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)

Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis are inflammatory disorders associated with decreased colonic contractility. Here we show that, in experimental colitis in rat induced by trinitrobenzenesulfonic acid, there is a decrease in contraction in response to carbamoylcholine and the sarco/endoplasmic reticulum Ca(+2) (SERCA) pump inhibitor thapsigargin. However, the decrease in contractility may occur due to decrease in the SERCA pump levels or their inactivation. Therefore, we examined the protein and mRNA levels for SERCA2 isoform, which is predominant isoform in colonic smooth muscle. There was a decrease in the levels of SERCA2 protein and mRNA levels in inflamed colonic muscle. These findings suggest that decreased SERCA pump levels is responsible for a decrease in the Ca(+2) stores in the sarco/endoplasmic reticulum that causes a decrease in the contractility in colonic smooth muscle leading to poor bowel movements.
Mol Cell Biochem 2007 Apr
PMID:Mechanism of reduced colonic contractility in experimental colitis: role of sarcoplasmic reticulum pump isoform-2. 1713 Oct 44

There is strong evidence to suggest that endothelial progenitor cells (EPCs) play a significant role in re-endothelialization and subsequent tissue repair. This study examined the role of EPCs in inflammatory bowel disease, a disease in which impairment of mucosal healing has been implicated. Peripheral blood mononuclear cells obtained from 50 patients with ulcerative colitis (UC), 29 patients with Crohn's disease (CD), 14 patients with infectious colitis, and 35 normal control subjects were cultured in EPC medium, harvested after 7 days, and characterized by immunocytochemistry and flow cytometry. Colony assay for hematopoietic progenitor cells was also performed. Patients with active UC had a significantly decreased number of circulating EPCs as compared with healthy controls (p=0.0013), patients with inactive UC (p=0.0099), patients with active CD (p=0.0235) and patients with infectious colitis (p=0.0002). On the other hand, patients with infectious colitis had a significantly increased number of circulating EPCs as compared with healthy controls (p=0.0406), patients with active UC (p=0.0002), and patients with active CD (p=0.0316). In patients with UC, the number of circulating EPCs was correlated with the serum hemoglobin levels (r=0.485, p=0.007) and inversely with the platelet count (r=-0.372, p=0.0382). The number of hematopoietic progenitor cell colonies was comparable among patients with UC, patients with CD, patients with infectious colitis, and healthy controls. Our observations indicate that the number of circulating EPCs in patients with UC is significantly reduced. Further studies are needed to define the mechanisms that underlie the reduction in the number of circulating EPCs and to better understand the pathophysiological consequences of this event in patients with UC.
Int J Mol Med 2007 Feb
PMID:Depletion of endothelial progenitor cells in the peripheral blood of patients with ulcerative colitis. 1720 95

The overproduction of reactive oxygen and nitrogen species (RONS) may play an important role in ulcerative colitis (UC)-associated carcinogenesis. In order to study the role of nitric oxide (NO) in UC-associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced model of chronic UC in inducible nitric oxide synthase (iNOS)-deficient mice. Female wild-type C57BL/6 (iNOS+/+) and iNOS-/- mice were administered 1% DSS (w/v) through the drinking fluid for 15 DSS cycles and fed twofold iron-enriched diet. Colorectal inflammation and mucosal ulceration of moderate severity were observed in both iNOS+/+ and iNOS-/- mice. Similar tumor incidence and multiplicity in the colon were observed that 15 out of 23 (65.2%) iNOS+/+ mice developed colorectal tumors with a tumor multiplicity of 1.47+/-0.17 (mean+/-SE) after 15 DSS cycles, and 13 out of 19 (68.4%) iNOS-/- mice developed colorectal tumors with a tumor multiplicity of 2.08+/-0.21. Histopathologically, the tumors were confirmed to be well-differentiated adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite-caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon in iNOS+/+ and iNOS-/- mice, and no difference in staining intensity was observed between the two groups. Immunostaining for endothelial NOS (eNOS) was observed in lamina propria macrophages and colonic blood vessels, and eNOS protein levels were increased in the inflamed colon. These results show that there is no difference in UC-associated cancer development in iNOS+/+ and iNOS-/- mice, and suggest that in the absence of iNOS, other factors, such as eNOS, may play a role in nitrosative stress and UC-associated carcinogenesis in this model system.
Mol Carcinog 2007 May
PMID:Colorectal carcinoma development in inducible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis. 1721 24

