A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.

LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis.

The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

Synthesis of novel 1,8-acridinediones derivatives: Investigation of MDR reversibility on breast cancer cell lines T47D and tamoxifen-resistant T47D.

Multi drug resistance (MDR) is a serious obstacle in the management of breast cancer. Therefore, overcoming MDR using novel anticancer agents is a top priority for medicinal chemists. It was found that dihydropyridines lacking calcium antagonistic activity (e.g acridinediones) possess MDR modifier potency. In this study, the capability of four novel acridine-1,8-diones derivatives 3a-d were evaluated as MDR reversing agents. In addition, the relationship between structural properties and biological effects of synthesized compounds was discussed. In vitro cytotoxicity of acridine-1,8-diones 3a-d derivatives in combination with doxorubicin (DOX) on T47D and tomoxifen-resistant T47D (TAMR-6) breast cancer cell lines were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Drug resistant index (DRI), which is equal to the ratio of IC50 in drug-resistant cells over IC50 in drug-sensitive cells, was calculated for each substance. Flowcytometry experiments were also implemented to distinguish cells undergoing apoptosis from those undergoing necrosis. The results from MTT and flowcytometry experiments indicated that 1 nM 3c derivative along with DOX significantly (P<0.05) increased the DOX cytotoxicity in T47D and TAMR-6 breast cancer cell lines. Synthesized compounds 3a and 3b also at concentrations of 1 nM with DOX significantly increased the cytotoxicity of DOX on T47D and TAMR-6 breast cancer cell lines. Meanwhile, 3d derivative with DOX did not exhibit good synergistic effect on cytotoxic activity of DOX, and slightly increased DOX cytotoxicity in both cell lines. Our results proposed that 3c may be an attractive lead compound for further development as a chemotherapeutic agent for MDR breast cancer therapy in combination with routine chemotherapeutic agents such as DOX.

Evaluation of anticonvulsant effect of two novels 4-[1-(4-fluorobenzyl)- 5-imidazolyl] dihydropyridine derivatives in mice.

In this study the anticonvulsant effect of two dihydropyridine derivatives [diethyl -1,4- dihydro -2,6-dimethyl -4-(4- fluoro benzyl-2- methylthio -5- imidazolyl)-3,5- pyridine dicarboxilat (A) and diethyl -1,4-dihydro -2,6- diethyl -4-(4- fluoro benzyl-2- methylthio -5- imidazolyl)-3,5- pyridine dicarboxilat (B)] by pentylenetetrazole (PTZ) and electroshock in mice was evaluated. The latency and HLTE (hind limb tonic extensions), the duration of HLTE and the mortality protection in pentylenetetrazole test and the HLTE duration in electroshock test were assessed. Both compounds had significant differences with negative control in all doses used. There was no significant difference between nifedipine and B (96.7 and 169.2 mg/kg doses) in the starting point of HLTE and between nifedipine andA(62.2 and 108.9 mg/kg doses) in the duration of HLTE in the PTZ test. Also, there was no significant difference between nifedipine and B (96.7 and 169.2 mg/kg doses) andA(62.2 and 108.9 mg/kg doses) in electroshock test. All doses ofAand B and nifedipine showed less effect than phenytoin and valproate. This study showed that bothAand B have anticonvulsant activity in the PTZ-induced seizure model and the MES test. These compounds, thus, might be useful in the petit mal and grand mal epilepsy.

Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method.

In this study, total crocin was extracted from saffron stigmas using crystallization method. Ethanol 80% was selected as the best extraction solvent. Crystallization process was carried out in one and two steps at different temperatures. Ethanol 80% was used as crystallization medium. Crocin crystals obtained from the first crystallization had low purity and thus were subjected to the second crystallization. The higher purity crystals were yielded in the second crystallization at -5 degrees C. The purity of crocin crystals was studied using UV-visible spectrophotometery and HPLC in comparison with Fluka product and methanolic extract of saffron stigmas. The results indicated that its purity was extremely higher, about 13 times, more than Fluka product. In spite of our expectation, the Fluka product was not a pure alpha-crocin sample; five other types of crocins in addition to an unknown impurity were seen in its chromatogram. The purity of crystallized total crocin in this work was more than 97%.

Sono-synthesis of imidazolidine-2-thione as a base compound of some pharmaceutical products.

This work describes the results of investigations carried out to investigate the synthesis of imidazolidine-2-thione as a heterocyclic compound in the presence of ultrasound (sono-synthesis) and in the absence of ultrasound (conventional method). Instead of reflux in the conventional method, the mixture was sonicated indirectly in sono-synthetic method with 500 kHz at different temperatures. Some experiments were also carried out without catalyst with 500 and 900 kHz. In the conventional method, the yield of the reaction was increased by increasing the temperature but in sono-synthetic method, the thermal dependence was different in the range of temperature studied (10-50 degrees C). In the presence of ultrasound, the yield was reached to more than 93% after 1h but in the conventional method it reached only 27% under the same conditions. Comparison was carried out with and without catalyst. It is also possible to achieve a high yield of product under sonication without the use of a catalyst.

Syntheses and calcium channel antagonist activity of nifedipine analogues with methylsulfonylimidazolyl substituent.

Various diester analogues of nifedipine in which the ortho nitrophenyl group at position 4 is replaced by 1-methyl-2-methylsulfonyl-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as a standard. Compound 6n was found to be the most active.

Synthesis, conformational analysis and antidepressant activity of moclobemide new analogues.

Three new analogues of moclobemide are synthesized. Antidepressant activity of compounds assayed by the Porsolt method reveals that the morpholine ring in moclobemide is one of the key structural parts necessary for antidepressant activity. Superimposition of norepinephrine and gauche forms of serotonin and mociobemide suggest that the phenyl ring, electronegative group attached to the aromatic ring and the amine terminal group may serve as the recognition elements for binding to monoamine oxidase-A (MAO-A).