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)

Our studies have concentrated on elucidating the role of the signaling protein Sin in T-lymphocyte function. We have previously shown that Sin overexpression inhibits T-lymphocyte development and activation. Here we show that Sin-deficient mice exhibit exaggerated immune responses characterized by enhanced cytokine secretion and T-cell-dependent antibody production. Excessive T-cell responses in young mice correlate with spontaneous development of inflammatory lesions in different organs of aged Sin(-/-) mice, particularly the small intestine. The intestinal inflammation is characterized by T- and B-cell infiltrates in the lamina propria, which correlate with crypt enlargement and marked villus expansion and/or damage. Similar to the human intestinal inflammatory disorder Crohn's disease (CD), and in contrast to most mouse models of mucosal inflammation, inflammatory lesions in the gastrointestinal tract of Sin(-/-) mice are restricted to the small bowel. Taken together, these results suggest that Sin regulates immune system and T-lymphocyte function and that immune system dysfunction in the absence of Sin may underlie the pathogenesis of tissue-specific inflammation and enteropathies such as CD.
Mol Cell Biol 2005 Dec
PMID:Deficiency in expression of the signaling protein Sin/Efs leads to T-lymphocyte activation and mucosal inflammation. 1631 25

High-frequency microsatellite instability has been reported to be associated with good prognosis in colorectal adenocarcinoma. However, methods to assess microsatellite instability (MIN) are based on genetic assays and are not ideally suited to most histopathology laboratories. The aim of the present study was to develop a model for prediction of MIN status in colorectal cancer based on phenotypic characteristics. Clinicopathological features of a cohort of 204 patients with primary colon cancer were retrospectively reviewed following predetermined criteria. Genetic assessment of MIN status was performed on DNA extracted from sections of formalin-fixed, paraffin-embedded specimens by testing a panel of 11 microsatellite markers. Logistic regression analysis generated a mathematical tool capable of identifying colorectal tumors displaying MIN status with a sensitivity of 77.8% and a specificity of 96.8%. Features associated with instability included the proximal location of the lesions, occurrence of solid and/or mucinous differentiation, absence of cribriform structures, presence of peritumoral Crohn-like reaction, expansive growth pattern, high Ki67 proliferative index, and p53-negative phenotype. This approach predicts microsatellite instability in colorectal carcinoma with an overall assigned accuracy of 95.1% and a negative predictive value of 97.8%. Implementation of this tool to routine histopathological studies could improve the management of patients with colorectal cancer, especially those presenting with stage II and III of the disease. It will also assist in identifying a subset of patients likely to benefit from adjuvant chemotherapy.
Diagn Mol Pathol 2005 Dec
PMID:A novel logistic model based on clinicopathological features predicts microsatellite instability in colorectal carcinomas. 1631 91

Recent studies have suggested that the enhanced release of reactive oxygen species (ROS) plays an important role in the pathogenesis of clinical inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. In the present study, we investigated the effects of the free radical scavengers edaravone and tempol in the development of experimental dextran sulfate sodium (DSS)-induced colitis in mice. Male BALB/cA mice were fed 4% (w/w of diet) DSS in standard powder chow for 8 days. Edaravone, tempol, or vehicle saline were then injected subcutaneously twice per day. After the experimental period, the colonic length, histological damage score, and mucosal myeloperoxidase (MPO) and serum interleukin-6 (IL-6) levels were measured. Edaravone (15 mg/kg/day) and tempol (5-15 mg/kg/day) suppressed the colonic shortening and the damage score. In particular, tempol at 15 mg/kg/day significantly attenuated the colonic shortening and damage score. Edaravone and tempol suppressed the serum IL-6 levels, and significantly suppressed the increased colonic MPO levels. These results strongly support the involvement of ROS in the pathogenesis of DSS-induced colitis. A clinical effect for edaravone and tempol in IBD patients is strongly expected.
Int J Mol Med 2006 Feb
PMID:The free radical scavengers edaravone and tempol suppress experimental dextran sulfate sodium-induced colitis in mice. 1639 34

