Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the cytokine network plays a key role in the inflammatory responses in inflammatory bowel disease, no comprehensive analysis of the intestinal cytokine network has been reported. We analyzed messenger RNA levels for various cytokines in human intestine by real-time quantitative polymerase chain reaction to clarify the cytokine profiles involved in the pathogenesis of inflammatory bowel disease. Biopsy specimens were obtained from 23 patients with ulcerative colitis (15 men, 8 women, mean age of 44.1 years), 17 patients with Crohn's disease (15 men, 2 women, mean age of 21.6 years), and 8 normal controls (6 men, 2 women, mean age of 62.7 years) who underwent colonoscopy for suspected colonic disease. Messenger RNA was isolated from two biopsy samples and reverse-transcribed to obtain cDNA. Mucosal mRNA levels for IL-1beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, IFN-gamma and TNF-alpha were simultaneously analyzed by real-time quantitative polymerase chain reaction. In patients with active ulcerative colitis, IL-1beta, IL-4, IL-5, IL-8, IL-12p40, IFN-gamma and TNF-alpha mRNA levels were significantly higher than those in controls. In patients with active Crohn's disease, IL-1beta, IL-8, and IL-12p40 mRNA levels were significantly higher than those in controls. Mucosal level of IL-12p40 mRNA was significantly higher in patients with inactive Crohn's disease than in controls. Both Th1 and Th2 cytokine mRNA levels were increased in colonic mucosa of patients with ulcerative colitis suggesting the possibility that cellular and humoral immunity play roles in the pathogenesis of this disease. In patients with Crohn's disease, Th1 cytokine mRNA levels were increased in colonic mucosa, suggesting predominance of cellular immunity in the pathogenesis of this disease.
Int J Mol Med 2003 Feb
PMID:Comprehensive analysis of intestinal cytokine messenger RNA profile by real-time quantitative polymerase chain reaction in patients with inflammatory bowel disease. 1252 73

Genetic variations are playing an increasing role in drug discovery, particularly in disease-specific drug target identification and in drug candidate profiling to predict drug response in genetically heterogeneous patient populations. Recently, genetic studies have successfully contributed to the identification of new susceptibility genes, disease mechanisms and potentially novel disease-specific drug targets for common diseases such as Type II diabetes, Crohn's disease, asthma and osteoporosis. Numerous variants of cytochrome P450 enzymes and the pregnane X receptor, recently associated with protein expression and altered catalytic activities, may prove to be of use in the future in drug candidate profiling.
Curr Opin Mol Ther 2002 Dec
PMID:The increasing importance of genetic variation in drug discovery and development. 1259 57

Crohn's disease (CD) is a chronic inflammatory bowel disease that may involve the whole gut. Marked intestinal T cell and macrophage activation is a key feature of the disease. Polymorphonuclear cell infiltration is also observed in the diseased gut, mainly during active inflammation. Scintigraphic detection of granulocytes and activated lymphocytes infiltrating the gut wall may be useful in identifying a subgroup of patients with clinically inactive CD who are undergoing early clinical relapse. The aims of the present study were (a) to compare the effectiveness of scintigraphy with (99m)Tc-labelled interleukin-2 ((99m)Tc-IL2) and with (99m)Tc-HMPAO labelled granulocytes ((99m)Tc-WBC) in detecting the presence and extent of bowel inflammation in patients with long-term inactive CD (>12 months) and (b) to assess the accuracy of these techniques in predicting future disease relapse. We studied 29 patients with ileal and/or colonic CD in stable clinical remission (Crohn's Disease Activity Index <150 for at least 12 months) using both (99m)Tc-IL2 and (99m)Tc-WBC scintigraphy in order to evaluate the extent of acute and chronic inflammation in the bowel. Planar and single-photon emission tomography images were acquired in each patient at 1 h p.i. For quantitative analysis of (99m)Tc-IL2 uptake, the abdomen was divided into 32 regions of interest. Despite the absence of symptoms, 18 patients (62%) showed a positive (99m)Tc-IL2 and 18 (62%) a positive (99m)Tc-WBC scan. Only 12 patients (41.4% of the total group) were positive on both scans, and the sites of IL2 and granulocyte bowel uptake were usually located in different segments, indicating that in CD, acute and chronic inflammation can be present in different sites. As far as the prognostic role of the two scans in predicting future disease relapse is concerned, both (99m)Tc-IL2 and (99m)Tc-WBC scintigraphy showed a high negative predictive value (1.00 and 0.91, respectively) but a weak positive predictive value (0.44 and 0.39, respectively). Nevertheless, Kaplan-Meier curves generated between scintigraphic findings and time free from disease relapse were statistically different only for (99m)Tc-IL2 scintigraphy (log-rank test, P=0.013). These results indicate that (99m)Tc-IL2 scintigraphy can be useful in selecting CD patients in clinical remission who could benefit from preventive therapy to avoid disease relapse.
Eur J Nucl Med Mol Imaging 2003 Mar
PMID:99mTc-interleukin-2 and (99m)Tc-HMPAO granulocyte scintigraphy in patients with inactive Crohn's disease. 1263 65

