*Cont.*

regulatory B cells; TF, transcription

adaptor inducing β

 factor; TGF-β, transforming

interferon; UBL, ubiquitin-like

 growth factor β; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor α; TRIF, toll/IL-1 receptor

 protein; XBP-1, X-box binding protein 1.

domain-containing

#### **4. Clinical Trials**

In light of the positive epidemiological evidence and the promising results from experimental studies, resveratrol has been investigated in the human population as a potential nutraceutical (Table 3). There are certain encouraging outcomes reported. Specifically, resveratrol intake (500 mg/day for 30 days) was demonstrated to reduce CVD risk factors by increasing SIRT1, enhancing total antioxidant capacity in healthy individuals, decreasing low-density lipoprotein cholesterol (LDL-C), ApoB, and oxidized LDL [113–115]. Moreover, resveratrol prevented bone density loss (500 mg/day for 6 months) in type-2 diabetic patients [116]. In addition, resveratrol showed benefits in obesity, NAFLD, and neurodegenerative diseases [15,16,117,118]. However, some null outcomes have also been reported. For instance, resveratrol intake (250 mg/day for 8 weeks) did not increase SIRT1 nor improve many cardiovascular risk factors in healthy aged men [58]. In some other studies, no significant improvements were found in metabolic biomarkers in patients with Alzheimer's disease, obesity or type-2 diabetes, respectively, though their resveratrol intake ranged from 150 to 1000 mg/day with different duration of 4–52 weeks [119–122]. Therefore, the outcomes of clinical studies are not always consistent. Of note, the health effects of resveratrol as a therapeutic intervention may be affected by many factors, such as baseline health status of the subjects, their demographic profile, lifestyle, eating pattern, resveratrol dose, and intervention period. Nevertheless, a well-designed study, proper sample size, and a scientific evaluation system are also needed. Furthermore, although resveratrol is well-tolerated and safe as reported by most of the clinical trials, very few adverse effects (e.g., nausea and diarrhea) were observed, as well as some unfavorable results like an increase in total cholesterol, ApoB, the homeostatic model assessment-insulin resistance (HOMA-IR) score, fasting blood glucose, body fat, and the inflammatory markers [15,114,118]. Interestingly, resveratrol was reported to mask the exercise training-induced benefits, blunting the improved cardiovascular health parameters [58]. It might be attributable to the potent antioxidant capability of resveratrol, which could scavenge the free radicals induced by exercise training, because the appropriate number of free radicals is necessary for health maintenance. Therefore, it could be suggested that foods containing resveratrol should not be consumed during exercise.


**Table 3.** The results of resveratrol from clinical research.



TSH,

thyroid-stimulating

 hormone; VCAM-1, vascular cell adhesion molecule 1; WC, waist

circumference;

 WHR, waist-hip ratio.

#### **5. Conclusions**

Resveratrol is one of the most investigated bioactive compounds in foods. A number of epidemiologic studies have demonstrated that resveratrol is effective in the prevention of some diseases such as CVDs and cancer, although the results are sometimes inconsistent. In addition, the experimental studies have shown that resveratrol possesses many bioactivities and health benefits like antioxidant, anti-inflammatory, immunomodulatory effects, and improving CVDs, cancer, liver diseases, diabetes, obesity, Alzheimer's disease, and Parkinson's disease. Furthermore, resveratrol showed some effects in patients with CVDs and obesity in clinical trials, although inconsistency has also been reported. In the future, more bioactivities and health benefits of resveratrol should be evaluated, and further clarification of the underlying mechanisms of action is required. In order to develop resveratrol into functional foods and pharmaceuticals, more clinical trials are essential to confirm its efficacy and observe the possible adverse events, and the dose–effect relationship should be paid special attention as well.

**Author Contributions:** Conceptualization, X.M., R.-Y.G., and H.-B.L.; Writing—original draft preparation, X.M. and J.Z.; Writing—review and editing, C.-N.Z., R.-Y.G., and H.-B.L.; supervision, R.-Y.G. and H.-B.L.; funding acquisition, R.-Y.G., and H.-B.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by China Central Public-interest Scientific Institution Basal Research Fund (Grant No. Y2020XK05), the National Key R&D Program of China (Grant No. 2018YFC1604400), and the Key Project of Guangdong Provincial Science and Technology Program (Grant No. 2014B020205002).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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