PPARγ x α-glucosidase

Gut microbial dysbiosis is associated with the development of critical clinical conditions of metabolic syndrome (obesity, type II diabetes), and calcium oxalate kidney stones. The human gut microbial eubiosis with functional probiotics and their heat-killed cells of lactic acid bacteria (LAB) is considered the current therapy for metabolic syndrome (MS). In accordance with this, our study aimed to isolate oxalate-degrading, cholesterol-lowering, and anti-adipogenic bacterial strains from raw donkey's milk and homemade fermented pickles. Nine LAB strains with potential in vitro oxalate degrading, α-glucosidase inhibiting, and cholesterol-lowering activities were pre-screened from fourteen isolates. Further, the heat-killed cells of selected strains were evaluated for anti-adipogenic activity in murine 3T3-L1 adipocytes. This activity was examined by studying the lipid storage, gene, and protein expression of adipogenic and lipogenic transcription factors. Subsequently, four potential isolates demonstrated a significant reduction in lipid storage by limiting adipogenesis (reducing C/EBPα, PPARγ expression), lipid transportation (downregulating aP2 expression), and lipogenesis (reducing PLIN-1 expression). These effective isolates were characterized using 16S rRNA molecular sequencing, and were identified as closest relatives to the Enterococcus (RRLA5, RRLA1, and RRLD6) and Lactobacillus (RRLM2) genera. Further, they displayed good survivability under in vitro gastric conditions and non-haemolytic activity. Taken together, the live cells of effective isolates depicted significant in vitro oxalate degradation, and their heat-killed cells demonstrated anti-adipogenic activity through downregulating the adipogenesis and lipogenesis. Moreover, future preclinical animal model studies on the synergistic role of probiotics and their heat-killed cells in disease prevention through gut microbial modulation could provide evidence as a biotherapeutic agent.

Type 2 diabetes accounts for the largest percentage of all diabetic cases worldwide. Cucurbitane-type triterpenes are mainly found in Momordica charantia and possess excellent pharmacological activities. This study was designed to identify cucurbitane-type triterpene from Momordica charantia using Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, examine its anti-diabetic property with molecular docking against diabetes enzymes (alpha-amylase, alpha-glucosidase, dipeptidyl dipeptidase IV and peroxisome proliferator-activated receptor gamma). The stability and interactions of the docked complexes were investigated using molecular dynamics simulation, while the pharmacokinetic and toxicity profile of the ligand was examined using an ADMET server. (23E)-Cucurbita-5,23,25-triene-3,7-dione (CUB) was identified from the LC-MS profiling of the methanolic extract of M. charantia. The molecular docking studies showed that the identified phytochemical elicited good binding energy against all the target receptors. The RMSD and RMSF plots obtained from the 100 ns molecular dynamics simulation showed that the ligand was stable and established substantial interactions with the amino acid residues of the diabetes enzymes which were confirmed by the MM\GBSA computations. The pharmacokinetic and toxicity properties of the ligand showed it was safer as an anti-diabetic drug candidate. Extensive isolation, in vitro and in vivo studies of the ligand against the diabetic enzymes is recommended.Communicated by Ramaswamy H. Sarma.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti‐diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti‐diabetics that bind to targets such as peroxisome proliferator‐activated receptor gamma (PPAR‐γ) and α‐glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13‐cis‐retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.