Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A computer-assisted multicomponent analytical system, developed for comparative biochemical studies, was used for a clinical study of Crohn's disease in which 73 subjects, of comparable age and sex distribution, were considered: 40 with Crohn's disease, 16 with ulcerative colitis and 17 healthy volunteers as controls. Blood samples (5 ml) were taken to recover plasma and red cells. After extraction and fractionation of low- and high-molecular weight substances, the samples were analysed by ion-exchange chromatography and electrophoresis. The contents of amino acids, sugars, polyamines and proteins in the plasma and the red cells from the three groups of individuals were compared using statistical (means, variance, principal components analysis) and graphical profile methods. The first results indicate that the content of red cells, in comparison with plasma, allows the best differentiation of the three groups of subjects considered. In particular, the amino acids (Asp, Thr, Ser, Glu, Gly, Ala and Leu), the polyamines (spermidine and spermine) and glucose, show the most significant differences. The methodology followed and the results obtained, together with possible uses of this computer-assisted multicomponent analytical system in problems concerning clinical research, are discussed.
 ...
PMID:Chromatography, flow injection analysis and electrophoresis in computer-assisted comparative biochemistry: its application and possibilities in clinical research. Preliminary studies on Crohn's disease. 340 65

A prospective study was carried out on 20 patients admitted for transurethral prostatic resection, measuring renal function, body hydratation and levels of glycine metabolic products. This study has shown that only the haematocrit measurement during surgery allowed the early and reliable recognition of resorption of the solution. High glycine levels after resorption were reduced by increasing urinary excretion of glycine, serine, creatinine and to a lesser extent, threonine. The increased production of oxalate, another elimination pathway, leads to a urinary saturation with consequent risk of lithogenesis. Furthermore, this hyperoxaluria may cause an intersticial nephropathy as do the other secondary hyperoxalurias, including Crohn's disease, bowel by-pass or xylitol intoxication.
 ...
PMID:[Catabolism of glycine used in lavage solutions in urologic surgery. Apropos of a prospective study of 20 patients undergoing endourethral resection of the prostate]. 408 75

Previous studies have shown the presence in faeces of sulphatases, sialidases, glycosidases, and proteases relevant to mucus degradation, but the relative role of these enzymes in the degradation of colonic mucus has been unclear. A total mucinase assay using 14C threonine biologically labelled human colonic mucin as substrate was therefore developed in this study. Faecal mucinase activity of a pooled normal faecal filtrate was capable of removing 80% of the 14C threonine label from mucin within eight hours incubation, but 20% remained intact despite prolonged incubation. The pH profile of mucinase activity is broad (pH 4.5-9.5) suggesting contribution from multiple enzymes. Mucinase activity was reduced by preincubation with 100 micrograms/ml chymostatin (82.8%), 0.5 mg/ml EDTA (91.6%), and 4 g/l bismuth subsalicylate (72.0%). All 55 faecal samples studied contained detectable mucinase activity, measured as dpm release/micrograms protein/hour, which was greater in samples from patients with ulcerative colitis (n = 17, median 52.7, interquartile range 32.9-66.9), than controls (n = 26, 34.4, 26.8-40.4, p < 0.02) or patients with Crohn's disease (n = 12, 35.5, 17.5-55.7, p < 0.05). There was, however, no significant difference in faecal mucinase activity between inactive and active ulcerative colitis. These results suggest that faecal mucinase activity is one factor contributing to the thin mucus layer in ulcerative colitis and represents a potential target for drug treatment.
 ...
PMID:Faecal mucinase activity assessed in inflammatory bowel disease using 14C threonine labelled mucin substrate. 767 82

Crohn disease is immunologically mediated and characterized by intestinal and systemic chronic inflammation. In a rat model, injection of peptidoglycan-polysaccharide complexes into the intestinal wall induced chronic inflammation in Lewis but neither Fischer nor Buffalo rats, indicating a differential genetic susceptibility. Proteolysis of plasma high molecular weight kininogen (HK) yielding bradykinin and cleaved HK (HKa) was faster in Lewis than in Fischer or Buffalo rat plasma. A single point mutation at nucleotide 1586 was found translating from Ser511 (Buffalo and Fisher) to Asn511 (Lewis). The latter defines an Asn-Xaa-Thr consensus sequence for N-glycosylation. We expressed these domains in Escherichia coli and found no differences in the rate of cleavage by purified kallikrein in the 3 strains in the absence of N-glycosylation. We then expressed these domains in Chinese hamster ovary (CHO) cells, which are capable of glycosylation, and found an increased rate of cleavage of Lewis HK. The Lewis mutation is associated with N-glycosylation as evidenced by a more rapid migration after treatment with N-glycosidase F. When CHO cells were cultured in the presence of tunicamycin, the kallikrein-induced cleavage rate of Lewis HK was not increased. This molecular alteration might be one contributing factor resulting in chronic inflammation in Lewis rats.
 ...
PMID:The mutation Ser511Asn leads to N-glycosylation and increases the cleavage of high molecular weight kininogen in rats genetically susceptible to inflammation. 1284 92

