Enhancing the Bioavailability of Resveratrol: Combine It, Derivatize It, or Encapsulate It?

1. Structure and Therapeutics of Resveratrol

1.1. General Structure

Resveratrol (hereafter RSV) is a well-known biologically active compound that exhibits a wide spectrum of properties, including antioxidant, cardioprotective, neuroprotective, anti-inflammatory, and anticancer effects [ 1 , 2 , 3 ]. Structurally, it is a lipophilic polyphenol stilbene synthesized from tyrosine with the action of tyrosine ammonia lyase (deamination), 4-hydroxycinnamoyl-CoA ligase, and stilbene synthase (condensation with three molecules of malonyl-CoA). The molecular structure of stilbene is composed of a 14 carbon backbone and two phenyl rings that are linked by an ethene double bond [ 4 , 5 , 6 ], and it has a simple structure with a molecular weight of 228.247 g/mol [ 7 , 8 ]. The presence of styrene double bonds allows RSV to exist in two isomeric forms, cis - and trans -RSV ( Figure 1 ), where the trans -form is more common in terms of biological activities and pharmaceutical applications [ 1 , 8 , 9 ].

1.2. Therapeutic Properties

Accordingly, RSV has received significant attention as a promising agent for treating and preventing various chronic diseases, such as neurodegenerative, respiratory, and cardiovascular diseases, as well as diabetes, arthritis, obesity, skin disorders, malignancies, and aging [ 3 , 10 ]. Among the diverse effects of RSV, its ability to act as an antioxidant is the best described [ 11 ]. It neutralizes and inhibits reactive oxygen species (ROS), inhibits lipid peroxidation, and chelates metal cations [ 10 , 12 ]. It can be utilized to prevent or minimize lipid oxidation in pharmaceutical products, thus delaying the formation of harmful oxidation products, preserving their nutritional quality and extending their shelf life [ 13 , 14 ]. It has also been effectively used to protect cells against the oxidative stress caused by hydrogen peroxide by promoting cell survival and protecting against cell death induced by UV irradiation [ 1 , 15 , 16 ]. The synthesis of different esterified acyl chloride derivatives of RSV with better lipophilicity showed that these derivatives may be employed as potential antioxidants in foods and biological systems [ 17 ]. Furthermore, studies have demonstrated that the cardioprotective effects of RSV include the inhibition of platelet aggregation [ 18 ], the protection of cardiomyocytes from oxidative stress in autophagy, cardiac fibrosis, apoptosis [ 19 ], vasodilation [ 20 ], antiarrhythmic actions [ 21 ], the reduction in the inflammatory state [ 22 ], the modulation of lipid metabolism [ 20 ], the protection of low-density lipoproteins (LDLs) against oxidative and free radical damage [ 10 ], the improvement of left-ventricular function and the reduction in ventricular remodeling in heart failure [ 23 ]. Therefore, RSV and its derivatives might be valuable resources for developing novel therapies for the management of heart failure, hypertension, atherosclerosis, ischemia/reperfusion, atrial fibrillation, and metabolic syndrome [ 21 , 24 ].

1.2.1. Neuroprotective Properties

In terms of neuroprotection, RSV has shown protective effects on a variety of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and alcohol-induced neurodegenerative disorders [ 25 , 26 ]. This action is believed to be related to neuronal protection against oxidative damage and toxicity and to prevention of apoptotic neuronal death [ 27 ]. RSV is also able to improve acute neurological function and attenuate cerebral edema after intracerebral hemorrhage [ 28 , 29 ]. Furthermore, RSV has a promising role in the prevention and treatment of numerous chronic autoimmune and inflammatory diseases by reducing the secretion and expression of proinflammatory IL-1β, cytokines, TNF-α, and COX-2 and inhibiting the expression of NF-κB and nitric oxide synthase (NOS) [ 30 , 31 ]. For instance, RSV prevented inflammation caused by acute pharyngitis in rabbit models [ 30 ]. It also alleviated lipopolysaccharide-induced intestinal and hepatic tissue damage and inflammatory cell infiltration [ 32 ]. We have recently shown that several aspirin–RSV derivatives alleviate intestinal inflammation by targeting NF-kB and modulating AMPK [ 7 ].

RSV is also effective in treating neurological disorders [ 33 ]. It plays a protective role in patients with Alzheimer’s disease [ 34 ]. When RSV is combined with donepezil hydrochloride, it improves patients’ inflammatory indicators, facilitates patient prognosis, and promotes patients’ cognitive function [ 35 ]. Two different doses of RSV per day, 1000 mg/day and 300 mg/day, in a clinical trial showed that the 1000 mg/day dose selectively increased the psychomotor processing speed from baseline to 90 days posttreatment but had no significant effect on other cognitive functions, such as attention or verbal fluency, across treatment groups [ 36 ].

