AUTHOR=Sahu Neha , Singh Nitesh , Arya Kamal Ram , Reddy Sabbu Sathish , Rai Amit Kumar , Shukla Vijaya , Pandey Jyotsana , Narender Tadigoppula , Tamrakar Akhilesh Kumar , Kumar Brijesh , Rajak Bikash Kumar , Malik Sumira , Rustagi Sarvesh 

TITLE=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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1073327

DOI=10.3389/fphar.2023.1073327

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> In this study, we examine the anti-diabetic potential of <italic>Lyonia ovalifolia</italic> (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 <italic>in vitro</italic> antiglycation activity and antidiabetic potential, i.e., stimulation of GLUT4 translocation.</p><p><bold>Result and Discussions:</bold> 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 <italic>L. ovalifolia</italic> plays an important role in insulin homeostasis, as shown in <italic>in vitro</italic> and <italic>in silico</italic> studies.</p>