Chugai, the Japanese subsidiary of Roche, is developing a humanized anti-interleukin (IL)-6 receptor monoclonal antibody MRA for the potential treatment of multiple myeloma, rheumatoid arthritis, Crohn's disease and other IL-6-related disorders. MRA is currently undergoing phase II clinical trials for these indications.
Curr Opin Mol Ther 2003 Feb
PMID:Technology evaluation: MRA, Chugai. 1266 73

OraSense Ltd (a joint venture between Isis Pharmaceuticals Inc and Elan Corp) is developing ISIS-104838, an antisense oligonucleotide specific for TNF alpha mRNA, as an inhibitor of TNF alpha synthesis. The compound is being developed for the potential treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. This antisense oligonucleotide is currently undergoing phase II clinical trials for RA and Crohn's disease.
Curr Opin Mol Ther 2003 Feb
PMID:Technology evaluation: ISIS-104838, OraSense. 1266 75

Mycobacterium avium subsp. Paratuberculosis (MAP) is a member of the Mycobacterium avium complex (MAC) and causes the inflammatory bowel disease, Johne's disease, in livestock. MAP has also been implicated as the causative agent of a similar disease, Crohn's disease, in humans. One of three major genetic differences between MAP and non-pathogenic MAC is the 6496-bp GS element. Based on the output from freely available protein sequence and structural bioinformatics tools, and the close homology of GS genes with the SER2 region of the closely related Mycobacterium avium subsp. Avium (MAA), we predict that GS encoded enzymes are involved in the biosynthesis of GDP-fucose, and the addition to, and modification of fucose on, the oligosaccharide moiety of GPL. GPL is a major constituent of the cell wall of the MAC and has immunomodulatory properties. Therefore, the enzymes involved in its synthesis may provide novel drug targets against MAP and other pathogenic MAC members.
J Mol Microbiol Biotechnol 2003
PMID:Use of bioinformatics to predict a function for the GS element in Mycobacterium avium subspecies paratuberculosis. 1267 62

Genetic determinants that co-operate with type 1 pili to mediate invasion were sought for in adherent-invasive Escherichia coli strain LF82 isolated from a patient with Crohn's disease. Two mutants selected for their impaired ability to invade epithelial cells carried insertions of a TnphoA transposon within genes of the flagellar regulon. An isogenic mutant LF82-DeltafliC deleted for the flagellin-encoding gene did not adhere, did not invade and, surprisingly, expressed only a few type 1 pili. Type 1 pili downregulation resulted from a preferential switch towards the off-position of the invertible DNA element located upstream of the fim operon. This was also correlated with a decrease in the flagellar regulator flhDC mRNA levels, suggesting that the transcriptional regulator FlhD2C2 could control type 1 pili expression directly or indirectly. Transformation with a cloned fim operon allowed bypass of the type 1 pili downexpression in the LF82-DeltafliC mutant. Thus, we showed that flagella play a direct role in the adhesion process via active motility. In addition to downregulating type 1 pili expression, flagella also play an undefined role in strain LF82 invasion, which is not restricted to motility or flagellar structure, but could be related to co-ordinate expression of invasive determinants.
Mol Microbiol 2003 May
PMID:Regulatory and functional co-operation of flagella and type 1 pili in adhesive and invasive abilities of AIEC strain LF82 isolated from a patient with Crohn's disease. 1269 21