1.2.2. Antitumor Properties and Clinical Trials

The antitumor properties of RSV have been extensively addressed in numerous studies, making it a candidate for the treatment and prevention of different types of malignancies [ 37 ]. RSV exerts its anticancer effects via multiple mechanisms [ 38 ], such as by inducing autophagy [ 39 ] and apoptosis in tumor cells [ 40 , 41 ], inhibiting tumor growth [ 42 ] and migration to healthy organs [ 43 ] and reprogramming cellular metabolism [ 40 ]. It is capable of acting on different protective and common pathways that are generally altered in many cancers, as well as attenuating/inhibiting all stages of carcinogenesis through the inhibition of inflammation, oxidative stress, and proliferation of cancer cells, in addition to the activation of tightly regulated mechanisms of cell death [ 44 , 45 , 46 ]. For instance, RSV and its derivatives exert anticancer effects on pancreatic cancer cells [ 47 ], human cervical carcinoma cells [ 48 ], colon cancer cells [ 49 ], breast cancer cells [ 50 , 51 ], lung cancer cells [ 52 ], and neuroblastoma cells [ 53 ], among others.

RSV efficacy has been addressed through more than 271 clinical trials [ 54 ] performed globally using different or similar criteria, either combined with another drug or administered alone (summarized in Table 1 ). RSV can also act as a cardiotonic enzyme inhibitor for dermal health, for platelet aggregation, and for weight management [ 55 ] in addition to promoting analgesic effects [ 56 ]. The efficacy of RSV depends on several factors, making it more suitable for treating some diseases rather than being a universal drug [ 33 ]. For instance, in cancers such as breast, colorectal, lung and prostate cancer, insulin-like growth factor (IGF-1) and IGF binding protein (IGFBP-3) are involved in malignant development. After treatment with RSV for four weeks, a small but significant decrease in IGF-1 and IGFBP-3 was observed compared to the baseline [ 34 ]. The potential of RSV to suppress carcinogenic metabolic activity and detoxification by modulating an enzyme involved in cancer progression and transformation results in alterations in cell proliferation and protection against DNA damage in humans [ 34 ].

RSV separately or combined with other drugs (such as metformin) can combat cancer. One study has shown that RSV can help in the treatment of glioblastoma (malignant brain tumor) by activating the mTOR signaling pathway, increasing AMPK phosphorylation, affecting different cascades in the MAPK pathway and down-regulating the PI3K/Akt pathway, thus leading to higher apoptosis levels and lower proliferation of cancerous cells reducing tumor volume [ 57 ]. Moreover, other studies on RSV also revealed that its anti-cancer effect can be due to the downregulation of circular RNAs, long non-coding RNAs and micro-non-coding RNAs (epigenetic modifications) [ 58 ]. Furthermore, the anti-cancer properties of RSV against colorectal cancer have been proven through many clinical trials. In one explanation, RSV acts as a chemosensitizer that modifies many subcellular pathways (p38-MAPK, Akt/STAT3, IL-6/JAK, and other signaling pathways) altering angiogenesis, apoptosis, metastasis, and transcription factors (RSV inhibits the NF-kB and its promoted end-proteins) suppressing cancer plasticity [ 59 , 60 ]. In lung cancer as well, signaling pathways involved in cancer progression such as the mTOR, PI3K/Akt, Wnt/B-catenin are targeted by RSV as a mechanism to reduce the cancer burden [ 61 ]. Moreover, RSV protects the liver against hepatocellular carcinoma and induces cancer cell death in cultured cells of hepatocytes in hepatocellular carcinoma by regulating Fas and Fas-ligand. It also inhibits the PI3K/Akt/mTOR pathway inducing apoptosis. In liver cancer, RSV has an anti-angiogenesis effect by blocking the vascular endothelial growth factor (VEGF). Additionally, hepatoma cell proliferation can be inhibited at 100–200 μM of RSV and hepatoma cell invasion suppression at 25 μM of RSV [ 62 , 63 ].

