Recent Overview of Resveratrol’s Beneficial Effects and Its Nano-Delivery Systems

Highlights1. Resveratrol is an antioxidant and exhibits numerous potential therapeutic applications. However, it suffers from low water-solubility, degradation, and poor bioavailability. The conventional dosage form of resveratrol shows various limitations, such as prolonged therapy, erratic bioavailability, and absence of effective drug concentrations in tissues.2. Nanocarrier-based delivery systems are being studied extensively to target tissues and cells to improve the therapeutic potential of poorly soluble molecules by enhancing their bioavaila-bility, solubility, and retention time.3. Resveratrol can act as a potential anti-cancer agent and lowers the progression of cancer disease. Abstract Natural polyphenols have a wide variety of biological activities and are taken into account as healthcare materials. Resveratrol is one such natural polyphenol, belonging to a group known as stilbenoids (STBs). Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is mainly found in grapes, wine, nuts, and berries. A wide range of biological activities has been demonstrated by resveratrol, including antimicrobial, antioxidant, antiviral, antifungal, and antiaging effects, and many more are still under research. However, as with many other plant-based polyphenol products, resveratrol suffers from low bioavailability once administered in vivo due to its susceptibility to rapid enzyme degradation by the body’s innate immune system before it can exercise its therapeutic influence. Therefore, it is of the utmost importance to ensure the best use of resveratrol by creating a proper resveratrol delivery system. Nanomedicine and nanodelivery systems utilize nanoscale materials as diagnostic tools or to deliver therapeutic agents in a controlled manner to specifically targeted locations. After a brief introduction about polyphenols, this review overviews the physicochemical characteristics of resveratrol, its beneficial effects, and recent advances on novel nanotechnological approaches for its delivery according to the type of nanocarrier utilized. Furthermore, the article summarizes the different potential applications of resveratrol as, for example, a therapeutic and disease-preventing anticancer and antiviral agent.


Introduction
Plant-based natural products are commonly used as an alternative to modern medicines. Since the beginning of human life, herbal medicines have developed and continued to exist This review article, after a brief introduction about natural polyphenols, focuses on the chemistry of RES and nanotechnology's role in the development of RES delivery sys- This review article, after a brief introduction about natural polyphenols, focuses on the chemistry of RES and nanotechnology's role in the development of RES delivery systems. The use of RES as anticancer drug is also discussed to understand how the carrier system can play a vital role in exploring the potential of natural phytochemicals, such as RES (see Figure 2). This review article, after a brief introduction about natural polyphenols, focuses on the chemistry of RES and nanotechnology's role in the development of RES delivery systems. The use of RES as anticancer drug is also discussed to understand how the carrier system can play a vital role in exploring the potential of natural phytochemicals, such as RES (see Figure 2).

Natural Polyphenols
Polyphenols are a phytochemical group with chemical properties and different structures ranging from simple molecules to polymers with high molecular weight [16]. Polyphenols are secondary plant metabolites, and their primary role is to attract pollinators and protect plants from insects, ultraviolet radiation, and microbial infection [17]. Polyphenols comprise a phenolic system with at least one phenyl ring and one or more hydroxyl substituents. Polyphenols are present in vegetables, fruits, herbs, spices, beverages such as tea and wine, chocolates, and whole grains [18].