The sphingosine-1-phosphate analogue FTY720 is known to alter migration and homing of lymphocytes via sphingosine-1-phosphate receptors. However, several studies indicate that its mode of action is more complex and that FTY720 may also directly influence cytokine effector functions. Therefore, we studied the effect of FTY720 in T helper type (Th2)-mediated oxazolone-induced colitis in mice. Following rectal oxazolone instillation, Th2 cells producing IL-13 induce a progressive colitis resembling human ulcerative colitis. A rectal enema of oxazolone [90 mg/kg body weight] was applied to BALB/c mice. FTY720 was administered i.p. from day 0 to 3 or from day 3 to 5 following the instillation of the haptenating agent. Assessment of severity of colitis was performed daily. FTY720 plasma levels were detected using LC-MS/MS-analysis. Colon tissue was analyzed macroscopically and microscopically, myeloperoxidase activity as well as cytokine levels of lamina propria CD4(+) T-cells and T1/ST2 expression were determined. Treatment with FTY720 prominently reduced the clinical and histopathologic severity of oxazolone-induced colitis, abrogating body weight loss, diarrhea, and macroscopic and microscopic intestinal inflammation. The therapeutic effects of FTY720 were associated with a prominent reduction of the key effector Th2 cytokines IL-13, IL-4 and IL-5. Strikingly, FTY720 inhibited GATA3 and T1/ST2 expression which represent highly relevant markers for Th2 differentiation and Th2 effector function, respectively. Our data provide the first evidence that FTY720 exhibits beneficial prophylactic as well as therapeutic effects in Th2-mediated experimental colitis by directly affecting Th2 cytokine profiles probably by reducing T1/ST2, thus offering a new auspicious therapeutic instrument for the treatment of human ulcerative colitis.
Mol Immunol 2007 Jul
PMID:FTY720 ameliorates oxazolone colitis in mice by directly affecting T helper type 2 functions. 1747 30

Hydrogen sulfide (H(2)S) is produced by indigenous sulfate-reducing bacteria in the large intestine and represents an environmental insult to the colonic epithelium. Clinical studies have linked the presence of either sulfate-reducing bacteria or H(2)S in the colon with chronic disorders such as ulcerative colitis and colorectal cancer, although at this point, the evidence is circumstantial and underlying mechanisms remain undefined. We showed previously that sulfide at concentrations similar to those found in the human colon induced genomic DNA damage in mammalian cells. The present study addressed the nature of the DNA damage by determining if sulfide is directly genotoxic or if genotoxicity requires cellular metabolism. We also questioned if sulfide genotoxicity is mediated by free radicals and if DNA base oxidation is involved. Naked nuclei from untreated Chinese hamster ovary cells were treated with sulfide; DNA damage was induced by concentrations as low as 1 micromol/L. This damage was effectively quenched by cotreatment with butylhydroxyanisole. Furthermore, sulfide treatment increased the number of oxidized bases recognized by formamidopyrimidine [fapy]-DNA glycosylase. These results confirm the genotoxicity of sulfide and strongly implicate that this genotoxicity is mediated by free radicals. These observations highlight the possible role of sulfide as an environmental insult that, given a predisposing genetic background, may lead to genomic instability or the cumulative mutations characteristic of colorectal cancer.
Mol Cancer Res 2007 May
PMID:Hydrogen sulfide induces direct radical-associated DNA damage. 1747 72

