Polyphenols are secondary metabolites produced by plants and also found in many natural products, such as fruit and vegetables, and their derivatives, such as tea, coffee, olive oil, and wine. Polyphenols are well known for their antioxidant properties, which confer to them health-beneficial effects. Among them, resveratrol is probably one of the most investigated molecules. It was first described in 1940 by Michio Takaoka, a Japanese student who was investigating extracts from traditional medicinal plants and called it “resveratrol” because the molecule had been extracted from the roots of Veratrum grandiflorum (white hellebore) and presented the skeleton of resorcinol in its molecular structure. The extract from this plant was exploited for treating several allergic and inflammatory diseases, among others. However, this molecule did not attract much interest until 1997, when Jang and colleagues published an article regarding its cancer chemopreventive activity.
Resveratrol is the common name for 3,5,4′-trihydroxy-trans-stilbene, a natural phytoalexin derived from phenylpropanoids, that is synthesized in plants under stress conditions, such as infections or UV exposure.
Polyphenols are secondary metabolites produced by plants and also found in many natural products, such as fruit and vegetables, and their derivatives, such as tea, coffee, olive oil, and wine 
. Polyphenols are well known for their antioxidant properties, which confer to them health-beneficial effects 
. Among them, resveratrol is probably one of the most investigated molecules. It was first described in 1940 by Michio Takaoka, a Japanese student who was investigating extracts from traditional medicinal plants and called it “resveratrol” because the molecule had been extracted from the roots of Veratrum grandiflorum
(white hellebore) and presented the skeleton of resorcinol in its molecular structure 
. The extract from this plant was exploited for treating several allergic and inflammatory diseases, among others. However, this molecule did not attract much interest until 1997, when Jang and colleagues published an article regarding its cancer chemopreventive activity 
Resveratrol is the common name for 3,5,4′-trihydroxy-trans
-stilbene, a natural phytoalexin derived from phenylpropanoids, that is synthesized in plants under stress conditions, such as infections or UV exposure. Under UV radiation it rapidly isomerizes to the cis
geometric form, but this compound, despite interesting biological activity, has been less investigated because of its lower abundance 
. Nevertheless, the trans
isomerization and fluorescence are the main deactivation pathways, although dependent on the environmental conditions 
The trans-resveratrol can be extracted in its free form or as glucoside directly from the plant but grapes are the preferred source due to the ease of extraction. Small concentrations of cis-resveratrol can be also present in wines despite its lack in grapes, suggesting its formation because of yeast isomerases during the fermentation process.
Similar to other polyphenols, resveratrol has multiple biological activities and many beneficial effects, such as anti-inflammatory and antioxidant properties, mainly related to its ability to scavenge free radicals, and, as such, it can also have a positive influence on the pathologies developed due or related to oxidative stress, such as cancer (Figure 1
Figure 1. Chemical structure of trans-resveratrol (in the dark-red rectangle) and main biological pathways affected.
2. Sources and Absorption of Resveratrol
The primary dietary sources of resveratrol include grapes, wine, apples, peanuts, and soy. Still, since the concentration of resveratrol present in all these food products is highly variable, it would be difficult to accurately estimate the average daily intake. This is related both to the fact that exogenous biological and physical stressors affect the resveratrol content in a specific food or drink and to the fact that endogenous factors interfere with the biosynthesis of resveratrol. Among the many varieties, wines made from grapes of the Pinot Noir and San Laurent showed the highest level of trans
-resveratrol. Nevertheless, red wines, such as those from Salento, are rich in this natural antioxidant, along with others 
. The resveratrol content is also influenced by various aspects of the wine-making process, including temperature, pH value, and SO2
However, getting a minimal health-beneficial dose of resveratrol through wine would mean drinking several liters. For this reason, some manufacturers sell pharmaceutically manufactured supplements with exactly specified resveratrol content. Nevertheless, the clinical potential of resveratrol in humans is somewhat difficult to estimate because there is still insufficient information on the optimal dosage, biotransformation, potential side effects, and pharmacokinetic parameters. In fact, resveratrol is characterized by a reduced bioavailability linked to its ability to be rapidly metabolized and subsequently eliminated in the urine and feces 
. The low availability of this compound is often associated with its low solubility in water (∼3 mg/100 mL) and the high permeability of the intestinal membrane. In fact, after oral administration, resveratrol is absorbed in the intestine by passive diffusion or thanks to membrane transporters. It can then be metabolized by glucuronidation and sulfation of the phenolic group (yielding resveratrol-4-O
-glucuronide, and resveratrol-3-O
-sulfate, respectively) or by hydrogenation of the aliphatic double bond and is subsequently released in the bloodstream, as observed in clinical trials 
. In the bloodstream, resveratrol can bind to proteins such as albumin or to lipoproteins, such as LDL, forming complexes that dissociate when, at the cell membrane level, LDL and albumin interact with specific receptors, allowing the entry of stilbene into the cell 
. In plasma, the concentration of unmodified free resveratrol is extremely low (around 1% of the ingested amount) and it generally depends on the ingested dose. However, exceptionally high amounts can be associated with a number of side effects, including diarrhea, nausea, and abdominal pain.
Since one of the major obstacles related to the administration of this antioxidant compound is its bioavailability, numerous research and studies focus precisely on the improvement of the pharmacokinetic profile of resveratrol 
. To this aim, different approaches have been proposed, such as those based on the use of emulsions and solid dispersions or on the encapsulation of resveratrol in nanocarriers, such as liposomes, micelles, and polymeric nanoparticles 
. It is also possible to use a similar compound extracted from the roots of the Polygonum Cuspidatum
plant, namely, polydatin, which differs from resveratrol by one molecule of glucose (Figure 2
. The presence of the conjugated carbohydrate makes the molecule more water-soluble, increasing its bioavailability.
Figure 2. Chemical structure of polydatin.
Other polyphenols present in red wine, such as quercetin, catechins, and gallic acid, could also potentially function as chemopreventive agents. For example, a mixture of polyphenols extracted from vine shoots showed anti-proliferative activity superior to resveratrol alone in cancer cells due to a synergistic action between the various polyphenols 
. Recently, numerous sulfonate derivatives of resveratrol were synthesized and some of them presented good antiproliferative activity in MCF-7 breast cancer cells due to their ability to inhibit aromatase, an enzyme with a key role in estrogen production and whose inhibitors have been shown to function as chemo-preventive agents in hormone-dependent breast cancers 
Furthermore, a substantial intake of resveratrol could interfere with the action of numerous drugs as well as, as mentioned above, with the action of CYP450 enzymes. In fact, resveratrol alters the effectiveness of some drugs, interacting precisely with the metabolism of the latter, mediated by CYPs’ enzymes, such as CYP3A4, CYP2D6, and CYP2C9 
. Inhibition of the CYP3A4 enzyme by resveratrol causes an increase in the blood levels of drugs metabolized by this enzyme, leading to an increase in toxicity related to the drugs themselves. On the other hand, CYP2D6 converts tamoxifen into endoxifen, a powerful antiestrogen that binds to the ER, inhibiting the binding with estrogens and, therefore, the estrogen-dependent proliferation of tumor cells that express this receptor. Inhibition of this liver enzyme decreases endoxifen levels in plasma and increases the risk of relapse. Finally, the inhibition of CYP2C9, particularly abundant in the liver and intestines, by resveratrol, causes a decrease in the clearance of a wide range of drugs, increasing their toxicity. For this reason, taking supplements containing high doses of resveratrol together with drugs must be done very carefully.