Hypolipidemic effect of novel 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole as potential peroxisome proliferation-activated receptor-α agonist in acute hyperlipidemic rat model.

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-α (PPARα) agonists and characterized using elemental analysis, FTIR, 1H-NMR, 13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPARα with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid ß oxidation and are part of PPARα signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.

Fluconazole conjugated-gold nanorods as an antifungal nanomedicine with low cytotoxicity against human dermal fibroblasts.

Herein, a nanotechnology-based approach was adopted to develop a facile and effective nanoplatform for the treatment of superficial fungal infections. Gold nanorods (GNR) functionalized with thiolated poly ethylene glycol (PEG-SH) or thiolated PEGylated cholesterol (Chol-PEG-SH) moieties were conjugated with Fluconazole and loaded into poloxamer 407 hydrogel. The obtained nanocomplexes; PEG-Fluc-GNR and Chol-Fluc-GNR were characterized by optical spectroscopy, hydrodynamic size and effective surface charge. The anti-fungal activity of the nanocomplexes was investigated by estimating the minimum inhibitory concentration (MIC) and the percentage reduction of fungal viable count against Candida (C.) albicans. PEG-Fluc-GNR and Chol-Fluc-GNR resulted in 5-fold and 14-fold reduction in MIC of GNR, and in 9-fold and 12-fold reduction in MIC of Fluconazole, respectively. The average log-reduction of the viable fungal cells upon treatment with the nanocomplexes was 5 log cycles, and it ranged from 1.3-3.7 log cycles when loaded into poloxamer 407 hydrogel. Transmission electron microscope imaging of the treated C. albicans revealed an enhanced uptake of the nanoparticles into the fungus's cell wall within the first 120 min of exposure. The nanocomplexes demonstrated low cytotoxicity towards human dermal fibroblasts which represent the human skin dermal cells. Conjugating Fluconazole with GNR is a promising approach for the effective treatment of superficial fungal infections.