Crohn's Disease (CD) is a chronic inflammatory bowel disease (IBD) that can affect any portion of the gastrointestinal tract and can cause significant morbidity. A variety of animal models of both acute and chronic intestinal inflammation have been developed to investigate disease pathogenesis and novel treatment modalities. These include chemically induced, genetically manipulated and immune-mediated models of gut inflammation, each of which possesses similarities to human IBD and offers unique advantages for studying specific aspects of disease pathogenesis. However, the majority of these models are characterized by colitis and, unlike human CD, do not involve the small intestine. More recently, murine models of chronic ileal inflammation have been characterized that spontaneously develop and closely resemble human CD with regard to disease location, histologic features and clinical response to therapy. Two mouse models of experimental ileitis will be discussed in this review: the TNF DeltaARE and SAMP1/YitFc strains. Studies using these new models might provide important insight into the pathogenesis of human CD and test the efficacy of potential therapies to treat this devastating disease.
Trends Mol Med 2003 May
PMID:Mouse models for the study of Crohn's disease. 1276 27

Recent studies suggest that the enhanced release of reactive oxygen species (ROS) plays an important role in the pathogenesis of clinical inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. In the present study, we investigated the effects of the free radical scavenger edaravone, which is used clinically as an anti-stroke agent, in the development of experimental dextran sulfate sodium (DSS)-induced colitis in rats. The rats were fed 4% (w/w of diet) DSS in standard powder chow for 8 days. The edaravone and vehicle saline were injected subcutaneously twice a day. After the experimental period, the wet colonic weight, macroscopic mucosal damaged area, histological damage score, mucosal myeloperoxidase (MPO) activity, mucosal tissue lipid peroxidate and serum interleukin-6 (IL-6) levels were measured. In the DSS-induced colitis model, edaravone treatment (1-20 mg/kg day) significantly reduced the wet colonic weight, macroscopic damaged area, and the histological damage score. Edaravone treatment also reduced mucosal MPO activity, mucosal tissue lipid peroxidate level and serum IL-6 level. In particular, edaravone at a dose of 20 mg/kg day significantly reduced mucosal MPO activity and serum IL-6 level. These results strongly support the involvement of ROS in the pathogenesis of DSS-induced colitis. A clinical effect for edaravone against IBD patients is strongly expected.
Int J Mol Med 2003 Jul
PMID:The free radical scavenger edaravone suppresses experimental dextran sulfate sodium-induced colitis in rats. 1279 22

In Crohn's disease (CD) CD4(+) T-cells producing tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are important for disease progression. T-cell vaccination with such attenuated (gamma-irradiated) CD4(+) T cells may ameliorate the auto-reactive actions of Type-1 T cells through stimulation of interleukin-10 (IL-10)-producing regulatory T cells. This study aimed to propagate and use gut-derived type-1 CD4(+) T-cells for vaccination in CD. In a case study, two patients with CD-activity index (CDAI) >150 for >1 year were vaccinated with 800 x 10(6) attenuated autologous gut-derived CD4(+) T cells producing Type-1 cytokine -- grown in the presence of high concentrations of only IL-2 and IL-4. The T-cell vaccination was safe, causing only minor redness and tenderness at the injection sites. In Case 2, the treatment brought 3-years with active steroid-resistant CD into remission. CDAI dropped from 171 to 76, CD-endoscopic index of severity fell from 20 to eight and C-reactive protein reduced from 165 to 70 nmol/L. Case 1 received rescue infliximab (there was disease progression before sufficient quantities of cells were ready for the second vaccination). We concluded that it is possible to propagate T cells for autologous vaccination for CD and that treatment was safe. One patient, vaccinated according to the protocol, improved with sustained result for >1 year.
Cytokines Cell Mol Ther 2002
PMID:T-cell vaccination in Crohn's disease: principles and presentation of the first two cases. 1285 Aug 11


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