Oxadiazolyl thiazolidinedione as a non-adipogenic PPAR-γ partial agonist and its effect on glucose homeostasis in type 2 diabetes.

The familiar glitazone anti-diabetics are thiazolidinedione derivatives, known to elicit action through full agonistic activity on PPAR-γ receptors. Full agonists are known for the side effect of weight gain, while partial agonists are weak to non-adipogenic compounds possessing anti-diabetic property. This work identified a new synthetic oxadiazolyl thiazolidinedione (OXTZD) as a ligand for PPAR-γ receptor with partial agonist activity and less transactivation potential compared to rosiglitazone through in-vitro PPAR-γ competitive binding assay and PPAR-γ transactivation-based luciferase reporter assay, respectively. OXTZD did not induce significant lipid accumulation when compared to differentiation control which contained insulin in PPAR-γ-dependent adipogenesis assay. In-vivo studies have proved that OXTZD effectively reduced blood glucose level in type 2 diabetic rats and also improved glucose tolerance and insulin sensitivity. After 15 days of oral treatment with OXTZD, rats did not gain weight, suggesting that OXTZD was effective in suppressing the weight gain. Molecular docking of OXTZD to PPAR-γ, predicted hydrogen bonds with SER342, ARG288, and CYS285 residues in arm III of the ligand binding domain which are unique to the partial agonists. Results of in-vitro, in-vivo, and docking studies were in good correlation to the fact that OXTZD is a PPAR-γ partial agonist having glucose-lowering property and lacks the side effect of weight gain. In conclusion, OXTZD could be developed as a therapeutic agent for diabetes and/or serve as a lead compound for further drug design studies targeting PPAR-γ for effective management of type 2 diabetes without inducing weight gain.

What is causing high polio vaccine dropout among Pakistani children?

OBJECTIVES: Although the antipolio drive is undertaken across Pakistan, there are still children who have not received any oral polio vaccine or are unable to complete recommended doses of polio vaccine. This study aims at empirically analyzing the associated factors with the no oral polio vaccination (OPV) and OPV dropout groups of children in Pakistan. STUDY DESIGN: This is a cross-sectional study. METHODS: Data were obtained from the three waves of Pakistan Demographic and Health Survey of children aged between 12 and 23 months (1990-1991: n = 1214; 2006-2007: n = 1522; 2012-2013: n = 2074). Children who received no OPV and those who drop out of polio vaccination (OPV1-OPV3) were considered as outcome variables. The bivariate relationship of outcome variable with each socio-economic, demographic, and spatial variable is estimated with a P-value of <0.01. For both no OPV and OPV dropout children, we used logistic regression analysis separately. RESULTS: The percentage of children aged 12-23 months who dropped out of OPV1-OPV3 vaccination was about 76% in the year 1990-1991; 21% in 2006-2007, and 17.5% in 2012-2013 at the national level. Among all indicators, provinces, rural versus urban residence, the mother's age at marriage, the child's birth place (home versus hospital), parental education, and household wealth status are significant predictors of no OPV and/or OPV dropout in Pakistan. Among provinces, Balochistan, Khyber Pakhtunkhwa (KPK), and Sindh are the lagging provinces. CONCLUSION: Improving the socio-economic status of women helps decrease the chance of polio dropout and thus improves service delivery and program implementation.

Investigation of transferrin interaction with medicinally important noble metal ions using affinity capillary electrophoresis.

Transferrins (TFs) consist of a large group of glycoproteins, whose function is to transport iron across the cell membrane. Apart from iron, serum transferrin can also bind several other metal ions and hence can offer a potential route for the delivery of these metal ions into the cellular fluids. In the present study the interaction behavior of nine noble metal ions, Ag+, Au+, Au3+, Os3+, Pd2+, Pt4+, Rh3+, Ru3+ and Ir3+ with transferrin was investigated by affinity capillary electrophoresis (ACE) using the dynamic mobility shift mode. A proper rinsing procedure was applied to regenerate the capillary tube. The influence of these metal ions on transferrin was studied through comparison of the mobility ratios of free protein and protein-metal ion complex. The interaction results were expressed by the normalized difference of the mobility ratios (ΔR/Rf) and its confidence intervals. Most of the tested metal ions showed significant interaction with transferrin with small confidence intervals, except Ag+, Au+ and Rh3+ that exhibited very weak interactions. Maximum interaction was observed between transferrin and Ir3+, followed by Pd2+ that also showed strong affinity towards the test protein. The screening results were compared with Bovine Serum Albumin (BSA)- and Human Serum Albumin (HSA)-noble metal ions interactions. An excellent precision (% RSD of mobility ratios were less than 1%, except for transferrin-Pd2+ interaction ≈ 4%) was recorded for repeated runs of transferrin-metal ions interactions. This study contributes to the understanding of the affinity of transferrin to the tested metal ions and will provide preliminary information for the investigation of other protein-ligands interactions.

Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid.

Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.