Classification of Polyphenols
Generally, polyphenols are mainly categorized into flavonoids and nonflavonoids, but according to the aglycone chemical structures, they can be also classified as phenolic acids, lignans, and stilbenes [16].
Flavonoids. It is the largest group of phenolic compounds and mostly present in fruits. The structures consist of two aromatic rings bound with a three-carbon bridge to form an oxygenated heterocycle. The biological activities, such as anticancer, anti-inflammatory, and antioxidant ones, depend on the flavonoids' structural difference and glycosylation pattern [19]. Based on the number, position of the -OH groups and degree of oxidation of the central ring, flavonoids can be further divided into subclasses of flavones, flavonols, flavanones, flavanols, isoflavones, and anthocyanidin. Flavones, such as apigenin and luteolin, are found in celery, parsley, and some herbs. The polymethoxylated flavones (e.g., tangeretin and nobiletin) are found only in the tissues and peels of citrus fruit, such as oranges, grapefruit, and tangerines. The flavones' characteristic feature is to have methylated -OH groups, which increases their metabolic stability and enhances their oral bioavailability [20]. Flavonols are one of the most ubiquitous flavonoids found in capers, saffron, dried Mexican oregano, yellow and red onions, and spinach.
Two representatives of this subclass are quercetin and kaempferol. Naringenin and hesperetin are valuable flavanones found in food. The maximum concentrations of flavanones are present in citrus fruits and dried herbs, and they are responsible for the bitter taste of fruits [21]. Isoflavones are present in legumes, and the chief source is soybeans, having substantial amounts of daidzein and genistein. Isoflavones show pseudo-hormonal characteristics because of their structural similarity to oestrogen, and their supplements can bind to the oestrogenic receptors and, as such, be used as potential substitutes for conventional hormone therapy [22]. Among all flavonoids, flavanols are the most complex subclass, being able to form monomers, oligomers, polymers, and other derivative compounds. They are responsible for the bitterness of chocolate and the acid-based character of some fruits and beverages. Anthocyanidins are a subgroup of flavonoids responsible for the colour of flowers, leaves, fruits, and roots. Pelargonidin, delphinidin, peonidin, petunidin, malvidin, and cyanidin are common anthocyanidins distributed in fruits and vegetables [23].
Phenolic acids. They can be divided into two groups, led by benzoic and cinnamic acid. Gallic and ellagic acid are the essential derivatives of benzoic acid, and they are found in cranberries, raspberries, pomegranates, and nuts. On the other hand, cinnamic acids' essential derivatives are ferulic, coumaric, caffeic, and sinapic acid [24].
Lignans. The highest amount of lignans is found in flaxseeds, grains, and certain vegetables. In plants, they are typically found as glycosides and are converted by intestinal bacteria to give metabolites having oestrogenic activity [25].
Stilbenes. They are phytoalexins produced by plants in response to injury and infections. In the human diet, they are present in low quantities, and only resveratrol is essential for the human health. Grapes and red wine are an important dietary source of resveratrol. Resveratrol is directly connected to the French paradox. It was observed that French people consume high amounts of saturated fatty acids but they hardly suffer from cardiovascular diseases, having a lower death rate than other European countries. It is thus supposed that the daily consumption of red wine plays a significant role in preventing heart diseases [26].

Chemistry of Resveratrol
Resveratrol is a stilbenoid polyphenol with two phenol rings linked to each other by an ethylene bridge. The IUPAC name of resveratrol is E-5-(4-hydroxystyryl)benzene-1,3-diol, but both geometric isomers of resveratrol, the cis and the trans, can be found ( Figure 3). supposed that the daily consumption of red wine plays a significant role in preventing heart diseases [26].