There is conflicting evidence regarding the significance of vasoactive intestinal peptide (VIP) in inflammatory bowel disease (IBD). Involvement of the VIP receptor in IBD has not been reported. We examined the expression and localization of the VIP receptor in IBD. We determined the location of VIP receptor 1 (VIPR1) immunohistologically in surgically resected intestinal samples from 10 controls, 15 patients with ulcerative colitis, and 10 patients with Crohn's disease. A fluorescein-linked immunohistological study was performed using anti-VIPR1 antibody, with double-staining with antibodies to CD3, CD19, and CD68. Correlations with interleukin (IL)-4 and TNF-alpha expression were also investigated. Results showed that the number of VIPR1-positive cells was significantly increased in the inflammatory mucosa. VIPR1 was expressed in CD3-, CD19-, and CD68-positive cells. The proportion of VIPR1-positive cells among CD3-positive cells was significantly higher in the lamina propria of patients with ulcerative colitis than in those with Crohn's disease and the controls. The proportion of VIPR1-positive cells among CD68-positive cells was significantly higher in patients with ulcerative colitis and Crohn's disease than in the controls. A correlation between the numbers of VIPR1- and IL-4-positive cells was found in patients with ulcerative colitis, and between the numbers of VIPR1- and TNF-alpha-positive cells in patients with Crohn's disease. In conclusion, VIPR1 was widely expressed in infiltrating inflammatory cells, especially CD3- and CD68-positive cells in ulcerative colitis mucosa and CD68-positive cells in Crohn's disease mucosa. The differential expression of VIPR1 in ulcerative colitis and Crohn's disease mucosa suggests that the VIP system plays different roles in the pathogenesis of IBD.
Int J Mol Med 2007 Aug
PMID:Differential expression of vasoactive intestinal peptide receptor 1 expression in inflammatory bowel disease. 1761 33

Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype, although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.3. We have assessed, in detail, the influence of germline NOD1/CARD4 variation on IBD susceptibility and phenotype in the Scottish population. Two thousand two hundred and ninety-six subjects, including 356 children with IBD, were involved in parallel case-control and family-based association studies. Nine tagging single-nucleotide polymorphisms (SNPs) were selected based on HapMap data spanning the whole of the NOD1/CARD4 gene. Our case-control SNP analysis was powered to detect an effect size with OR 1.5 for IBD and OR 1.6 for CD. No significant associations were observed between any of nine the NOD1/CARD4 SNPs studied and IBD, CD or ulcerative colitis (UC) (P > 0.05 for all). Haplotype case-control analysis was also negative (P > 0.05 in IBD, CD and UC). Multimarker transmission disequilibrium testing analysis was negative (P > 0.05 in IBD, CD and UC). NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility. This study represents the first application of a gene -wide haplotype-tagging approach to assess, in detail, the contribution of NOD1/CARD4 in IBD.
Hum Mol Genet 2007 Sep 15
PMID:Investigation of NOD1/CARD4 variation in inflammatory bowel disease using a haplotype-tagging strategy. 1761 38

The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.
Hum Mol Genet 2007 Dec 15
PMID:An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. 1788 57

Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (-/-), Ogg1 (+/-), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 +/- 5.2 mm(3). Ogg1 (-/-) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 +/- 6.1 mm(3). Ogg1 mice (+/-) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 +/- 7.2 mm(3). Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (-/-) and (+/-) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis.
Mol Carcinog 2008 Aug
PMID:Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. 1830 Feb 66

In approximately one-fourth of patients with Crohn's disease (CD) and ulcerative colitis (UC), disease onset occurs during childhood and adolescence. In addition to gastrointestinal and extraintestinal symptoms of inflammatory bowel disease (IBD), children with these conditions often experience one or more nutritional complications of their disease including growth failure, delayed puberty, osteoporosis, anemia, and micronutrient deficiencies. This article provides an overview of the epidemiology, pathophysiology, evaluation, and management of selected nutritional complications in pediatric IBD.
Mol Nutr Food Res 2008 Aug
PMID:Nutritional concerns in pediatric inflammatory bowel disease patients. 1832 5


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