Infection imaging is complicated due to multitude of factors interfering with the design of radiopharmaceuticals. More than 3 decades ago, labeled leukocytes have been introduced for infection imaging and new radiopharmaceuticals have been emerging on regular basis. However, labeled leukocytes by in vivo and in vitro methods are very effective for diagnosing various lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease and in distinguishing prosthetic infection from loosening of prosthesis. But in vitro labeling method using (111)In-oxine, (99m)Tc-HMPAO or (99m)Tc-stannous colloid have the inherent limitation of personnel safety risks of infection and cross contamination. To overcome these problems, attempts have been made to directly target leukocytes by in vivo labeling techniques. There are several receptors present on the leukocytes and the granulocytes, which can be targeted with suitable ligands. These will include anti-NCA90-Fab, murine MoAb IgG(1) that is cross-reactive to antigen 95 on neutrophils, anti-CD15 antigen and DPC-11870 that targets the leukotriene B4 receptors of granulocytes. In a new approach, (99m)Tc-labeled ciprofloxacin has been developed to directly target ''live bacteria'' to detect infection by in vivo method. This approach showed considerable promise in the preliminary studies but clinical trials showed limitations. Analogs of a natural mammalian antimicrobial agents, such as Ubiquicidin were successful in animal studies and have now entered clinical trials. (99m)Tc-labeled fluconazole (a fungal antibiotic) and labeled Chitinase ((123)I-ChiB_E144Q), have been developed to detect fungal infection. The ability to distinguish between fungal and bacterial infection is considered important, as patients undergoing chemotherapy are prone to fungal infection. Undoubtedly, the new trends and new radiopharmaceuticals developed for infection and inflammation imaging have contributed towards a better understanding of the underlying processes.
Q J Nucl Med Mol Imaging 2005 Dec
PMID:Radiolabeled white blood cells and direct targeting of micro-organisms for infection imaging. 1640 16

Several lines of evidence suggest a role for the multidrug resistance gene (ABCB1/MDR1) and its product, P-glycoprotein 170, in the pathogenesis of inflammatory bowel disease (IBD). In addition, P-glycoprotein activity determines bioavailability of many drugs used regularly in many medical specialties, and ABCB/MDR1 variation appears to be a critical pharmacogenetic determinant. We have utilized a gene-wide haplotype tagging approach to further define the identity of germ-line variations in the ABCB1/MDR1 gene contributing to IBD susceptibility. Six haplotype tagging single nucleotide polymorphisms (tSNPs) representing the haplotypic variations of the ABCB1/MDR1 gene were identified initially following the characterization of the haplotype structure of this gene in 24 Centre d'Etude du Polymorphisme Humain Caucasian trios. Genotyping was performed in 249 ulcerative colitis (UC) and 179 Crohn's disease (CD) patients and 260 healthy controls. Using log-likelihood analysis, we observed a highly significant association between the common haplotypes and UC (P=4.22 x 10(-7)) but not CD (P=0.22). This significant association was critically dependent on one tSNP, intronic variant rs3789243. All haplotypes with this variant retained a highly significant association (P=3.2 x 10(-7)-3.6 x 10(-12)), whereas significance was lost when rs3789243 was dropped in systematic haplotypic analysis. The effect of this tSNP was independent of C3435T SNP, previously suggested to be the critical variant in disease susceptibility and drug transport. The association with UC was shown to be strongest with the phenotype of extensive disease (P=1.7 x 10(-7)). This 'candidate gene' approach provides compelling evidence to support the contribution of the ABCB1/MDR1 gene in determining risk to UC but not to CD and provides new insights into the localization of the critical susceptibility determinants within the gene. In addition, these findings have potentially important implications in the application of pharmacogenetics across a range of common diseases, including HIV, epilepsy and colorectal cancer.
Hum Mol Genet 2006 Mar 01
PMID:ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. 1643 79

Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard diagnosis of UC and CD.
J Mol Diagn 2006 Feb
PMID:Molecular classification of Crohn's disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells. 1643 34

Since Jun-N-terminal kinase participates in intracellular signaling cascades resulting in inflammatory responses, inhibiting this pathway may represent a new treatment for inflammatory bowel disease including ulcerative colitis and Crohn's disease. However, the functional significance of the activation of this kinase in inflammatory bowel disease remains unclear. We investigated whether Jun-N-terminal kinase activation is increased in inflammatory bowel disease and analyzed the effects of SP600125, which decreases inflammatory cytokine synthesis by inhibiting the phosphorylation of this kinase. Phosphorylation of the kinase was examined in affected human colon using an enzyme-linked immunosorbent assay and immunohistochemistry. The effect of SP600125 on cytokine production was examined in cultures of patients' leukocytes and colonic tissue. Finally, rats received injection of SP600125 (30 mg/kg, s.c.) or vehicle twice daily 2 h before the induction of colitis with dextran sulfate sodium. SP600125 effects were determined observationally and histologically. Colonic tissue contained increased phosphorylated kinase in patients with inflammatory bowel disease with expression localized to the nucleus of epithelial and lamina propria mononuclear cells in lesions. Culturing mononuclear cells or colonic tissue with SP600125 down-regulated inflammatory cytokine production. Prophylactic treatment with SP600125 significantly reduced clinical and pathological scores in dextran sulfate sodium-treated rats. This first demonstration of the pathogenetic role of Jun-N-terminal kinase in the development of intestinal inflammation suggests that inhibiting its phosphorylation could benefit patients with inflammatory bowel disease.
Int J Mol Med 2006 Mar
PMID:Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease. 1646 91

