 1683 16

Adenosine A3 receptors (ADOA3Rs) are emerging as novel purinergic targets for treatment of inflammatory diseases. Our goal was to assess the protective effect of the ADOA3R agonist N(6)-(3-iodobenzyl)-adenosine-5-N-methyluronamide (IB-MECA) on gene dysregulation and injury in a rat chronic model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)--induced colitis. It was necessary to develop and validate a microarray technique for testing the protective effects of purine-based drugs in experimental inflammatory bowel disease. High-density oligonucleotide microarray analysis of gene dysregulation was assessed in colons from normal, TNBS-treated (7 days), and oral IB-MECA-treated rats (1.5 mg/kg b.i.d.) using a rat RNU34 neural GeneChip of 724 genes and SYBR green polymerase chain reaction. Analysis included clinical evaluation, weight loss assessment, and electron paramagnetic resonance imaging/spin-trap monitoring of free radicals. Remarkable colitis-induced gene dysregulation occurs in the most exceptional cluster of 5.4% of the gene pool, revealing 2 modes of colitis-related dysregulation. Downregulation occurs in membrane transporter, mitogen-activated protein (MAP) kinase, and channel genes. Upregulation occurs in chemokine, cytokine/inflammatory, stress, growth factor, intracellular signaling, receptor, heat shock protein, retinoid metabolism, neural, remodeling, and redox-sensitive genes. Oral IB-MECA prevented dysregulation in 92% of these genes, histopathology, gut injury, and weight loss. IB-MECA or adenosine suppressed elevated free radicals in ex vivo inflamed gut. Oral IB-MECA blocked the colitis-induced upregulation (<or=20-fold) of Bzrp, P2X1R, P2X4R, P2X7R, P2Y2R, P2Y6R, and A2aR/A2bR but not A1R or A3R genes or downregulated P2X2R, P2Y1R, and P2Y4R. Real-time SYBR green polymerase chain reaction validated gene chip data for both induction of colitis and treatment with IB-MECA for >90% of genes tested (33 of 37 genes). We conclude that our validated high-density oligonucleotide microarray analysis is a powerful technique for molecular gene dysregulation studies to assess the beneficial effects of purine-based or other drugs in experimental colitis. ADOA3R is new potential therapeutic target for inflammatory bowel disease.
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PMID:ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. 1691 33

Inflammatory bowel disease (IBD) affects more than 1 million Americans with more than 30,000 new cases diagnosed each year. IBD increases patient morbidity and susceptibility to colorectal cancer, yet its etiology remains unknown. Current models identify two key determinants of IBD pathogenesis: hyperpermeability of the gut epithelial barrier to bacterial products and an abnormal immune response to these products. Two factors seem critical for hyperpermeability: oxidant-induced stress and proinflammatory cytokines (e.g., tumor necrosis factor-alpha). The aim of this study was to investigate the role of oxidant stress-mediated transactivation of the epidermal growth factor receptor (EGFR) in intestinal hyperpermeability. This study used the Caco-2 human colonic epithelial cell in vitro model of intestinal epithelium. Cells were grown on inserts for permeability and signaling studies and glass coverslips for microscopy studies. show that oxidant-induced intestinal hyperpermeability can be blocked by specific inhibitors of the EGFR, tumor necrosis factor convertase (TACE) metalloprotease, transforming growth factor (TGF)-alpha, and mitogen-activated protein kinases, especially extracellular signal-regulated kinase 1/2. We also show that oxidant initiates these signaling events, in part by causing translocation of TACE to cell-cell contact zones. In this study, our data identify a novel mechanism for oxidant-induced intestinal hyperpermeability relevant to IBD. We propose a new intestinal permeability model in which oxidant transactivates EGFR signaling by activation of TACE and cleavage of precursor TGF-alpha. These data could have a significant effect on our view of IBD pathogenesis and provide new therapeutic targets for IBD treatment.
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PMID:Regulation of oxidant-induced intestinal permeability by metalloprotease-dependent epidermal growth factor receptor signaling. 1722 Apr 28

The c-Jun NH2-terminal Kinase (JNK) pathway represents one sub-group of the mitogen-activated protein (MAP) kinases which plays an important role in various inflammatory diseases states, including inflammatory bowel disease (IBD). Significant progress towards understanding the function of the JNK signaling pathway has been achieved during the past few years. Blockade of the JNK pathway with JNK inhibitors in animal models of IBD lead to resolution of intestinal inflammation. Current data suggest specific JNK inhibitors hold promise as novel therapies in IBD.
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PMID:Role of the JNK signal transduction pathway in inflammatory bowel disease. 1818 55

Probiotics are defined as nonpathogenic living microorganisms, including some commensal bacterial flora, which have beneficial effects on host health and disease prevention and/or treatment. Clinical trials have shown beneficial effects of probiotics on several human diseases, such as inflammatory bowel diseases (IBDs), which are among the most-studied diseases testing probiotics as a potential therapy. However, a significant question regarding clinical use of probiotics is the mechanism underlying the wide range of actions. Studies discussed in this review suggest 3 distinct cellular and molecular mechanisms for probiotic regulation in IBD therapy: 1) Probiotics block pathogenic bacterial effects by producing bactericidal substances and competing with pathogens and toxins for adherence to the intestinal epithelium; 2) Probiotics regulate immune responses by enhancing the innate immunity and modulating pathogen-induced inflammation via toll-like receptor-regulated signaling pathways; and 3) Probiotics regulate intestinal epithelial homeostasis by promoting intestinal epithelial cell survival, enhancing barrier function, and stimulating protective responses. Probiotics modulate host cell signaling pathways, including Akt, mitogen-activated protein kinases, and nuclear factor-kappaB to mediate these intestinal epithelial functions. It is hoped that developing a mechanistic understanding of probiotic action will provide the rationale to support the development of new hypothesis-driven studies to define the clinical efficacy in preventive, adjunctive, or alternative treatments for IBD.
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PMID:Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases. 1862 73

Recently, inflammatory bowel disease (IBD) has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase (SPAK) is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases (such as p38, JNK, NKCC1, PKCtheta, WNK and MLCK), and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-like kinases and downstream mitogen-activated protein kinases (MAPKs) pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation.
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PMID:Ste20-related proline/alanine-rich kinase: a novel regulator of intestinal inflammation. 1898

The p38 mitogen-activated protein (MAP) kinase plays a central role in inflammation. It has been the subject of extensive efforts in both basic research and drug discovery for the treatment of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, where aberrant cytokine signaling is the driver of the disease. This article reviews the patent and journal publication activities during 2006-2008 describing novel small molecule p38alpha inhibitors.
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PMID:Small molecule p38 MAP kinase inhibitors for the treatment of inflammatory diseases: novel structures and developments during 2006-2008. 1899 31

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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PMID:Glucocorticoid resistance in inflammatory diseases. 1948 16


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