Chemistry of Resveratrol
Resveratrol is a stilbenoid polyphenol with two phenol rings linked to each other by an ethylene bridge. The IUPAC name of resveratrol is E-5-(4-hydroxystyryl)benzene-1,3diol, but both geometric isomers of resveratrol, the cis and the trans, can be found ( Figure  3). After exposure to the UV radiation, the trans isomer can transform into the cis one. However, the trans form is dominant because of its occurrence, and it is also more interesting because of its many biological activities. The trans form induces cell differentiation, cell cycle arrest, apoptosis, and increased antiproliferation in cancerous cells [27]. The stability of trans-resveratrol powder depends on humidity (75%) and temperature (40 °C) in the presence of air. The isomerization of trans-resveratrol is influenced by irradiation time, wavelength, temperature, pH, and physical status of the molecule. Waterhouse and coworkers investigated the reaction kinetics [28]. trans-Resveratrol's stability is 42 h in neutral aqueous buffer and 28 days in acidic media when protected from light. At pH 10.0 the initial half-life for trans-resveratrol is nearly 1.6 h. The bioavailability of resveratrol is very low. Therefore, modification of its structure has received great attention from the scientific community and various resveratrol derivatives have been synthesized. Nanoformulations containing resveratrol have been considered as a promising approach for retaining its bi- After exposure to the UV radiation, the trans isomer can transform into the cis one. However, the trans form is dominant because of its occurrence, and it is also more interesting because of its many biological activities. The trans form induces cell differentiation, cell cycle arrest, apoptosis, and increased antiproliferation in cancerous cells [27]. The stability of trans-resveratrol powder depends on humidity (75%) and temperature (40 • C) in the presence of air. The isomerization of trans-resveratrol is influenced by irradiation time, wavelength, temperature, pH, and physical status of the molecule. Waterhouse and coworkers investigated the reaction kinetics [28]. trans-Resveratrol's stability is 42 h in neutral aqueous buffer and 28 days in acidic media when protected from light. At pH 10.0 the initial half-life for trans-resveratrol is nearly 1.6 h. The bioavailability of resveratrol is very low. Therefore, modification of its structure has received great attention from the scientific community and various resveratrol derivatives have been synthesized. Nanoformulations containing resveratrol have been considered as a promising approach for retaining its biological functions until delivery [28]. To enhance the oral bioavailability, two delivery systems of resveratrol, i.e., stable lipid nanoparticles and nanostructured lipid carriers, have been developed [29]. Moreover, as compared with the free form, resveratrol nanoparticles improve its solubility and increase its antioxidant potential [30].
In 1940, resveratrol was first isolated from white hellebore (Veratrum grandiflorum O. Loes) roots. After that, in 1963, it was isolated from Polygonum cuspidatum roots, which are used as antiplatelet and anti-inflammatory agents in traditional Chinese and Japanese medicine [31]. Resveratrol acts as a phytoalexin in plants synthesized in response to UV irradiation, mechanical injury, and fungal attacks. In industry, resveratrol is generally prepared by chemical or biotechnological synthesis from yeasts of Saccharomyces cerevisiae [32]. Ninety-two new resveratrol derivatives have been reported from the Leguminosae, Paeoniaceae, Dipterocarpaceae, Vitaceae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae, and Poaceae families. Among these families, Dipterocarpaceae alone contains more than 50 resveratrol derivatives, and it is from seven genera [33]. Because of the broad range of pharmacological effects, resveratrol is sold on the market as a nutritional supplement [34].

