Modulatory Effects of Alpha-Mangostin Mediated by SIRT1/3-FOXO3a Pathway in Oxidative Stress-Induced Neuronal Cells

Waralee Ruankham; Wilasinee Suwanjang; Kamonrat Phopin; Napat Songtawee; Virapong Prachayasittikul; Supaluk Prachayasittikul

doi:10.3389/fnut.2021.714463

Modulatory Effects of Alpha-Mangostin Mediated by SIRT1/3-FOXO3a Pathway in Oxidative Stress-Induced Neuronal Cells

Front Nutr. 2022 Jan 28:8:714463. doi: 10.3389/fnut.2021.714463. eCollection 2021.

Authors

Waralee Ruankham¹, Wilasinee Suwanjang¹, Kamonrat Phopin^{1

2}, Napat Songtawee³, Virapong Prachayasittikul², Supaluk Prachayasittikul⁴

Affiliations

¹ Faculty of Medical Technology, Center for Research and Innovation, Mahidol University, Bangkok, Thailand.
² Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
³ Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
⁴ Faculty of Medical Technology, Center of Data Mining and Biomedical Informatics, Mahidol University, Bangkok, Thailand.

Abstract

Background: alpha-Mangostin, a polyphenolic xanthone, is primarily found in the pericarp of mangosteen throughout Southeast Asia and is considered as the "Queen of Fruit" in Thailand. Nonetheless, it is not clarified how alpha-mangostin protects neuronal cells against oxidative stress.

Objective: In this study, molecular mechanisms underlying the neuroprotective effect of alpha-mangostin in defending hydrogen peroxide (H₂O₂)-induced neurotoxicity was explored.

Methods: cytotoxicity, reactive oxygen species (ROS) generation, apoptotic cascades, and protein expression profiles were performed incorporation of molecular docking.

Results: Human SH-SY5Y cells were pretreated with 1 μM alpha-mangostin for 3 h prior to exposure to 400 μM H₂O₂. alpha-Mangostin significantly inhibited oxidative stress-induced cell death in neuronal cells by reducing BAX protein, decreasing caspase-3/7 activation, and increasing anti-apoptotic BCL-2 protein. Collectively, alpha-mangostin was demonstrated to be a prominent ROS suppressor which reversed the reduction of antioxidant enzymes (CAT and SOD2). Surprisingly, alpha-mangostin significantly promoted the expression of the sirtuin family and the FOXO3a transcription factor exerting beneficial effects on cell survival and longevity. A molecular docking study predicted that alpha-mangostin is directly bound to the active site of SIRT1.

Conclusion: Findings from this study suggest that alpha-mangostin potentially serves as a promising therapeutic compound against oxidative stress by activation of the SIRT1/3-FOXO3a pathway comparable to the effect of memantine, an anti-AD drug used for the treatment of moderate to severe dementia.

Keywords: Alzheimer's disease; alpha-mangostin; antioxidant; oxidative stress; sirtuin.