Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.
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PMID:Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-gamma production in patients with Crohn's disease on AZA therapy. 1499 47

Two Aeromonas strains, IBS S6874(T) and IBS S6652, were isolated from the faeces of two healthy monkeys (Macaca fascicularis) from Mauritius that were kept in quarantine in the Centre for Primatology, Strasbourg, France. Phylogenetic analysis based on 16S rRNA gene sequences showed that the two isolates formed an unknown genetic lineage within the genus Aeromonas. The two isolates had nearly identical sequences (0.1 % nucleotide substitution) that were related closely to those of recognized Aeromonas species (1.7-3.5 % nucleotide substitution). DNA-DNA hybridization showed that strains IBS S6874(T) and IBS S6652 had high DNA-DNA similarity (89 %) to each other and a low level of DNA-DNA similarity to closely related taxa (18 % relatedness to Aeromonas trota and 16 % relatedness to Aeromonas schubertii). Phenotypically, the two monkey isolates differed from most previously described mesophilic Aeromonas species by their lack of haemolysis on sheep-blood agar and inability to produce indole, gas from glucose or acid from mannitol. They differed from the most closely related species, A. schubertii, by their ability to produce acid from D-cellobiose and D-sucrose and by their pyrazinamidase activity. The name Aeromonas simiae sp. nov. is proposed for these isolates; strain IBS S6874(T) (=CIP 107798(T)=CCUG 47378(T)) is the type strain.
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PMID:Aeromonas simiae sp. nov., isolated from monkey faeces. 1502 64

The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. Differences in SERT expression and function produced by three SERT genes and their variants show associations with multiple human disorders. Screens of DNA from patients with autism, ADHD, bipolar disorder, and Tourette's syndrome have detected signals in the chromosome 17q region where SERT is located. Parallel investigations of SERT knockout mice have uncovered multiple phenotypes that identify SERT as a candidate gene for additional human disorders ranging from irritable bowel syndrome to obesity. Replicated studies have demonstrated that the SERT 5'-flanking region polymorphism SS genotype is associated with poorer therapeutic responses and more frequent serious side effects during treatment with antidepressant SERT antagonists, namely, the serotonin reuptake inhibitors (SRIs).
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PMID:Serotonin transporter: gene, genetic disorders, and pharmacogenetics. 1508 84

Azathioprine is an immunosuppressive drug used in the treatment of inflammatory bowel disease. It is a prodrug that is hydrolysed to 6-mercaptopurine, which represents the active form. Azathioprine is also used in the treatment of leukaemia in children and in organ transplantation. Azathioprine treatment is associated with adverse effects such as leukopenia and aplasia. These adverse effects are related to a single nucleotide polymorphism, including the inability of cells to synthesize thiopurine methyltransferase (TPMT). TPMT is a detoxification enzyme that limits 6-thioguanine nucleotide production and thereby interferes with normal DNA and RNA synthesis. This review presents the different approaches used for azathioprine therapeutic monitoring in IBD treatment and discusses the discrepancies in recent clinical trials.
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PMID:[Genetic polymorphism and treatment of chronic bowel inflammatory diseases: the example of azathioprine]. 1519 72

Therapeutic interventions in the case of gastrointestinal disease are based on the understanding of the role of different inflammatory mediators. Reactive O2 and N2 metabolites are involved in IBD. Pro-inflammatory cytokines, apoptosis signalling and redox-response transcription factors are depended on free radicals. NO activates COX enzymes. PGE2 negatively modulates induction of NO synthase by interleukins and therefore regulation of gastric mucosal integrity by endogenous NO depends on arachidonic acid cascade. PG-s have pro-inflammatory and anti-inflammatory effects on the immune system. Dietary PUFA-s and eicosanoids have potential effects on the modulation of inflammatory processes and immune cells. The cholesterol level lowering activity of several cytokines and colony stimulating factor can be observed. Therapeutic efficacy of N-3 PUFA is described in cases of patients with chronic gastrointestinal disorders, but N-3 PUFA-s only delay early relapse of ulcerative colitis in remission. TNF is known as a pleiotropic cytokine. Strategies for TNF in IBD is very important part of therapeutical approaches. Therapy with infliximab and related ones are encouraging in critical cases. It is also believed recently, that NF-kappaB also may be a target of IBD treatment. It became known, that oxidized LDL can inhibit LPS-induced binding of the NF-kappaB to DNA and the subsequent expression of TNF-alpha and interleukin-1beta in macrophages as well as oxidized LDL modulates activation of NF-kappaB in mononuclear phagocytes by altering the degradation of I-kappaBs. 15-d-PGJ2 inhibits multiple steps in the NF-kappaB signaling pathway. 15-d-PGJ2 metabolite binds PPAR-gamma promotes adipocyte differentiation. PPAR-gamma ligand inhibits growth of cells through induction of apoptosis. Several nutritional polyphenols (the secondary metabolites of plants) are COX2 and/or LOX inhibitors and iNOS activators. The moderate nutritional customs with natural antioxidants can help restore to normal function of gastrointestinal tract, but the immoderate consumption of vitamins and polyphenol type antioxidant molecules is contraindicated.
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PMID:[Cytokines, prostaglandins, nutritive and non-nuitritive factors in inflammatory bowel diseases]. 1566 52