1.2.3. Antimicrobial and Antiaging Properties

Additionally, RSV has been evaluated for its potential to inhibit the growth of some pathogens, such as Gram-positive and Gram-negative bacteria and fungi [ 74 ]. It has been found to be a potential beneficial agent for the treatment of Staphylococcus aureus pneumonia and other infections induced by S. aureus [ 75 ]. Pterostilbene, a methoxylated derivative of RSV, has demonstrated antibacterial activity against drug-resistant S. aureus [ 76 ]. In addition, RSV and dimethoxy RSV derivatives possess antifungal activity against Candida albicans [ 77 , 78 ]. It also provides antiviral protection by improving diarrhea induced by rotavirus infection [ 79 ] and inhibiting the replication of Pseudorabies virus [ 80 ]. RSV is also well known in dermatological applications as a cosmeceutical to enhance skin health as a result of its potential use as a topical anti-aging agent because of its ability to downregulate significant transcription factors implicated in photoaging [ 81 , 82 ].

1.2.4. Cardiovascular Protective Properties

RSV was found to be protective against cardiovascular diseases. Compared with patients in the baseline group, patients with heart failure treated with RSV showed obvious improvement in red blood cell aggregation after three months of treatment, which positively influenced the microcirculation and improved tissue perfusion and the oxygen supply [ 83 ]. However, in patients with atherosclerosis, endothelial function, which is a key regulator of vascular homeostasis, is lost. RSV did not seem to improve the cardiometabolic risk factors, sympathetic activity or endothelial dysfunction and did not change endothelium-dependent or endothelium-independent vasodilation [ 84 ]. Moreover, RSV also acts as a vasoactive phytoestrogen, affecting cerebrovascular function [ 85 ], and can also alter cerebral blood flow variables [ 34 ]. Notably, the effect of RSV on patients with migraine was investigated in a three-month randomized, double-blind, placebo-controlled trial, which revealed no worsening or improvement in migraine severity, possibly due to an inadequate duration of treatment or an insufficient/inappropriate dose of RSV [ 85 ]. In diabetic patients, RSV was able to reduce insulin resistance, thus improving glycemic control [ 86 ], but it had no significant effect on cardiovascular indices or hepatic steatosis in patients with type 2 diabetes [ 87 ]. On the other hand, combining RSV with hesperetin (tRES-HESP) improved low-grade inflammation and dysglycemia by reversing insulin resistance and decreasing the expression of CCL2, COX-2, IL-8, and RAGE [ 88 ]. In addition, combining RSV with zinc, magnesium, curcumin, selenium, and vitamin D supplements lowered the risk of cardiovascular disease development in overweight and obese children, thus decreasing the possibility of type 2 diabetes, insulin resistance and hypertension and significantly increasing flow-mediated dilation. These observations were revealed by improving both Dickey–Fuller (DF) and post occlusive reactive hyperemia (PORH) tests and DF in the heat provocation test [ 89 ].

1.2.5. Other Therapeutic Properties

As an “add on” to meloxicam, RSV has shown efficacy against pain and other symptoms caused by osteoarthritis, which is a painful inflammatory form of joint disease [ 56 ]. However, there is still a weak correlation between serum biomarkers and clinical outcomes in patients with knee osteoarthritis [ 90 ]. As a phytoestrogen, RSV combined with calcium and vitamin D has a bone-protective effect on postmenopausal women, especially on bones at increased risk of fracture, such as those of the lumbar spine and femoral neck [ 91 ].

In addition, negative symptoms such as verbal output, social communication, and loss of emotional and facial expressions developed in patients with schizophrenia and were found to be reduced when RSV was combined with risperidone in another study [ 92 ]. Additionally, RSV has been shown to have some beneficial effects on patients with muscular dystrophies, especially on motor function and muscular growth, and it has been shown to reduce ROS levels by inducing the expression of superoxide dismutase [ 93 ].

RSV also acts as an antidepressant and has remarkable health benefits. A clinical trial revealed that abnormalities such as anxiety, depression, and serum ammonia levels, which are complications of cirrhosis, developed in patients with minimal hepatic encephalopathy and were reduced when patients were treated with RSV, resulting in improved quality of life [ 94 ].

Patients with periodontitis treated with RSV showed improved symptoms in comparison to those treated with the placebo due to a decrease in inflammatory markers in gingival crevicular fluid (GCF) and serum [ 95 ].

However, another clinical trial investigating the efficacy of the combination of 500 mg of RSV and 500 mg of curcumin revealed a beneficial effect on muscle and body mass, fat percentage, body mass index (BMI), basal and final serum levels of triglycerides (VLDL), and decreased levels of circulating ferritin in comparison to those in the group treated with the placebo, but there was no significant difference in thiobarbituric acid reactive substances (TBARS) in either group [ 96 ]. In a double-blind randomized placebo-controlled trial, patients who received 500 mg of RSV showed a greater increase in Sirtuin-1, resulting in a significant decrease in histone 3 acetylation at the 56-lysine residue (H3K56ac), a decrease in body fat, and a change in ROS balance in patients with chronic diseases (diabetes mellitus and obesity). The small sample size was a limitation of this study [ 97 ].