Designing of Nanocarriers for Resveratrol Delivery
Nanocarriers are drug carrier systems usually having <500 nm particle size [35]. They have high surface-area-to-volume ratios, the ability to alter bioactivity of drugs, enhanced pharmacokinetics and biodistribution, and potential site-specific delivery, due to which they have already shown promising results as therapeutic agents in the drug delivery area [36]. In anticancer therapy, several problems arise when chemotherapeutics are delivered through conventional administration routes, such as low specificity, high toxicity, and induction of drug resistance, thus reducing the therapeutic value of most anticancer drugs [37]. To overcome this obstacle, nanocarrier-based platforms have been used to deliver anticancer drugs into the tumours and disturb the tumour microenvironment's pathophysiology, thus improving the therapeutic efficiency [38].
Organic nanocarriers. SLNs increase controlled drug delivery, lack biotoxicity, present high drug-carrying efficiency and good stability, improve the bioavailability of poorly water-soluble drugs, and can be easily produced large scale [39]. SLN nanocarriers have been exploited to deliver anticancer drugs, such as methotrexate, docetaxel, paclitaxel, 5-fluorouracil (5-FU), and doxorubicin [40,41]. Liposome nanocarriers have shown several advantages over conventional therapy. They can increase delivery of the drug, prevent early degradation of the encapsulated drug, improve the performance of the drugs, are cost-effective formulations, and represent an effective treatment with reduced toxicity. They are generally used as carriers for drugs, vaccines, cosmetics, and nutraceuticals [42]. Dendrimers are spherically-shaped, monodispersed macromolecules with an average diameter of 1.5-14.5 nm and unique characteristics [43]. Lai et al. used dendrimers to enhance the efficacy of doxorubicin [44]. They used photochemical internalization technology to enhance the cytotoxicity to cancerous tissue. Polymeric nanoparticles (PNPs) are solid biodegradable polymers, nanosized colloidal particles ranging from 10 to 1000 nm [45]. Based on the structure, PNPs are categorized as nanospheres and nanocapsules. Nanospheres are a type of PNPs entrap the drug in the polymer matrix whereas, in nanocapsules, the drug is dispersed in the liquid core of oil or water encap-sulated by a solid polymeric membrane [46]. PNPs are highly versatile. Examples of PNPs as a carrier for anticancer molecules are PLGA, PCL, chitosan, PLA, and alginate NPs [47,48]. Polymeric micelles (PMs) are 10-100 nm nanosized colloidal particles formed by the self-assembly of synthetic amphiphilic copolymers in an aqueous solution [49]. They have a core-shell structure with a hydrophobic core and hydrophilic shell [50]. The hydrophobic core of PMs captures the hydrophobic drugs and controls the drug release, thus increasing their water-solubility, whereas the hydrophilic shell of the PMs stabilizes the core and controls the in vivo pharmacokinetics [51]. Various chemotherapeutic agents, such as methotrexate, paclitaxel, docetaxel, cisplatin, and doxorubicin, have successfully been formulated in PMs for cancer treatment. Poloxamer-based micelles, PEGylated polyglutamic acid micelles, PEG-PLA micelles, and PEG-PAA micelles have been used as delivery systems [52]. VNPs are self-assembled protein cages with a diameter <100 nm, having uniform nanostructures. Recently, VNPs have been widely explored for various applications, such as drug delivery, vaccination, imaging, gene therapy, and targeting [53].
Inorganic nanocarriers. From the last few years, silica materials hold great promises in nanomedicine due to their straightforward and cost-effective synthesis and functionalization, and their multiple uses. Among silica materials, mesoporous silicas are catching the attention of researchers in drug delivery because of their honeycomb-like structure with hundreds of pores ranging from 2 to 50 nm, with narrow pore size and versatility of loading large amounts of drugs [54]. MSNs possess promise as nanoscale drug carriers because of good biocompatibility, controllable pore diameters, high specific surface area and pore volume, high loading capacity, and good chemical stability, which enhances therapeutic efficacy and decreases the toxicity of drugs [47]. Paclitaxel, camptothecin, doxorubicin, and methotrexate anticancer drugs have been effectively delivered via MSNs [55]. CNTs have a nanoneedle shape, hollow monolithic structure, high mechanical strength, electrical and thermal conductivities, and the ability of easy surface modification [56]. The needle-like shape of CNTs crosses the cell membrane and enters into the cell. One of the drawbacks of CNTs is insufficient water solubility, as well as their toxicity. However, after surfacefunctionalization, CNTs become water-soluble, biocompatible, less toxic, serum-stable, and ideal nanocarriers for cancer therapy [57]. Examples of the application of CNTs in anticancer drug delivery are methotrexate, paclitaxel, cisplatin, carboplatin, doxorubicin, and mitomycin C [58].
Hybrid nanocarriers. Hybrid nanocarriers have been developed to combine the properties of organic and inorganic materials. Surface coating with polyethyleneimine (PEI) increased the cellular uptake of MSNs for efficient nucleic acid delivery [59]. These hybrid nanocarriers prevented premature release of the loaded drug, multidrug resistance, extended the retention of hydrophilic drug cargo, and yielded stimuli-responsive drug release. Desai and co-workers reported the intracellular delivery of zoledronic acid in breast cancer cells [60]. Han et al. developed doxorubicin-loaded, hybrid, lipid-capped MSNs with pH and redox-responsive release of the drug cargo. These hybrid nanocarriers increased the uptake of doxorubicin, thus improving its accumulation, efficiency, and cytotoxicity [61].
The solubility of resveratrol has been shown to be very low, leading to low bioavailability [15] Hence, while designing delivery system for resveratrol, efforts should be made to enhance its bioavailability. This aim has been attempted by using cyclodextrin complexes, dendrimers, liposomes, self-nano-emulsifying drug delivery systems, solid lipid nanoparticles, nanosuspensions, nanocapsules, microparticles and both nano-and microencapsulation (Table 1). Table 1. Brief overview of most important type of nanocarriers used for delivering resveratrol.

