Abstract

Due to its health benefits, resveratrol (RE) is one of the most researched natural polyphenols. Resveratrol’s health benefits were first highlighted in the early 1990s in the French paradox study, which opened extensive research activity into this compound. Ever since, several pharmacological activities including antioxidant, anti-aging, anti-inflammatory, anti-cancerous, anti-diabetic, cardioprotective, and neuroprotective properties, were attributed to RE. However, results from the available human clinical trials were controversial concerning the protective effects of RE against diseases and their sequelae. The reason for these conflicting findings is varied but differences in the characteristics of the enrolled patients, RE doses used, and duration of RE supplementation were proposed, at least in part, as possible causes. In particular, the optimal RE dosage capable of maximizing its health benefits without raising toxicity issues remains an area of extensive research. In this context, while there is a consistent body of literature on the protective effects of RE against diseases, there are relatively few reports investigating its possible toxicity. Indeed, toxicity and adverse effects were reported following consumption of RE; therefore, extensive future studies on the long-term effects, as well as the in vivo adverse effects, of RE supplementation in humans are needed. Furthermore, data on the interactions of RE when combined with other therapies are still lacking, as well as results related to its absorption and bioavailability in the human body. In this review, we collect and summarize the available literature about RE toxicity and side effects. In this process, we analyze in vitro and in vivo studies that have addressed this stilbenoid. These studies suggest that RE still has an unexplored side. Finally, we discuss the new delivery methods that are being employed to overcome the low bioavailability of RE.

Highlights

  • Resveratrol (RE; (3,4’,5 trihydoxystilbene)) is a stilbenoid natural polyphenol

  • Resveratrol exists as two isomeric forms, yet the trans form is the predominant form and it has the most potent therapeutic benefits owing to the lower steric hindrance of its side chains [3,4]

  • Ex vivo, and animal studies have indicated that RE may exert several health benefits and cardiovascular protection, in particular [20,21,29], the human clinical studies available so far have shown controversial results concerning the protective effects of RE against diseases and their sequelae [30,31,32,33,34,35,36]

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Summary

Introduction

Resveratrol (RE; (3,4’,5 trihydoxystilbene)) is a stilbenoid natural polyphenol. RE was first isolated in 1939 by Takaoka from Veratrum grandiflorum [1,2]. Ex vivo, and animal studies have indicated that RE may exert several health benefits and cardiovascular protection, in particular [20,21,29], the human clinical studies available so far have shown controversial results concerning the protective effects of RE against diseases and their sequelae [30,31,32,33,34,35,36] The reasons behind these conflicting findings is varied; differences in the characteristics of the enrolled patients, RE doses used, and the duration of RE supplementation were proposed, at least in part, as possible causes [30,37]. Resveratrol appears to have a different effective dosage range in vitro (micromolar range in cell culture media) than its in vivo bioavailability (nanomolar range in the blood), making it difficult to identify the actual biologically effective concentration range at which this compound should be supplemented to human subjects. Despite its low bioavailability and relatively rapid metabolism and elimination, RE shows a relevant biological efficacy, which may be due to its conversion/interconversion into sulfonate and glucuronide metabolites and/or its binding/unbinding to plasma proteins, two potential primary aspects in the delivery of RE at target organ sites [68,80]

RE Metabolites Can Exhibit Cytotoxic Effects
Resveratrol Cytotoxic Mechanisms Can Induce DNA Breaks
Resveratrol Cytotoxic Mechanisms Can Induce Oxidative Stress
In Vitro Evidence of the Harmful Effects Induced by RE
Resveratrol Alters the Redox State of Endothelial Human Cells
Resveratrol Chemotherapeutic Doses Are Cytotoxic to Normal Healthy Cells
In Vivo Non-Human Evidence of the Harmful Effects of Resveratrol
In Vivo and In Vitro Human Evidence of the Harmful Effects of Resveratrol
Resveratrol Can Increase DNA Damage and Proteolysis
Human Trials with Resveratrol
Resveratrol Impacts Cancer Onset
Resveratrol as a Complementary Therapy
Findings
Current Concerns and Recommendations
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