Plants treated with the nonprotein amino acid beta-aminobutyric acid (BABA) develop an enhanced capacity to resist biotic and abiotic stresses. This BABA-induced resistance (BABA-IR) is associated with an augmented capacity to express basal defense responses, a phenomenon known as priming. Based on the observation that high amounts of BABA induce sterility in Arabidopsis thaliana, a mutagenesis screen was performed to select mutants impaired in BABA-induced sterility (ibs). Here, we report the isolation and subsequent characterization of three T-DNA-tagged ibs mutants. Mutant ibs1 is affected in a cyclin-dependent kinase-like protein, and ibs2 is defective in AtSAC1b encoding a polyphosphoinositide phosphatase. Mutant ibs3 is affected in the regulation of the ABA1 gene encoding the abscisic acid (ABA) biosynthetic enzyme zeaxanthin epoxidase. To elucidate the function of the three IBS genes in plant resistance, the mutants were tested for BABA-IR against the bacterium Pseudomonas syringae pv tomato, the oomycete Hyaloperonospora parasitica, and BABA-induced tolerance to salt. All three ibs mutants were compromised in BABA-IR against H. parasitica, although to a different extent. Whereas ibs1 was reduced in priming for salicylate (SA)-dependent trailing necrosis, mutants ibs2 and ibs3 were affected in the priming for callose deposition. Only ibs1 failed to express BABA-IR against P. syringae, which coincided with a defect in priming for SA-inducible PR-1 gene expression. By contrast, ibs2 and ibs3 showed reduced BABA-induced tolerance to salt, which correlated with an affected priming for ABA-inducible gene expression. For all three ibs alleles, the defects in BABA-induced sterility and BABA-induced protection against P. syringae, H. parasitica, and salt could be confirmed in independent mutants. The data presented here introduce three novel regulatory genes involved in priming for different defense responses.
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PMID:Dissecting the beta-aminobutyric acid-induced priming phenomenon in Arabidopsis. 1572 64

Chronicles in Drug Discovery is a series of brief reports on timely topics in the field of drug R&D. This month's chronicles contain the following reports: Targeting DNA repair enzymes instead of viral proteins provides a great advantage in preventing the emergence of resistant mutants. A striking increase in therapeutic approaches for the treatment of IBD has been fueled by an improved understanding of the mechanisms that underlie its pathophysiology. Peptide deformylase inhibitors are under active investigation for bacterial infections and cancer treatment. Dopamine D3 receptors present an attractive target for alcoholism therapy since they are involved in the mechanisms of alcohol dependency and abuse.
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PMID:Chronicles in drug discovery. 1619 5

There has been a major improvement in our understanding in the area of the genetics of CRC in the last decade. Reason for this is partly that CRC has a strong hereditary trait and premalignant lesions are frequent and easily accessible. In the 1990-ies the mutations responsible for the adenoma-carcinoma sequence were discovered on after the other. In the second part of the review the authors discuss the genetic background of sporadic and IBD associated colorectal cancers as well as the role of genetics in the diagnosis, prognosis and prediction of therapy. Chromosomal instability (85%) and microsatellite instability with or without change in DNA methylation (15%) are the main mechanisms involved in the pathogenesis of sporadic colorectal cancers. It became evident that no ultimate mutations exist. Most of neoplasms are genetically heterogeneous, independent pathways and simultaneous tumorigenesis may exist within the same organ, also in the colon. Gene expression profile, clinical phenotype and prognosis may also vary according to the location. Similar genetic mutations may be found in IBD associated colorectal cancers, however, the typical sequence and importance of mutations is different. In future, fecal DNA testing may be an important screening tool for colorectal cancer; however, its routine use is still limited by its low sensitivity. Similarly, genetic investigation may play an increasing role in the prediction of prognosis, therapy and complication of chemotherapy. A more distant goal may be the individualization of the therapy.
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PMID:[Current concepts in the genetics of hereditary and sporadic colorectal cancer and the role of genetics in clinical practice: sporadic and IBD-associated colorectal tumors, significance of genetic tests in diagnosis, prognosis and assessment of chemotherapy outcome]. 1657 74