Nano System Effect Key Properties Reference
Liposomes Antioxidant activity Enhanced solubility and stability of curcumin and resveratrol. Minimum particle size, lower polydispersity index and high encapsulation efficiency [62] Anticancer activity HepG2 cells exhibited a higher uptake of encapsulated-RES than the free form [63] Dendrimers Enhanced RES solubility and stability in aqueous solution. Dendrimers can be engineered to control pharmacokinetics and target for oral, mucosal, transdermal, or parenteral administration (PAMAM) dendrimer assembly overcame the problems of low bioavailability and poor water solubility [64] Solid lipid nanoparticles In vitro cytotoxicity against C6 glioma cell lines The resveratrol-TPGS-SLNs showed 11.12 and 9.37-times higher area under the curve (AUC) and plasma half-life, respectively, than the unprocessed resveratrol. Additionally, the concentration of resveratrol-TPGS-SLNs in the brain was found to be 9.23-times higher compared to free resveratrol [65] Polymeric nanoparticles Fatty liver disorder The prepared poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing resveratrol increased its stability and solubility, yielding better in vitro results as compared to free drug [66]

Prophylactic and Therapeutic Applications of Resveratrol
Cancer remains one of the main reasons for mortality in the world. Despite cuttingedge research, the mortality rate has not improved in the last 5 years. More than 1.6 million new cancer diagnoses and approximately 600,000 cancer-related deaths are expected in the United States of America in 2016 alone [67]. Despite the use of novel approaches, such as monoclonal antibodies (MABs) and personalized chemotherapy, the clinical outcomes are not satisfying [68,69]. The complexity of the diseases may justify the failure of cancer treatments. Carcinogenesis is a complicated and multistep process which involves molecular and cellular alterations, which are distinct but closely connected phases of initiation, promotion, and progression [70][71][72] (see Figure 4). Polymeric nanoparticles Fatty liver disorder The prepared poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing resveratrol increased its stability and solubility, yielding better in vitro results as compared to free drug [66]

Prophylactic and Therapeutic Applications of Resveratrol
Cancer remains one of the main reasons for mortality in the world. Despite cuttingedge research, the mortality rate has not improved in the last 5 years. More than 1.6 million new cancer diagnoses and approximately 600,000 cancer-related deaths are expected in the United States of America in 2016 alone [67]. Despite the use of novel approaches, such as monoclonal antibodies (MABs) and personalized chemotherapy, the clinical outcomes are not satisfying [68,69]. The complexity of the diseases may justify the failure of cancer treatments. Carcinogenesis is a complicated and multistep process which involves molecular and cellular alterations, which are distinct but closely connected phases of initiation, promotion, and progression [70][71][72] (see Figure 4). A possible reason for the failure of current cancer therapies, including chemotherapy, radiation, surgery, and immunosuppression, is emergency resistance [73]. Natural molecules are devoid of developing resistance, and delivering therapeutic effects without side effects remains a primary objective in the fight against cancer.

Resveratrol in Cancer Prevention and Treatment
Recent research has suggested that resveratrol can prevent the events linked to the initiation of tumours, which plays a vital role in developing resistance towards the current A possible reason for the failure of current cancer therapies, including chemotherapy, radiation, surgery, and immunosuppression, is emergency resistance [73]. Natural molecules are devoid of developing resistance, and delivering therapeutic effects without side effects remains a primary objective in the fight against cancer.

