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)

Recent research points to the connection between behavioral and gut disorders. Early adverse events are associated with inflammatory bowel disease (IBD). In animal models, maternal deprivation and social isolation predispose to gastric erosion and brain pathology. This study examined (1) brain effects of chronic gastrointestinal inflammation in a rat model of acquired IBD and (2) whether such changes are resolved by individual secretin (S) or oxytocin (OT) peptide treatment. Neurological manifestations of IBD were mapped by c-fos gene expression in male Sprague-Dawley rats (n = 10) with trinitrobenzene sulfonic acid (TNBS)-induced IBD vs controls (n = 11). IBD was characterized by moderate/severe infiltration of inflammatory cells 10 d after TNBS infusion. Age-matched pairs were processed for immunocytochemical detection of Fos, expressed when neurons are stimulated. S or OT (100 mg/250 mL saline) or equivolume saline was administered iv by Alzet pump for 20 d after disease onset. Degree of resolution of colitis-induced brain activation was assessed by c-fos expression, and mean numbers of Fos-immunoreactive nuclei for each group were compared using Independent Samples T-test. Chronic IBD activated periventricular gray, hypothalamic/visceral thalamic stress axes and cortical domains, and septal/preoptic/amygdala, brain areas abnormal in autism. Single peptide treatment with S or OT did not alter the effects of inflammation on the brain. Brain areas concomitantly activated by visceral inflammation are those often abnormal in autism, suggesting that IBD could be a model for testing treatments of autism. Other single and combined peptide treatments of IBD should be tested. The clinical implications for treating autism, IBD, and concomitant sickness behaviors with peptide therapy, with or without maternal nurturing as a natural equivalent, are presented.
J Mol Neurosci 2005
PMID:Brain effects of chronic IBD in areas abnormal in autism and treatment by single neuropeptides secretin and oxytocin. 1580 Mar 79

The chronic idiopathic inflammatory bowel diseases (IBDs), namely Crohn's disease and ulcerative colitis, appear to be derived from an inappropriate reaction towards a luminal agent, most probably driven by the intestinal microflora, which upregulates the synthesis and release of different pro-inflammatory mediators, thus contributing to tissue damage that characterizes these intestinal conditions. Several studies have reported that IBD is associated with impairment in short-chain fatty acid (SCFA) production, mainly acetate, propionate, and butyrate. They are produced in the large bowel by anaerobic bacterial fermentation of undigested dietary carbohydrates and fiber polysaccharides, with butyrate being considered as the major fuel source for colonocytes. These SCFAs have been proposed to play a key role in the maintenance of colonic homeostasis. Therefore, it is reasonable to consider therapeutic approaches that increase colonic SCFA production, as it can be achieved by administration of dietary fiber to IBD patients. Unfortunately, there is quite limited documentation of efficacy of dietary fiber in properly designed trials. This review discusses the rationale, available evidence for the use of dietary fiber and its mechanisms of action in the treatment and prevention of IBDs.
Mol Nutr Food Res 2005 Jun
PMID:Effects of dietary fiber on inflammatory bowel disease. 1584 96

Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, localization of eosinophils to nerves is associated with nerve plasticity, specifically remodeling. In previous in vitro studies, we have shown that eosinophil adhesion to IMR-32 nerve cells, via nerve cell intercellular adhesion molecule-1, results in an adhesion-dependent release of granule proteins. We hypothesized that released eosinophil granule proteins may affect nerve cell signaling and survival, leading to nerve cell remodeling. Culture in serum-deprived media induced apoptosis in IMR-32 cells that was dose-dependently abolished by inclusion of MBP1 but not by EDN. Both MBP1 and EDN induced phosphorylation of Akt, but with divergent time courses and intensities, and survival was independent of Akt. MBP1 induced activation of neural nuclear factor (NF)-kappaB, from 10 min to 12 h, declining by 24 h, whereas EDN induced a short-lived activation of NF-kappaB. MBP1-induced protection was dependent on phosphorylation of ERK 1/2 and was related to a phospho-ERK-dependent upregulation of the NF-kappaB-activated anti-apoptotic gene, Bfl-1. This signaling pathway was not activated by EDN. Thus, MBP1 released from eosinophils at inflammatory sites may regulate peripheral nerve plasticity by inhibiting apoptosis.
Am J Respir Cell Mol Biol 2005 Aug
PMID:Diverse effects of eosinophil cationic granule proteins on IMR-32 nerve cell signaling and survival. 1586 Jul 94

Interleukin (IL)-8 plays a central role in the initiation and maintenance of inflammatory responses in the inflammatory bowel disease. The proinflammatory cytokine-mediated production of IL-8 requires activation of various kinases, which leads to the I kappa B degradation and NF-kappa B activation. We investigated the role of 18 beta-glycyrrhetinic acid (GA), a saponin isolated from licorice roots, on TNF-alpha-induced IL-8 production in human colonic epithelial cells. HT29 cells were stimulated with TNF-alpha in the presence or absence of GA (1, 5 or 10 microM). IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction analysis, and the mitogen-activated protein kinases (MAPKs) activation and I kappa B alpha degradation were determined by Western blot analysis. GA suppressed TNF-alpha-induced IL-8 production in a concentration-dependent manner. In addition, GA inhibited TNF-alpha-induced phosphorylation of p38 MAPK and extracellular-regulated kinases (ERK), I kappa B alpha degradation, and NF-kappa B activation. These results suggest that GA has the inhibitory effects on TNF-alpha-induced IL-8 production in the intestinal epithelial cells through blockade in the phosphorylation of MAPKs, following I kappa B alpha degradation and NF-kappa B activation.
Int J Mol Med 2005 Jun
PMID:Inhibition of interleukin-8 production in the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. 1587 Sep 3

