Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The idiopathic inflammatory bowel diseases (IBDs), consisting of Crohn's disease and ulcerative colitis, are complex genetic disorders involving chronic inflammation of the intestines. Multiple genetic loci have been implicated through genome-wide searches, but refinement of localization sufficient to undertake positional cloning efforts has been problematic. This difficulty can be obviated through identification of ancestrally shared regions in genetic isolates, such as the Chaldean population, a Roman Catholic group from Iraq. We analyzed four multiply affected American Chaldean families with inflammatory bowel disease not known to be related. We observed evidence for linkage and linkage disequilibrium in precisely the same region of chromosome band 1p36 reported previously in an outbred population. Maximal evidence for linkage was observed near D1S1597 by multipoint analysis (MLOD = 3.01, P = 6.1 x 10(-5)). A shared haplotype (D1S507 to D1S1628) was observed over 27 cM between two families. There was homozygous sharing of a 5 cM portion of that haplotype in one family and over a <1 cM region in the second family. Homozygous sharing of this haplotype near D1S2697 and D1S3669 was observed in one individual in a third multiply affected family, with heterozygous sharing in a fourth family. Linkage in outbred families as well as in this genetic isolate indicates that a pathophysiologically crucial IBD susceptibility gene is located in 1p36. These findings provide a unique opportunity to refine the localization and identify a major susceptibility gene for a complex genetic disorder.
Hum Mol Genet 2000 May 22
PMID:Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease. 1081 24

To elucidate the biological dysregulation underlying two forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), we examined global gene expression profiles of inflamed colonic tissue using DNA microarrays. Our results identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3, IGLL2 and CD74, inflammation-related lipocalins HNL and NGAL, and proliferation-related GRO genes were over-expressed in UC. Certain cancer-related genes such as DD96, DRAL and MXI1 were differentially expressed only in UC. Other genes over-expressed in both UC and CD included the REG gene family and the calcium-binding S100 protein genes S100A9 and S100P. The natural antimicrobial defensin DEFA5 and DEFA6 genes were particularly over-expressed in CD. Overall, significant differences in the expression profiles of 170 genes identified UC and CD as distinct molecular entities. The genomic map locations of the dysregulated genes may identify novel candidates for UC and CD genetic susceptibility.
Hum Mol Genet 2001 Mar 01
PMID:Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. 1118 68

Monosaccaride transporter proteins are responsible for transmembrane transport of monosaccarides into cells. Glucose transporter protein 1 (Glut-1) is most prevalent in the cell membranes of erythrocytes and facilitates transport of glucose in tissues with barrier functions, i.e. blood brain barrier. Expression of Glut-1 in malignant tumors is increased due to increased metabolic need of the proliferating cell populations. In colorectal adenomas and carcinomas, membranous expression of Glut-1 has been associated with higher grade of tumors and decreased survival time. We studied the expression of Glut-1 in dysplastic proliferations of the colon which included sporadic adenomas and dysplasia associated lesions (DALM) in patients with ulcerative colitis and reactive/regenerative proliferations of the colon, including non-dysplastic chronic colitis, acute colitis and ischemia. Two patterns of Glut-1 expression were detected. Most adenomas and DALMs showed at least focal membranous expression of Glut-1. In addition a second staining pattern was recognized which consisted of prominent supranuclear dots. This pattern of staining was not only seen in adenomas and DALM but also in non-dysplastic areas immediately surrounding sporadic adenomas, in regenerative chronic colitis and in areas surrounding acute inflammation. Areas away from dysplasia did not show any positive staining for Glut-1. We conclude that two distinct patterns of Glut-1 expression may be found in colonic epithelial proliferation: membranous staining, associated with dysplasia, and, heretofore not described, supranuclear staining which may be related to Glut-1 expression secondary to expression of specific growth factors and not necessarily related to dysplasia.
Int J Mol Med 2001 Jun
PMID:Glut-1 expression in dysplastic and regenerative lesions of the colon. 1135 Dec 74