Resveratrol in Cancer Prevention and Treatment
Recent research has suggested that resveratrol can prevent the events linked to the initiation of tumours, which plays a vital role in developing resistance towards the current line of therapeutics. This characteristic of resveratrol has attracted great attention toward this molecule compared to other natural polyphenols. Another important mode of action is the prevention of free radical formation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). It has been seen over the course that TPA is one of the primary carcinogens mostly seen in the liquid tumours (e.g., in human leukaemia HL-60 cells) [74]. The various antioxidant properties of resveratrol have already been described previously [75,76]. Resveratrol is an excellent scavenger of hydroxyls and superoxides as well as the radicals induced by metals/enzymes and generated by cells [77]. It also protects against lipid peroxidation within cell membranes and damages DNA resulting from reactive oxygen species (ROS) [78]. Furthermore, resveratrol can function as an antimutagen, as shown by the inhibition of the mutagenicity of N-methyl-N -nitro-N-nitrosoguanidine in the Salmonella typhimurium strain TA100 [79]. It has been proposed that resveratrol can be a possible chemo preventive agent, and its antimutagenic and anticarcinogenic properties have been demonstrated in several models [80]. Moreover, resveratrol showed a protective role in preclinical models of osteoarthritis and rheumatoid arthritis by reducing the production of pro-inflammatory and pro-degradative soluble factors, and through modulation of cellular and humoural responses [81].
Furthermore, resveratrol could enhance oxidative stress in adjuvant-arthritis (AA) rats and increase mtROS production by reducing the autophagy protein Beclin1, LC3A/B, and oxidative stress protein MnSOD, favouring the apoptosis of FLSs [82] (see Figure 5 for details). induced by metals/enzymes and generated by cells [77]. It also protects against lipid peroxidation within cell membranes and damages DNA resulting from reactive oxygen species (ROS) [78]. Furthermore, resveratrol can function as an antimutagen, as shown by the inhibition of the mutagenicity of N-methyl-N′-nitro-N-nitrosoguanidine in the Salmonella typhimurium strain TA100 [79]. It has been proposed that resveratrol can be a possible chemo preventive agent, and its antimutagenic and anticarcinogenic properties have been demonstrated in several models [80]. Moreover, resveratrol showed a protective role in preclinical models of osteoarthritis and rheumatoid arthritis by reducing the production of pro-inflammatory and pro-degradative soluble factors, and through modulation of cellular and humoural responses [81]. Furthermore, resveratrol could enhance oxidative stress in adjuvant-arthritis (AA) rats and increase mtROS production by reducing the autophagy protein Beclin1, LC3A/B, and oxidative stress protein MnSOD, favouring the apoptosis of FLSs [82] (see Figure 5 for details). Resveratrol reduced the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2-related factor 2 (Nrf2), and increased the expression of matrix metalloproteinase (MMP)-2, MMP-9, cyclooxygenase-2, and Toll-like receptor-4 in rats and further inhibited the formation of osteoclasts, the production of inflammation-related proteins, and of circulating ROS in periodontitis rats [83]. Treatment of monosodium iodoacetate (MIA)-injected rats with resveratrol (5 or 10 mg per kg BW) considerably reduced hyperalgesia and Resveratrol reduced the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2-related factor 2 (Nrf2), and increased the expression of matrix metalloproteinase (MMP)-2, MMP-9, cyclooxygenase-2, and Toll-like receptor-4 in rats and further inhibited the formation of osteoclasts, the production of inflammation-related proteins, and of circulating ROS in periodontitis rats [83]. Treatment of monosodium iodoacetate (MIA)-injected rats with resveratrol (5 or 10 mg per kg BW) considerably reduced hyperalgesia and reduced the vertical and horizontal movements, additionally reducing any increase in the COX-2 and iNOS mRNA signalling pathways [84]. Very recently, it was also reported that in human bone mesenchymal stem cells, resveratrol suppressed interleukin-1β and thus downregulated metalloproteinase-13 mRNA expression and that it upregulated the chondrocyte markers (aggrecan, Col2, and Sox9 mRNA expression) [85].

Resveratrol in Wound Healing
Inflammation, proliferation, maturation, and remodelling are the four phases related to tissue integrity process after injury. The proliferation phase, starting within few days after injury, presents healing processes such as angiogenesis, granulation tissue formation, collagen deposition, and epithelialization [86]. Resveratrol seems to be a promising treatment approach, interacting with the healing cascade at different levels [87][88][89]. Several studies suggest that resveratrol could increase wound healing [87,90,91]. Figure 6 shows RES-induced angiogenesis blocked by PI3K and MEK inhibitors in HUVEC cells, as investigated by Wang et al. [88].
Moreover, resveratrol has also a significant impact on the regulation of inflammation and consequently in processes related to skin repair [101]. In vitro investigations showed that due to its antioxidant properties resveratrol can influence cell proliferation, ultrastructural preservation, and migration quality [102,103], whereas in vivo studies reported a significant improvement in wound healing properties [104].

