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Chrysin and luteolin are two flavonoids with Peroxisome proliferators-activated receptor γ (PPAR-γ) stimulating activity. Here, we investigated the protective effect of chrysin and luteolin from vascular complications associated with insulin resistance (IR). IR was induced in rats by drinking fructose for 12 weeks while chrysin and luteolin were given for 6 weeks with or without PPAR-γ antagonist, bisphenol A diglycidyl ether (BADGE). Then, blood pressure (BP) was recorded and serum levels of glucose, insulin, advanced glycation end products (AGEs) and lipids were measured. Concentration response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in thoracic aorta rings. Aortic reactive oxygen species (ROS) and nitric oxide (NO) generation were also studied. Chrysin and luteolin significantly alleviated systolic BP elevations caused by IR, while the co-administration of BADGE prevented chrysin alleviation. Although, neither chrysin nor luteolin affected ACh impaired vasodilatation, they both alleviated exaggerated vasoconstrictions to PE and KCl in IR animals. In addition, incubation of the aorta from IR animals with chrysin or luteolin prevented exaggerated vasoconstrictions to PE and KCl. On the other hand, co-administration of BADGE or co-incubation with GW9662, the selective PPAR-γ antagonist, prevented chrysin alleviation. Both chrysin and luteolin inhibited the developed hyperinsulinemia and increases in serum AGEs, lipids while, BADGE reduced the effect of chrysin on hyperinsulinemia and dyslipidemia. Chrysin and luteolin markedly inhibited elevated NO and ROS in IR aortae while BADGE did not change their effect on NO and ROS. In conclusion, chrysin and luteolin alleviate vascular complications associated with IR mainly through PPAR-γ dependent pathways.

Diabetes mellitus, a metabolic disorder, arises from insufficient insulin levels or increased insulin resistance. An alternative approach to address this pathogenesis involves targeting PPAR-$\gamma$, which activates glucose homeostasis and improves peripheral glucose utilization. In this study, we aimed to investigate the designed 2-thioxothiazolidin-4-one derivatives (T1-25) and assess their potential as PPAR-$\gamma$ regulators by an in silico approach. Physicochemical properties and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles were evaluated. Docking studies were performed using Schrödinger software, with the protein target being PPAR-$\gamma$ (PDB ID: 2ZNO). Additionally, MD simulation studies were conducted, and the key interactions in the protein-ligand complexes were identified. The results demonstrate the drug-likeness of compounds T11, T24 and T25, with docking scores of –7.953 kcal/mol, –7.973 kcal/mol and –8.212 kcal/mol, respectively, and exhibit significant activity against PPAR-$\gamma$ agonist and compared with the standard drug Pioglitazone (–7.367 kcal/mol). The density functional calculations were also performed to determine the geometrical properties, thermal parameters, chemical reactivity descriptors and molecular electrostatic potential of the compounds using the B3LYP functional and 6-31G++ basis sets. The energy difference between the highest occupied molecular orbitals and lowest unoccupied molecular orbitals for all the investigated compounds is in the range of 2.8–3.4 eV which allows for easy transfer of electrons and reactivity. Further research and development of these designed compounds could contribute to the advancement of effective antidiabetic treatments.