1.3. Limitations of Structure and Efficacy

Despite the health and therapeutic benefits of RSV mentioned previously, its translation from natural sources to being used as a therapeutic drug is limited [ 98 ], partly because it is rapidly metabolized into glucuronide and sulfate metabolites [ 99 ]. In fact, FDA approval has not been granted for the medical use of resveratrol mainly for the lack of robust clinical evidence to meet the FDA’s stringent standards to ensure safety. The FDA approval process may be further hindered by regulatory challenges and bioavailability concerns. Naturally, the quantity of RSV in a source depends on different factors, such as the species, the environment, and the location; RSV may be stored in the skin or the seeds of fruits, which are not usually consumed. At different consumption levels, it is pharmacologically unfeasible to attain the required dose for a desired biological effect. Moreover, RSV is chemically unstable [ 100 ], poorly soluble in water [ 101 ] and has low bioavailability (less than 1%) because of its extensive metabolism in the intestine and liver [ 100 , 102 ]. Due to its instability, RSV is susceptible to chemical degradation when exposed to UV light, high temperature, pH changes, and oxidative enzymes. Degradation often involves the isomerization of the trans isomer of RSV, which has relatively high antioxidant and anti-inflammatory activity, to cis -RSV, leading to a loss of bioactivity after isomerization [ 103 ]. In addition, the poor water solubility of RSV makes it difficult to incorporate it into aqueous-based food products. Moreover, its use as a bioactive agent in the pharmaceutical field has also been limited due to its high dose requirement, poor pharmacokinetics, rapid metabolism and elimination [ 104 , 105 ] and low delivery and targeting efficacy at tumor sites [ 106 ].

To overcome these limitations, it is often desirable to isolate RSV from a natural source and then incorporate it into an appropriate delivery system. In the next sections, we will systematically summarize common approaches to overcome the limitations associated with the bioavailability, delivery, and therapeutic efficacy of RSV. We will discuss approaches intended to enhance RSV efficacy through combination treatments with other therapeutics, derivatizing the parent RSV compound and encapsulating RSV for potential use within the medical and food industries. The RSV combinations section will address the more common therapeutics and how RSV modulates their activity. Next, we discuss the more relevant RSV derivatives and what is known regarding their biological efficacy in different treatment modalities. We then provide analysis on the major role of nanoparticles (NPs) in overcoming bioavailability limitations and the efficacy of RSV.

2. RSV Modifications

2.1. RSV Combinations

Oxaliplatin, a platinum-based chemotherapeutic drug, is widely used to treat different cancers, including colon cancer. It induces apoptosis through binding covalently to DNA, thus preventing replication and transcription [ 107 ]. However, long-term treatment with oxaliplatin results in drug resistance. A study conducted by Huang H. showed that inhibiting PGE 2 /EP4 receptor signaling can enhance oxaliplatin efficacy in oxaliplatin-resistant colon cancer cells [ 108 ]. PGE 2 , the main product of the enzyme cyclooxygenase-2 (COX-2), is a well-known inflammatory mediator that is upregulated in advanced colon cancers since it plays an important role in inducing cell proliferation [ 109 ]. Thus, targeting this inflammatory pathway can enhance the efficacy of drugs for treating inflammation-related cancers. RSV was shown to induce apoptosis in different colon cancer cell lines in parallel with the significantly decreased expression of the COX-2 and prostaglandin receptor [ 110 ]. Hence, combination therapy including oxaliplatin and RSV should enhance drug efficacy and reduce any associated toxicity. Furthermore, another study showed that this combinatorial treatment resulted in caspase-3 activation, PARP cleavage, and depolarization of the mitochondrial membrane potential, which are all known steps in programmed cell death [ 111 ].

Cisplatin, another platinum-based chemotherapeutic drug, is used to treat different types of cancers, including melanoma and lung and liver cancers [ 112 ]. The combination of RSV with cisplatin enhances the apoptotic effect of cisplatin in hepatoma cells [ 113 ]. RSV can negatively regulate the expression of the glutamine transporter ASCT2, which plays a critical role in the uptake of glutamine, an important amino acid for cancer cells, as it is converted into glutathione for ROS scavenging purposes. This leads to reduced transport of glutamine into cancer cells, therefore altering the redox state in cells treated with cisplatin and increasing their sensitivity to the chemotherapeutic drug cisplatin. The advantage of this treatment is that RSV increases the sensitivity of cancer cells but not normal liver cells to cisplatin, resulting in less toxicity [ 113 ].

