Assessment of the dual role of Lyonia ovalifolia (Wall.) Drude in inhibiting AGEs and enhancing GLUT4 translocation through LC-ESI-QTOF-MS/MS determination and in silico studies.

Introduction: Diabetes mellitus (DM) is a metabolic disorder that results in glucose accumulation in the blood, accompanied by the production of advanced glycation end products (AGEs) through glycation of cellular proteins. These AGEs interfere with insulin signaling and prevent GLUT4 membrane translocation, thereby promoting the accumulation of more glucose in the blood and causing post-diabetic complications. Methods: In this study, we examine the anti-diabetic potential of Lyonia ovalifolia (Wall.) Drude, a well-known ethnomedicinal plant of the Indian Himalayas. Considering its various medicinal properties, we analyzed its ethanolic extract and various solvent fractions for in vitro antiglycation activity and antidiabetic potential, i.e., stimulation of GLUT4 translocation. Result and Discussions: The results showed that the extract and fractions exhibited increased antiglycation activity and an increased level of GLUT4 translocation. Analysis of a further 12 bioactive compounds of ethanolic extract, identified through LC-ESI-QTOF-MS/MS, revealed the presence of three new compounds: leucothol B, rhodoterpenoids A, and leucothol A. Moreover, we performed molecular docking of identified compounds against key proteins of diabetes mellitus: the sirtuin family of NAD (+)-dependent protein deacetylases 6 (SIRT6), aldose reductase (AR), and tyrosine kinase (TK). The results showed that flavonoid luteolin showed the best binding affinity ((-12.3 kcal/mol), followed by eriodictyol, astilbin, and syringaresinol. An ADMET study showed that luteolin, eriodictyol, astilbin, and syringaresinol may be promising drug candidates belonging to the flavonoid class of compounds, with no harmful effects and complying with all the drug-likeness guidelines. Furthermore, molecular dynamics (MD) simulations on a 50 ns timescale revealed that AR protein was most stable with luteolin throughout the simulation period. Therefore, this study reveals for the first time that L. ovalifolia plays an important role in insulin homeostasis, as shown in in vitro and in silico studies.

Identification of Natural Products as Potential Pharmacological Chaperones for Protein Misfolding Diseases.

Defective protein folding and accumulation of misfolded proteins is associated with neurodegenerative, cardiovascular, secretory, and metabolic disorders. Efforts are being made to identify small-molecule modulators or structural-correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Using a metastable-reporter-based primary screen, we evaluated pharmacological chaperone activity of a diverse class of natural products. We found that a flavonoid glycoside (C-10, chrysoeriol-7-O-ß-D-glucopyranoside) stabilizes metastable proteins, prevents its aggregation, and remodels the oligomers into protease-sensitive species. Data was corroborated with additional secondary screen with disease-specific pathogenic protein. In vitro and cell-based experiments showed that C-10 inhibits α-synuclein aggregation which is implicated in synucleinopathies-related neurodegeneration. C-10 interferes in its structural transition into ß-sheeted fibrils and mitigates α-synuclein aggregation-associated cytotoxic effects. Computational modeling suggests that C-10 binds to unique sites in α-synuclein which may interfere in its aggregation amplification. These findings open an avenue for comprehensive SAR development for flavonoid glycosides as pharmacological chaperones for metastable and aggregation-prone proteins implicated in protein conformational diseases.

Glucose uptake stimulatory potential and antidiabetic activity of the Arnebin-1 from Arnabia nobelis.

The enhanced disposal of glucose by the peripheral tissue is an important mechanism to regulate hyperglycemia. Here, we investigated the effect of Arnebin-1 from Arnebia nobilis, on glucose disposal in skeletal muscle cells and explored its in vivo antihyperglycemic potential. In L6 myotubes, Arnebin-1 stimulated glucose uptake, mediated through the enhanced translocation of the glucose transporter-4 (GLUT4) to plasma membrane, without changing the amount of GLUT4 or GLUT1. These effects of Arnebin-1 were synergistic with that of insulin. The effect of Arnebin-1 on glucose uptake was abolished in presence of wortmannin, and Arnebin-1 significantly stimulated the phosphorylation of Akt and downstream marker GSK-3ß. Moreover, treatment with Arnebin-1 lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats, and improved glucose tolerance and suppressed the rises in the fasting blood glucose, serum insulin, triglycerides, and total cholesterol in db/db mice, associated with enhanced expression of the major marker of the PI-3-Kinase-mediated signaling cascade in skeletal muscle. These findings suggest that Arnebin-1 exert antihyperglycemic activity through stimulating glucose disposal in peripheral tissues via PI-3-Kinase-dependent pathway.