Resveratrol as Cardioprotective Agent
Resveratrol is a natural compound with anti-inflammatory effects. Xiuyue Huo et al. evaluated the cardio protective effects of RES in a diabetic rat model with coronary heart disease [105]. RES maintained pancreatic tissue, reducing levels of glucose and triglyceride glycerides in serum. Inflammatory factors were also suppressed by RES. TLR4/MyD88/NF-kB signalling pathway was downregulated after RES treatment [105]. To confirm the cardioprotective effects of RES, the authors harvested heat tissues from rats and examined pathological changes using H&E staining. They demonstrated that RES can offer protective effects on cardiovascular tissues in diabetic rats. By downregulating a wide range of inflammatory factors, RES strongly improved coronary injuries from inflammation. Based on this effect, RES might show a beneficial outcome or has a promising effect in diabetic cases with coronary heart disease according to its protective effects on cardiovascular tissues [105].
Resveratrol and its analogues have been shown in preclinical studies to protect against cancer treatment-induced cardiovascular toxicity. They have also been reported to possess significant anticancer properties on their own and to enhance the anticancer effect of other cancer treatments. Thus, they hold significant promise to protect the cardiovascular system and fight the cancer at the same time [106]. Thus, they hold significant promise to protect the cardiovascular system and fight the cancer at the same time. Despite the very promising preclinical findings of resveratrol as a cardioprotective agent, there are still several questions that need to be answered before advancing resveratrol into clinical trials. Considering the possible hormetic dose-response properties of resveratrol [107], it is important to show that the same dose of resveratrol can protect the heart and fight cancer. On the other hand, to determine the effect of resveratrol on the pharmacokinetics and tissue distribution of chemotherapeutic agents, considering the potential of resveratrol to alter several drug metabolizing enzymes is also rather important [108].

Resveratrol in Fighting Infections
Resveratrol has been reported to show anti-inflammatory, cardioprotective, and antiproliferative properties and also to affect many viruses like retroviruses, influenza A virus, and polyomavirus by altering cellular pathways influencing viral replication itself. Epstein-Barr Virus (EBV), the agent causing mononucleosis, relates to different proliferative diseases and establishes a latent and/or a lytic infection. De Leo and co-workers [109] examined the antiviral activity of RES against the EBV replicative cycle and studied the molecular targets involved. In a cellular context that allows in vitro EBV activation and lytic cycle progression, they found that RES inhibited EBV lytic genes expression and the production of viral particles in a dose-dependent manner. They demonstrated that RES decreased reactive oxygen species (ROS) levels, inhibited protein synthesis, and suppressed the EBV-induced activation of the redox-sensitive transcription factors NF-kB and AP-1 [109]. RES action causes downregulation of EBV-lytic genes at the post-transcriptional level by influencing multiple cellular targets. The molecular mechanisms involved could be divided in three parts: (1) inhibition of protein synthesis, (2) decrement of ROS levels, and (3) fast suppression of NF-kB and AP-1 activities, augmented by EBV-lytic cycle reactivation [109]. With this work, De Leo and co-authors constructed the basis for evaluating the antiviral activity of RES against EBV infection, envisaging the possibility to extend it to other types of infections.
In a recent article, Palomera-Ávalos et al. [110] demonstrated that RES induced higher expression in cytokines with regard to LPS. Oxidative stress (OS) markers indicated nonsignificant changes after LPS or RES, although for the RES-treated groups a slight increment in several study parameters was observed, reaching significance for NF-kB protein levels and iNOS expression. The authors focused on the role of long-term resveratrol treatment as a tool to increase brain defenses in ageing animals against acute LPS proinflammatory stimuli. Their results showed an improvement in cellular response against LPS injury cellular modulation response in the ageing brain. Finally, they concluded that resveratrol treatment induced a different cellular response in ageing animals when they encountered acute inflammatory stimuli [110].
Shevelev and co-workers have compared the antimicrobial activity of resveratrol (a stilbene), dihydroquercetin, and dihydromyricetin (two flavonols) extracted from the bark and wood of conifers against the dermatophytes Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. This study suggests a significantly higher bactericidal activity of polyphenols in comparison with those traditionally used against S. aureus at 24.2 mM [111].
It has been shown that RES can block the critical pathways involved in SARS-CoV-2 pathogenesis, including control of both RAS and ACE2, and body immune activation, and downregulate pro-inflammatory cytokine release. It was also discovered to activate SIRT1 and p53 signalling pathways and increase cytotoxic T lymphocytes (CTLs) and natural killer (NK) immune cells. RES has also been a fetal hemoglobin stimulator and a potent antioxidant capable of blocking ROS [112,113].
RES also blocked MERS-CoV replication in vitro by inhibiting RNA synthesis and had other pleiotropic consequences, and it inhibited viral replication and reduced the death risk in piglets infected with the duck enteritis virus [114]. Similarly, Lin et al. (2017) showed that resveratrol can prevent MERS-CoV infections in a Vero E6 cell model. Two resveratrol concentrations of 250 and 125 µM were investigated, demonstrating that resveratrol can reduce the cell death induced by infection at this concentration range [115] (see Figure 7). Currently there is no evidence that RES has been used to treat SARS-CoV-2; however, available studies may envisage that it could be a strategic adjunctive antiviral agent to use in synergy with others.