The caspase recruitment domain-containing protein 15 gene (CARD15) was recently identified as an important susceptibility gene for Crohn's disease (CD). The purpose of this study was to assess the likelihood that the three most common CARD15 mutations, R702W, G908R and 1007fs, contribute to inflammatory bowel disease (IBD) susceptibility in the South African colored population. The study cohort included 76 IBD patients, 41 with CD and 35 with ulcerative colitis (UC), and 100 population-matched controls. Mutations R702W, G908R and 1007fs were present at relatively low frequencies (<20%) in our study population. No statistically significant differences were furthermore, observed for these mutations between UC and CD patients or when compared with normal control individuals. Two additional mutations were identified, one novel (A661P) and one previously described (A725G), with the latter being identified in 4 of 35 (11%) UC patients. Statistically significant differences were obtained between UC and control individuals when comparing both allele (p<0.004, chi2 with Yates' correction=8.01) and genotype frequencies (p<0.004, chi2 with Yates' correction=8.14) for the A725G mutation, suggesting a possible role for this variant in disease expression.
Mol Cell Probes 2005 Aug
PMID:Analysis of the three common mutations in the CARD15 gene (R702W, G908R and 1007fs) in South African colored patients with inflammatory bowel disease. 1596 35

Tumor necrosis factor (TNF) is involved in pathologies like septic shock, inflammatory bowel disease and rheumatoid arthritis. TNF and lipopolysaccharide can incite lethal shock, in which cardiovascular collapse is centrally orchestrated by the vasodilating free radical nitric oxide (NO). However, NO synthase (NOS) inhibition causes increased morbidity and/or mortality, suggesting a dual role for NO. To investigate the potential protective role of NO during TNF shock, we treated mice with TNF with or without NOS inhibition. Experiments in endothelial- NOS- and inducible NOS-deficient mice identified inducible NOS as the source of protective NO. Distinctive TNF-induced lipid peroxidation, especially in liver and kidney, was aggravated by NOS inhibition. In addition, various antioxidant treatments and a phospholipase A2 (PLA2) inhibitor prevented sensitization by NOS inhibition. Together, these in vivo results indicate that induced NO not only causes hemodynamic collapse, but is also essential for curbing TNF-induced oxidative stress, which appears to hinge on PLA2-dependent mechanisms.
Cell Mol Life Sci 2005 Jul
PMID:Dual role of endogenous nitric oxide in tumor necrosis factor shock: induced NO tempers oxidative stress. 1599 Sep 56

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.
J Mol Med (Berl) 2005 Aug
PMID:Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. 1601 May 82

Recent evidence demonstrates that the increased expression and activity of matrix metalloproteinases (MMPs) may contribute to intestinal tissue injury and inflammation in inflammatory bowel disease, and that MMP inhibition might be a new therapeutic approach to controlling inflammatory response. In addition, MMPs may play a crucial role in physiological and pathophysiological reactions such as leukocyte accumulation into inflamed tissue, cytokine production from inflammatory and epithelial cells, T lymphocyte homing to the intestine, wound healing and proliferation of epithelial cells, and intestinal innate immunity. This review focuses on recent progress in elucidating the biological and pathological roles of MMPs in inflammatory bowel disease.
Mol Aspects Med
PMID:Role of matrix metalloproteinases in inflammatory bowel disease. 1611 87

The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease (IBD), we evaluated the development of dextran sulfate sodium (DSS)-induced colitis in genetically complement C5-deficient mice. We used DBA2/J mice, which are genetically deficient in complement C5. DBA1/J mice have a normal complement system, and were used as controls. Experimental colitis was induced by the oral administration of 3.5% (w/v) DSS in their drinking water for 10 days. On day 10, all mice were sacrificed and their colons were collected. The development of colitis was assessed by the histological score, disease activity index, myeloperoxidase (MPO) activity, and macroscopic changes of the colon. Body weight loss was more apparent in the DBA2/J mice than in control DBA1/J mice. The colon length was shorter in the DBA2/J mice than in DBA1/J mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in the DBA2/J mice than in DBA1/J mice. Microscopically, mucosal edema, cellular infiltration and disruption of the epithelium were much more severe in the DBA2/J mice than in DBA1/J mice. The development of DSS colitis was aggravated in genetically C5-deficient DBA2/J mice. These findings suggest that the complement system might play a protective role in the development of DSS-induced experimental colitis.
Int J Mol Med 2005 Oct
PMID:Development of dextran sulfate sodium-induced colitis is aggravated in mice genetically deficient for complement C5. 1614 93

The involvement of genetic factors in the etiology of autism has been clearly established. We undertook a genome-wide search for regions containing susceptibility genes for autism in 12 subjects with childhood autism and related pervasive developmental disorders (PDDs) and 44 controls from the relatively isolated population of the Faroe Islands. In total, 601 microsatellite markers distributed throughout the human genome with an average distance of 5.80 cM were genotyped, including 502 markers in the initial scan. The Faroese population structure and genetic relatedness of cases and controls were also evaluated. Based on a combined approach, including an assumption-free test as implemented in CLUMP, Fisher's exact test for specific alleles and haplotypes, and IBD(0) probability calculations, we found association between autism and microsatellite markers in regions on 2q, 3p, 6q, 15q, 16p, and 18q. The most significant finding was on 3p25.3 (P(T1)=0.00003 and P(T4)=0.00007), which was also supported by other genetic studies. Furthermore, no evidence of population substructure was found, and a higher degree of relatedness among cases could not be detected, decreasing the risk of inflated P-values. Our data suggest that markers in these regions are in linkage disequilibrium with genes involved in the etiology of autism, and we hypothesize susceptibility genes for autism and related PDDs to be localized within these regions.
Mol Psychiatry 2006 Jan
PMID:A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands. 1620 37


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