Design, synthesis and neuroprotective evaluation of nitrogen heterocyclic and triazole derivatives of sarracinic acid.

Novel sarracinic acid derivatives bearing triazole or N-heterocyclic moiety were prepared via two separate reaction schemes. The triazoles and the N-heterocyclic derivatives were synthesised using standard click chemistry approach and amination of 2-bromoethyl ester of sarracinic acid respectively. All the synthesised derivatives were screened for in vitro neuroprotective activity against corticosterone induced impairment in neuroblastoma cell line SH-SY5Y. Two analogs SA-2 and SA-12 exhibited strong neuroprotective activity. The cell viability, after high dose corticosterone induced cell death, increased remarkably with the pre treatment of SA-2 and SA-12. The in vitro biological activity of SA-2 and SA-12 was verified through docking studies. The docking studies were in good agreement with the biological results. SA-2 and SA-12 showed strong binding affinities with the target protein having ΔGb = -8.88 and -7.52; inhibition constant (ki) = 3.08 nM and 30.9 nM respectively.

Genetic variation at ERBB3/IKZF4 and sexual dimorphism in epitope spreading in single autoantibody-positive relatives.

AIMS/HYPOTHESIS: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. METHODS: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression. RESULTS: In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan-Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. CONCLUSIONS/INTERPRETATION: In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes.

Isolation, purification and characterization of naturally derived Crocetin beta-d-glucosyl ester from Crocus sativus L. against breast cancer and its binding chemistry with ER-alpha/HDAC2.

Saffron plant (Crocus sativus L.) is being used as a source of saffron spice and medicine to cure or prevent different types of diseases including cancers. We report the isolation, characterization of bioactive small molecule ([crocetin (ß-d-glucosyl) ester] from the leaf biowastes of saffron plant of Kashmir, India. MTTC assay and Bio-autography aided approach were used to assess anti-oxidant activity and anti-cancer properties of crocin (s) against DPPH free radical and breast cancer cell line respectively. Crocetin beta-d-glucosyl ester restrained proliferation of human breast adeno-carcinoma cell model (MCF-7) without significantly affecting normal cell line (L-6). Further studies involving molecular mechanics generalized born surface area and molecular docking showed that crocetin beta-d-glucosyl ester exhibits strong affinity for estrogen receptor alpha and histone deacetylase 2 (crucial receptors involved in breast cancer signalling) as evidenced by the negative docking score and binding free energy (BFE) values. Therefore, crocetin beta-d-glucosyl ester from Crocus sativus biowastes showed antiproliferative effect possibly by inhibiting estrogen receptor alpha and HDAC2 mediated signalling cascade.