Sporadic adenomas are said to exhibit an orderly growth pattern with a reversal of proliferative and apoptotic cell distribution as compared with normal colonic crypts. Dysplastic polyps of patients with ulcerative colitis (UC) may represent dysplasia-associated lesions or masses (DALM) with a high associated cancer risk, or, alternatively, may represent sporadic adenomas. Histologic criteria to differentiate between sporadic adenomas and DALM have not focused on the balance between cell renewal and cell loss. The expression of the novel anti-apoptosis gene product, survivin, and the proliferation markers, Ki-67 and Y-box binding protein (YB-1), were investigated by immunohistochemical localization in sporadic adenomas and DALM lesions of patients with UC. In adenomas, KI-67 was expressed preponderantly at the luminal aspect of the polyp, whereas its expression was diffuse in DALM. Survivin was detected diffusely in both adenomas and DALM. YB-1 showed positive staining in the deep aspect of adenomatous glands but only to a minor degree at the surface, whereas both deep and diffuse expression patterns of YB-1 were seen in DALM. The authors conclude that DALM and sporadic adenomas exhibit different patterns of cellular proliferation and that molecular markers of cell proliferation, Ki-67 and YB-1, may be useful to distinguish sporadic adenomas from DALM. However, the similar expression of survivin suggests that the underlying mechanisms that regulate apoptotic cell death are uniform in these lesions.
Appl Immunohistochem Mol Morphol 2001 Jun
PMID:Expression of survivin, YB-1, and KI-67 in sporadic adenomas and dysplasia-associated lesions or masses in ulcerative colitis. 1139 32

Splice variants of the glycoprotein CD44 are transiently expressed on lymphocytes during T cell activation. Increased expression of CD44v6 on peripheral blood lymphocytes (PBL) of patients with inflammatory bowel disease (IBD) was described recently. The aim of this study was therefore to characterize CD44v6 expression on CD4(+) lamina propria lymphocytes (LPL) of patients with active IBD in comparison to controls. CD44v6 expression on CD4(+) LPL (n = 19) of controls and patients with active IBD (Crohn's disease n = 14, ulcerative colitis n = 15) was analyzed by flow cytometry and compared to that on autologous PBL. Thereby, in vitro regulation of CD44v6 on LPL and PBL via CD3 and CD2 and the costimulatory signal B7-1 was examined. In addition, the role of protein kinase C (PKC) in CD44v6 expression was tested. CD44v6 expression was increased in CD4(+) LPL (median, 45%) compared to PBL (median, 38%). Surprisingly, in IBD CD44v6 was downregulated on CD4(+) lamina propria T cells, irrespective of their state of inflammation (median, 28%). CD44v6 expression on LPL was not upregulated upon CD3 activation alone but following costimulation with B7-1. However, CD2-mediated T cell activation sufficiently induced upregulation of CD44v6 on LPL and PBL. In our study, downregulation of CD44v6 on LPL of patients with IBD was not due to defective PKC activation. Taken together, these data indicate that decreased CD44v6 expression on LPL in IBD might be a feature of an inappropriate costimulatory signal in T cell activation.
Exp Mol Pathol 2001 Dec
PMID:Decreased CD44v6 expression in lamina propria lymphocytes of patients with inflammatory bowel disease. 1173 44

There is increasing evidence that intestinal microflora play an important role in the pathogenesis of ulcerative colitis. Therefore, modification of the microflora by prebiotics, probiotics, and antibiotics may be a rational approach for controlling intestinal inflammation. Germinated barley food-stuff (GBF) is an insoluble mixture of glutamine-rich protein and hemicellulose-rich dietary fiber. GBF is utilized efficiently by Bifidobacterium, Lactobacillus, and Eubacterium and converted by them into lactate, acetate, and butyrate. These bacterial organic acids preserve a favorable intestinal condition. We have previously shown that GBF has attenuated intestinal inflammation in patients with ulcerative colitis and experimental colitis models through prebiotic actions. The aim of this study was to compare the effect of GBF with that of probiotics and antibiotics in an experimental colitis model. Colitis was induced by feeding male SD rats with a diet containing 3.0-3.5% dextran sodium sulfate (DSS). The therapeutic effect of oral administration of a prebiotic (GBF), probiotics (mixture of Lactobacillus and Clostridium butyricum), antibiotics (vancomycin, metronidazole), and the vehicle was determined by assessing clinical and pathological scores on day 6 after initiation of colitis. Butyrate concentrations in the cecal content were also determined. GBF treatment significantly reduced colonic inflammation as assessed by clinical scores with an increase in cecal butyrate levels. Probiotic treatment with a mixture of Lactobacillus and Clostridium butyricum did not show such an effect. Both antibiotic treatments significantly attenuated clinical and pathological scores. However, in contrast to GBF, this treatment led to a significant decrease in cecal butyrate levels. These data suggest that modification of the intestinal microflora by prebiotics, including GBF, may serve as a useful adjunct in the treatment of ulcerative colitis as well as antibiotic treatment.
Int J Mol Med 2002 Jan
PMID:Prebiotic treatment of experimental colitis with germinated barley foodstuff: a comparison with probiotic or antibiotic treatment. 1174 99