Mutated variants of NOD2, a cytosolic Toll-like receptor (TLR) that recognizes bacterial peptidoglycan, are responsible for increased susceptibility to Crohn's disease (CD). TLRs and their related plant counterparts, the disease-resistance R proteins, undergo alternative splicing as a means of controlling activity. Here we report that regions of NOD2 RNA transcripts that encode the N-terminal and leucine-rich repeat (LRR) domains are alternatively spliced, potentially creating at least eight putative NOD2 variants. The most common variant is a short truncated isoform designated NOD2-short which terminates at residue position 820 leaving three LRR domains. An N-terminally spliced variant designated NOD2-190 contains only CARD1 and a partial CARD2 domain. The expression of transcripts encoding full-length and alternatively spliced forms of NOD2 was altered in blood mononuclear cells and monocytic cell lines stimulated by bacterial products. NOD2-short and NOD2-190 were inactive and unresponsive to muramyl dipeptide (MDP), but did not antagonize the activity of wild-type NOD2. Alternative splicing of NOD2 transcripts represents a potential mechanism by which the intracellular bacterial sensing activity of NOD2 is altered or down-regulated.
Mol Immunol 2007 Jan
PMID:Splicing of NOD2 (CARD15) RNA transcripts. 1667 18

Sulfasalazine is used in the treatment of ulcerative colitis, Crohn's disease, and rheumatoid arthritis. When administered orally, sulfasalazine is poorly absorbed with an estimated bioavailability of 3-12%. Recent studies using the T-cell line (CEM) have shown that sulfasalazine is a substrate for the ATP-binding cassette (ABC) efflux pump ABCG2. ABCG2 is known to efflux a number of xenobiotics and appears to be a key determinant of efficacy and toxicity of ABCG2 substrates. To date, there has not been any systematic study on the mechanisms involved in the transport of sulfasalazine in vivo. Accordingly, we investigated whether Bcrp (abcg2) is involved in the disposition of sulfasalazine. After oral administration of 20 mg/kg sulfasalazine, the area under the plasma concentration (AUC) time profile in Bcrp1 (abcg2)-/- knockout (KO) mice was approximately 111-fold higher than that in FVB wild-type (WT) mice. After intravenous administration of 5 mg/kg sulfasalazine, the AUC in Bcrp1 (abcg2)-/- KO mice was approximately 13-fold higher than that in WT mice. Moreover, treatment of WT mice with a single oral dose of gefitinib (Iressa; 50 mg/kg), a known inhibitor of Bcrp, given 2 h prior to administering a single oral dose of sulfasalazine (20 mg/kg), resulted in a 13-fold increase in the AUC of sulfasalazine compared to the AUC in vehicle-treated mice. Since gefitinib is also an inhibitor of P-glycoprotein (P-gp), the impact of P-gp on sulfasalazine absorption in vivo was also examined. The sulfasalazine AUC in mdr1a-/- KO versus WT mice did not differ significantly after either an oral (20 mg/kg) or an intravenous dose (5 mg/kg). We conclude that Bcrp (abcg2) is an important determinant for the oral bioavailability and the elimination of sulfasalazine in the mouse, and that sulfasalazine has the potential to be utilized as a specific in vivo probe of Bcrp (abcg2).
Mol Pharm
PMID:Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. 1668 69

Few of the studied genes demonstrate association with inflammatory bowel disease (IBD). Three mutations in the nucleotide-binding oligomerization domain 2 gene have consistently shown to be independent risk factors for Crohn's disease, but none of the alleles exhibited high sensitivity or specificity for IBD. Linkage analysis implicated several loci on various chromosomes, and epistasis has been demonstrated. The etiopathogenesis of IBD remains unknown, and environmental contribution to their pathogenesis is evident from genetic studies that demonstrated incomplete monozygotic twins concordandance rate for both Crohn's and ulcerative colitis. Smoking has shown an opposite effect on disease phenotype, with an adverse effect on disease course for Crohn's disease, but a slight beneficial effect in ulcerative colitis. The contribution of infectious agents to susceptibility to IBD appears to be strong. However, the role of nutrition on the etiology and therapy of IBD is not clear. Inconsistencies in environmental risk factors could be due to gene-environment interactions, making it essential to study the role of genetics and environmental contribution to the etiopathology of IBD. Transgenic or knockout mice, such as interleukin-10(-/-), T-cell receptor alpha(-/-), Galphai(2) (-/-) and N-cadherin(-/-), develop colitis-like inflammation similar to humans. Therefore, animal models must be further studied to explore mechanistic interactions.
Expert Rev Mol Diagn 2006 May
PMID:Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases. 1670 38


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