Conclusions
Resveratrol is a very promising natural molecule because of its enormous therap potential. However, the potential of resveratrol has not been fully explored due to its bioavailability. In the past two decades, nano-based delivery systems have created hopes for delivering numerous drug molecules. Regardless of the encouraging resu preclinical trials, the suitability of resveratrol for humans has encountered only in quate accomplishment, mostly due to its incompetent systemic delivery and, su quently, its low bioavailability enterohepatic recirculation. Whether or not enterohe recirculation of resveratrol contributes expressively to the complete pharmacologica tion needs to be determined. To overcome these issues, it has been shown that enca lating resveratrol into nanocarriers drastically improves the obstacles to its physicoc ical characteristics. Furthermore, nanocarriers can enhance the bioavailability and pe ability of resveratrol molecules, which are otherwise challenging to deliver orally.

Conclusions
Resveratrol is a very promising natural molecule because of its enormous therapeutic potential. However, the potential of resveratrol has not been fully explored due to its poor bioavailability. In the past two decades, nano-based delivery systems have created new hopes for delivering numerous drug molecules. Regardless of the encouraging results in preclinical trials, the suitability of resveratrol for humans has encountered only inadequate accomplishment, mostly due to its incompetent systemic delivery and, subsequently, its low bioavailability enterohepatic recirculation. Whether or not enterohepatic recirculation of resveratrol contributes expressively to the complete pharmacological action needs to be determined. To overcome these issues, it has been shown that encapsulating resveratrol into nanocarriers drastically improves the obstacles to its physicochemical characteristics. Furthermore, nanocarriers can enhance the bioavailability and permeability of resveratrol molecules, which are otherwise challenging to deliver orally.

Current Limitations and Future Perspectives
Several resveratrol-based nanoformulations are being explored for clinical applications. Despite these achievements, the 'ideal' resveratrol delivery system still needs to be disclosed. Significant progress has been made over last few years for developing the next generations of resveratrol-based nanocarriers that will play an essential role in curing human diseases and improving healthcare. The main limitations of these nanocarriers rely on difficulties in increasing bioavailability and targeting. By developing and designing novel nanovectors, one may also take into account the obstacles related to overcoming biological barriers in delivering cargos as well as the impendence to maintain intact or still-active, large quantities of RES during the transport to the target. For these reasons, additional studies (in vitro and more in vivo) are needed, and they will allow the development of novel strategies to overcome such challenges still limiting the use of resveratrol for therapy and/or prevention in deadly diseases such as cancer.

Conflicts of Interest:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.