Crohn disease (CD) and ulcerative colitis (UC) are overlapping chronic inflammatory bowel diseases (IBDs). Suggestive evidence for linkage at chromosome 7q has been reported for both CD and UC. Contained within this region is the gene for MDR1 (multidrug resistance), a membrane transport protein for which human polymorphisms have been reported in Ala893Ser/Thr and C3435T that alter pharmacokinetic profiles for a variety of drugs. Because mdr1 knockout mice spontaneously develop colitis, exonic regions were resequenced and tested for IBD association in a large, multicenter North American cohort. Two missense mutations, Asn21Asp and Ala893Ser/Thr, as well as the expression-associated polymorphism C3435T, described elsewhere, were genotyped in the entire cohort. Significant association of Ala893 with IBD was observed by both case-control analysis (P=.002) and the pedigree disequilibrium test (PDT [P=.00020-.00030]) but not for the Asn21Asp or C3435T polymorphisms. Significant association by PDT was observed within the subset with CD (P=.0014-.00090), with similar, nonsignificant trends in a smaller subset with UC. The Ala893Ser/Thr variant is triallelic, and the associated, common allele is Ala893, with undertransmission of the 893Ser (common) and the 893Thr (rare) variants. The Ala893 variant has decreased activity compared with the 893Ser variant; therefore, the association with human IBD is consistent with the murine model of mdr1 deficiency. Taken together, these data support the association of the common Ala893 polymorphism with IBD specifically and, more broadly, provides additional support for its contribution to interindividual pharmacogenetic variation.
 ...
PMID:MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. 1461 Jul 18

Human thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. TPMT is genetically polymorphic and is associated with large interindividual variations in thiopurine drug toxicity and therapeutic efficacy. During routine genotyping of patients with Crohn's disease, one novel missense mutation, 365A>C (TPMT*19, Lys(122)Thr), and a recently described missense mutation, 488G>A (TPMT*16, Arg(163)His), were identified in a Caucasian and a Moroccan patient, respectively. Using a heterologous yeast expression system, kinetic parameters (K(m) and V(max)) of the two variants with respect to 6-thioguanine S-methylation were determined and compared with those obtained with the wild-type enzyme. The Lys(122)Thr exchange did not significantly decrease the intrinsic clearance value (V(max)/K(m)) of the variant enzyme. In contrast, the Arg(163)His substitution significantly decreased the intrinsic clearance value by three-fold. The Arg(163) is located in a highly conserved region of the human TPMT protein and, as such, the Arg(163)His substitution is expected to result in a marked reduction of enzyme activity, as confirmed by the in vitro data. Phenotyping by measurement of red blood cell TPMT activity indicated that the patient heterozygous for the Lys(122)Thr mutation had normal TPMT activity, whereas the patient heterozygous for the Arg(163)His mutation was an intermediate methylator, which demonstrated a positive correlation between TPMT phenotyping and the in vitro data. The identification of a novel non-functional allele of the TPMT gene improves our knowledge of the genetic basis of interindividual variability in TPMT activity. These data further enhance the efficiency of genotyping methods to predict patients at risk of an inadequate response to thiopurine therapy.
 ...
PMID:Identification and functional analysis of two rare allelic variants of the thiopurine S-methyltransferase gene, TPMT*16 and TPMT*19. 1565 43

The p38 mitogen-activated protein (MAP) kinases are a family of serine/threonine protein kinases that play important roles in cellular responses to inflammation and external stress. Inhibitors of the p38 MAP kinase have shown promise for potential treatment of inflammatory disorders such as rheumatoid arthritis, acute coronary syndrome, psoriasis, and Crohn's disease. We identified a novel class of p38 inhibitors via high-throughput screening. PS200981 [3-(4-(1,4-diazepan-1-yl)-6-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a representative compound identified from screening a collection of combinatorial libraries, amounting to 2.1 million compounds, inhibits p38alpha kinase and the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor (TNF) alpha levels in cell media of human monocytes with IC50 values of 1 microM. The screening data revealed a preferred synthon, 3-amino-4-methyl benzamide, which is critical for the activity against p38. This synthon appeared almost exclusively in screening hits including PS200981, and slight variations of this synthon including 3-amino benzamide and 2-amino-4-methyl benzamide also contained in the library were inactive. PS200981 is equally potent against the alpha and beta forms of p38 but did not inhibit p38 gamma and is >25-fold selective versus a panel of other kinases. PS200981 inhibited the LPS-induced increase in TNFalpha levels when administered at 30 mg/kg to mice. Selectivity and in vivo activity of this class of p38 inhibitors was further demonstrated by PS166276 [(R)-3-(4-(isobutyl(methyl)-amino)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a highly structurally related but more potent and less cytotoxic inhibitor, in several intracellular signaling assays, and in LPS-challenged mice. Overall, this novel class of p38 inhibitors is potent, active in vitro and in vivo, and is highly selective.
 ...
PMID:Discovery and characterization of triaminotriazine aniline amides as highly selective p38 kinase inhibitors. 1670 43

