Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

Abstract

Resveratrol is a bioactive compound in many foods. Since its anticancer activity was reported in 1997, its health benefits have been intensively investigated. Resveratrol has antioxidant, anti-inflammatory, immunomodulatory, glucose and lipid regulatory, neuroprotective, and cardiovascular protective effects, therefore, can protect against diverse chronic diseases, such as cardiovascular diseases (CVDs), cancer, liver diseases, obesity, diabetes, Alzheimer's disease, and Parkinson's disease. This review summarizes the main findings of resveratrol-related health benefits in recent epidemiological surveys, experimental studies, and clinical trials, highlighting its related molecular mechanisms. Resveratrol, therefore, has been regarded as a potent candidate for the development of nutraceuticals and pharmaceuticals to prevent and treat certain chronic diseases.

Keywords: anti-obesity; anticancer; antidiabetes; bioactivities; molecular mechanisms; resveratrol.

Figure 1

The antioxidant molecular mechanisms of resveratrol. ① Resveratrol unanchors Nrf2 in the cytoplasm, disrupting its Keap1-dependent ubiquitination and degradation. The built-up Nrf2 translocates into the nucleus, binds to ARE, and initiates the transcription of many antioxidative genes such as SOD and CAT to reduce oxidative stress. ② Resveratrol promotes the transcriptional functions of FoxOs in the nucleus to facilitate the transcription of many antioxidative genes like HO-1, contributing to the reduction of oxidative stress. ③ Resveratrol upregulated PTEN, a major antagonist of PI3K, blocking the Akt activation. Consequently, the activated Akt reduces, leading to decreased FoxOs phosphorylation. Therefore, less p-FoxOs translocate from the nucleus to the cytoplasm, and more FoxOs remain in the nucleus to act as transcriptional factors. ④ Resveratrol activates AMPK to maintain the structural stability of FoxOs, facilitate its translocation, and accomplish its transcriptional function. In addition, the activated AMPK phosphorylates PGC-1α, which can translocate into the nucleus, and be deacetylated by SIRT1. Then PGC-1α promotes Nrf2, leading to increased antioxidative gene expression and then reduced oxidative stress. Resveratrol activates AMPK, leading to SIRT1 activation, which inhibits MAPK signaling pathways and results in autophagy. ⑤ Resveratrol induces autophagy by activating TFEB, which promotes the formation of autophagosome and lysosome as well as their fusion into an autolysosome, leading to reduced oxidative stress. Abbreviations: AC, acetyl; Akt, protein kinase B; AMPK, AMP-activated protein kinase; ARE, antioxidant response element; CAT, catalase; ERK, extracellular signal-regulated kinase; FoxO, forkhead box protein O; GPx, glutathione peroxidase; GβL, G protein β subunit-like; HO-1, heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; LKB1, liver kinase B1; MAP2K, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; mSIN1, mammalian stress-activated protein kinase interacting protein 1; mTOR, mammalian target of rapamycin; mTORC2, mTOR Complex 2; NAD, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor (erythroid-derived 2)-like 2; P, phosphorylation; p53, phosphoprotein p53; PDK1, phosphoinositide dependent kinase 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; Rictor, the rapamycin-insensitive companion of mTOR; SIRT1, sirtuin 1; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TF, transcription factor; TFEB, transcription factor EB.