Nerve growth factor (NGF), a target-derived factor for survival and maintenance of peripheral and central neurons, has been implicated in inflammatory processes. Mast cells are the principal effector cells in IgE-dependent hypersensitivity reactions, and also play a role in diseases characterised by inflammation, including those of the nervous system like multiple sclerosis. Mast cells are capable of synthesising and responding to NGF, although the occurrence of other members of the NGF family of neurotrophins and their protein forms have not been described. Immunoblot analysis with highly selective neurotrophin antibodies has now been used to show that rat peritoneal mast cells express a higher molecular weight form (73 kDa) of NGF, but not the monomeric (13 kDa) NGF polypeptide. Mast cells also expressed 73 kDa forms of neurotrophin-4 and neurotrophin-3; brain-derived neurotrophic factor was not detected. Medium conditioned by degranulating peritoneal mast cells contained similar high molecular weight forms of NGF and neurotrophin-4 on Western blots, but no neurotrophin-3. Mast cell-derived neurotrophin immunoreactivities were inhibited by the respective peptide antigen, further demonstrating the specificity of the mast cell-derived neurotrophic protein. Mast cell-released proteins supported the survival of cultured chicken embryonic neural crest- and placode-derived sensory neurons; neurotrophic activities were inhibited by neutralising antibodies for NGF and neurotrophin-4, respectively. High molecular isoforms of neurotrophins have been reported to occur in experimental colitis and in the inflamed gut of patients with Crohn's disease and ulcerative colitis, tissue sites rich in mast cells. The data suggest an important role for neurotrophins in the pathophysiology of inflammatory disease.
Brain Res Mol Brain Res 2001 Dec 30
PMID:Mast cells differentially express and release active high molecular weight neurotrophins. 1175 74

Ulcerative colitis and colonic Crohn's disease (together known as inflammatory bowel disease or IBD) are both associated with increased risk for colorectal cancer. Although it is customary to emphasize differences in the biology of IBD-associated and sporadic colon cancer, we believe these are far outweighed by the similarities. These similarities suggest that they might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to speculate that both IBD-associated and sporadic colon cancer might be the consequence of bacteria-induced inflammation.
Trends Mol Med 2002 Jan
PMID:Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared. 1179 61

Immunohistochemical decrease in staining for mismatch repair proteins may be seen in either microsatellite instability or inactivation (methylation) of mismatch repair proteins. Both are features of the malignant phenotype in a range of colorectal neoplasms. Expression of mismatch repair proteins in dysplastic lesions in ulcerative colitis (UC) has not been studied extensively. The authors analyzed protein expression of hMLH1, hMSH2, and hMSH6 in 18 cases of dysplasia-associated lesion or mass (DALM) in patients with UC and 10 sporadic adenomas. Immunohistochemical studies revealed adequate staining in almost all of the cases. A significant decrease in protein expression was seen in 2 DALM and 2 sporadic adenomas. The authors conclude that immunohistochemical studies of mismatch repair proteins can be applied to dysplastic lesions in UC with adequate staining results. Decreased wild type expression of hMLH1, hMSH2, and hMSH6 is not a feature of DALM in the setting of UC.
Appl Immunohistochem Mol Morphol 2002 Mar
PMID:Immunohistochemical screening of mismatch repair genes hMLH1, hMSH2, and hMSH6 in dysplastic lesions of the colon. 1189 37

An autoimmune mechanism has been postulated for the pathogenesis of ulcerative colitis (UC). The aim of this study was to evaluate the presence of anti-carbonic anhydrase (CA) I and anti-CA II antibodies in a series of inflammatory bowel disease (IBD) patients. We studied 58 IBD patients [36 UC patients and 21 patients with Crohn's disease (CD)]. As a control, 24 healthy individuals and 12 patients with non-IBD diarrheal diseases were tested. Serum anti-CA I and anti-CA II antibodies were quantified by enzyme-linked immunosorbent assay. Anti-CA II antibody was detected in 27.8% of UC patients, whereas anti-CA I antibody was detected in only 5.6% of UC patients. Positive rate of anti-CA II antibody was significantly higher in UC patients as compared to the control. In CD patients and non-IBD diarrheal patients, there were no significant increase in positive rate of either anti-CA I or II antibody. These results suggest that autoimmune responses against CA II may be involved in the pathogenesis of UC, and similar mechanism may participate in the development of pancreatic lesions in UC patients.
Int J Mol Med 2002 May
PMID:Elevated serum anti-carbonic anhydrase II antibodies in patients with ulcerative colitis. 1195 56


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