Inflammatory bowel disease constitutes two related clinical entities, Crohn's disease (CD) and ulcerative colitis (UC), both of which have increased in prevalence over the last decade. Family and twin studies have strongly indicated that genetic factors play a large role in an individual's risk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolate disease genes that confer susceptibility to this disease using classical candidate gene and linkage approaches, with the notable exception of the isolation of the caspase recruitment domain family, member 15 (CARD15) gene. However, over the last 2 years, genome-wide association (GWA) studies have become feasible, where modern high-throughput single nucleotide polymorphism (SNP) genotyping technologies can be applied to large and comprehensively phenotyped patient cohorts. Such approaches have enabled scientists to robustly associate specific variants with many complex diseases, including age-related macular degeneration, Type 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positive associations with CD and UC coming from GWA studies have been reported for an ever increasing number of genes. The most consistently and strongly associated variants have been in the CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiple association studies to confer strong risk for CD, although its association with UC remains more debatable. This SNP is in fact a common coding variant, specifically a threonine-to-alanine substitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears to account for all of the disease risk conferred by this locus. This review addresses recent advances in GWA studies of inflammatory bowel disease, with specific focus on the growing evidence of the ATG16L1 gene's role in CD and how its protein product operating within the autophagic pathway makes autophagy an attractive therapeutic target for this debilitating disorder.
 ...
PMID:Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene. 1836 6

The genetic risk factors predisposing individuals to the development of inflammatory bowel disease are beginning to be deciphered by genome-wide association studies. Surprisingly, these new data point towards a critical role of autophagy in the pathogenesis of Crohn's disease. A single common coding variant in the autophagy protein ATG16L1 predisposes individuals to the development of Crohn's disease: while ATG16L1 encoding threonine at amino acid position 300 (ATG16L1*300T) confers protection, ATG16L1 encoding for alanine instead of threonine (ATG16L1*300A, also known as T300A) mediates risk towards the development of Crohn's disease. Here we report that, in human epithelial cells, the Crohn's disease-associated ATG16L1 coding variant shows impairment in the capture of internalized Salmonella within autophagosomes. Thus, we propose that the association of ATG16L1*300A with increased risk of Crohn's disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.
 ...
PMID:Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant. 1885 89

Similar changes in glycosylation occur in the colonic epithelium in inflammatory conditions such as ulcerative colitis and Crohn's disease and also in colon cancer and precancerous adenomatous polyps. They include reduced length of O-glycans, reduced sulfation, increased sialylation and increased expression of oncofetal carbohydrate antigens, such as sialyl-Tn (sialylalpha2-6GalNAc), and the TF antigen (Thomsen-Friedenreich antigen) Galbeta1-3GalNAcalpha-Ser/Thr. The changes affect cell surface as well as secreted glycoproteins and mediate altered interactions between the epithelium and lectins of dietary, microbial or human origin. Different TF-binding lectins cause diverse effects on epithelial cells, reflecting subtle differences in binding specificities e.g. for sialylated TF; some of these interactions, such as with the TF-binding peanut lectin that resists digestion, may be biologically significant. Increased TF expression by cancer cells also allows interaction with the human galactose-binding lectin, galectin-3. This lectin has increased concentration in the sera of patients with metastatic cancer and binds TF on cancer cell surface MUC1 (mucin 1), causing clustering of MUC1 and revealing underlying adhesion molecules which promote adhesion to endothelium. This is likely to be an important mechanism in cancer metastasis and represents a valid therapeutic target. Tools are now available to allow fast and accurate elucidation of glycosylation changes in epithelial disease, characterization of their potential lectin ligands, whether dietary, microbial or human, and determination of the functional significance of their interactions. This should prove a very fruitful area for future research with relevance to infectious, inflammatory and cancerous diseases of the epithelia.
 ...
PMID:Lectin-epithelial interactions in the human colon. 1902 80


1 2 Next >>