The differences in faecal bacterial population between irritable bowel syndrome (IBS) and control subjects have been reported in several studies. The aim of the present study was to compare the predominant and clostridial faecal microbiota of IBS subjects and healthy controls by applying denaturing gradient gel electrophoresis (DGGE) and a recently developed multiplexed and quantitative hybridization-based technique, transcript analysis with the aid of affinity capture (TRAC). According to the results, the studied clostridial groups (Clostridium histolyticum, Clostridium coccoides-Eubacterium rectale, Clostridium lituseburense and Clostridium leptum) represented the dominant faecal microbiota of most of the studied subjects, comprising altogether 29-87% of the total bacteria as determined by the hybridized 16S rRNA. The C. coccoides-E. rectale group was the dominant subgroup of clostridia, contributing a mean of 43% of the total bacteria in control subjects and 30% (constipation type) to 50% (diarrhoea type) in different IBS symptom category subjects. The proportion of the C. coccoides-E. rectale group was found to be significantly lower in the constipation-type IBS subjects than in the control subjects. DNA-based PCR-DGGE and RNA-based RT-PCR-DGGE analyses targeted to the predominant bacterial population showed considerable biodiversity as well as uniqueness of the microbiota in each subject, in both control and IBS subject groups. The RT-PCR-DGGE profiles of the IBS subjects further indicated higher instability of the bacterial population compared to the control subjects. The observations suggest that clostridial microbiota, in addition to the instability of the active predominant faecal bacterial population, may be involved in IBS.
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PMID:Prevalence and temporal stability of selected clostridial groups in irritable bowel syndrome in relation to predominant faecal bacteria. 1658 52

In the present study the efficacy of recombinant plasmids DNA vaccine encoding VP2 gene of very virulent strain of infectious bursal disease virus (vvIBDV) isolated from Pakistan was investigated with or without coadministration of cytocine-phosphate-guanine oligodeoxynucleotide (CpG ODN) to protect the chickens against the disease. VP2 gene of vvIBDV was successfully amplified by reverse transcription-polymerase chain reaction (RT-PCR) and was cloned into eukaryotic expression plasmid vector, which consisted of human cytomegalovirus (HCMV) immediate early enhancer and promoter, adenopartite leader sequences and SV-40 polyadenylation signal, and this was designated as pRc-VP2. Seven-day-old maternal antibodies free chickens were intramuscularly injected with 500 microg of pRc-VP2 with or without CpG ODN twice at 1-week interval. At the age of 21 days the broiler chickens were challenged with 10(5) EID(50) of homologous strain of IBDV and observed for 14 days post-challenge. Immunization with pRc-VP2 plus CpG ODN conferred protection in 93% of the chickens as evidenced by the absence of clinical signs, atrophy of bursa of Fabricius (BF) and mortality followed by the group vaccinated with attenuated IBD vaccine and boosted with killed oil based IBDV vaccine, which conferred 90% protection. The protection of chickens injected with pRc-VP2 alone was 67% where as only 20% of the chickens in the negative control group were protected. However, enzyme-linked immunosorbent assay (ELISA) antibody titre in the group vaccinated with pRc-VP2 plus CpG ODN were significantly higher (P<0.05) than the group vaccinated with pRc-VP2 alone as well as the group vaccinated with commercial attenuated IBDV vaccine boosted with commercial oil adjuvanted killed IBDV vaccine. Responsiveness to a mitogenic lectin, phytoheamagglutinin-P was significantly reduced in group immunized with conventional vaccines (live boosted with killed) as compared to all the other groups (P<0.05). The results revealed that co-administration of recombinant plasmids with CpG ODN could protect chickens efficiently from IBDV challenge.
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PMID:Protection capability of recombinant plasmid DNA vaccine containing VP2 gene of very virulent infectious bursal disease virus in chickens adjuvanted with CpG oligodeoxynucleotide. 1660 Apr 40


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