5-Fluorouracil (5-FU), a chemotherapeutic antimetabolite, is known as a base analog for both uracil and thymine. Its incorporation into growing RNA or DNA strands during replication or transcription interferes with the synthesis of nucleic acids, DNA and RNA and induces cell cycle arrest and apoptosis [ 114 ]. Like all chemotherapeutic drugs, 5-FU can cause intolerable toxicity in the majority of patients; thus, using lower doses or combining 5-FU with other drugs can reduce its toxicity, improve its efficacy, and reduce drug resistance [ 114 ]. In a study on colorectal cancer cells, it was demonstrated that combining 5-FU with RSV enhanced the efficacy of 5-FU by inhibiting epithelial–mesenchymal transition and downregulating the NF-κB pathway, which is also an important pathway upregulated during inflammation [ 115 ]. In a more recent study on human colorectal cancer cells, it was shown that combining RSV with 5-FU enhanced the telomerase activity and apoptosis by inhibiting the STAT3 and Akt signaling pathways [ 116 ]. In a murine model of liver cancer, tumor growth was significantly reduced upon cotreatment with RSV and 5-FU [ 117 ].

Gemcitabine (Gem) is also a chemotherapeutic antimetabolite that is widely used for treating patients with pancreatic cancer. Similar to other treatments, the development of resistance is the main reason behind lower drug efficacy [ 118 ]. In an in vivo study in nude mice, combining RSV and Gem resulted in a greater reduction in tumor growth [ 119 ]. In 2019, a study on human pancreatic cancer cells showed that combining RSV with Gem resensitized the cells to Gem treatment by inhibiting the stemness of these cells [ 103 ]. Similarly, another recent study conducted in 2021 on pancreatic cancer cells showed that RSV works in combination with Gem in these cells. The decrease in the expression of the angiogenic factor VEGF-B and the inhibition of the activity of the serine/threonine kinase GSK3β by Gem treatment were enhanced upon the combination of RSV with Gem. Furthermore, the decrease in tumor size in mice was more noticeable after this combined treatment [ 120 ].

Doxorubicin is an anthracycline used in cancer treatment. This drug acts on cancer cells by blocking the activity of the enzyme topoisomerase II and intercalating into DNA, hence impairing DNA replication and transcription [ 121 ]. Combining doxorubicin with RSV has shown promising results in treating different types of cancers, such as breast, gastric, and bladder cancers [ 122 ]. SGC7901 gastric cancer cells acquired resistance to doxorubicin through the activation of Akt, which resulted in the induction of EMT. Combined treatment with RSV and doxorubicin has been shown to have synergistic effects on minimizing tumor growth and inhibiting cell migration via the suppression of EMT triggered by RSV through the control of the PTEN/Akt signaling pathway [ 123 ]. In a study on HCT116 colon cancer cells, an increase in the expression of the pro-apoptotic protein Bax was observed after the combination of doxorubicin and RSV. Moreover, the sensitivity of these cells to doxorubicin increased upon treatment with RSV since the latter blocks the p-glycoprotein pump, thus favoring higher intracellular levels of doxorubicin [ 107 ].

In addition to its effect on inflammation-related cancers, the efficacy of the chemotherapeutic drugs used in endocrine therapy, especially for breast and prostate cancers, is enhanced by RSV. The combination of raloxifene and RSV increased the expression of p53 and caspases 3 and 8 and increased the Bax expression in estrogen receptor-positive MCF-7 breast cancer cells [ 124 ]. Another combinatorial treatment composed of RSV and tamoxifen blocked the cell cycle and activated the p53 and p38/MAPK/CK2 signaling pathways in tamoxifen-resistant MCF-7 cancer cells [ 125 ]. Bicalutamide, an androgen receptor antagonist, is commonly used in patients diagnosed with prostate cancer. A study conducted in 2019 revealed that the combination of RSV with bicalutamide or an antagonist of CXCR4 (a chemokine receptor known to be upregulated in several cancers) inhibited the AKT signaling pathway, which resulted in the inhibition of prostate cancer progression [ 126 ].

2.2. RSV Derivatization

Researchers have attempted to produce RSV derivatives with improved bioavailability and more potent biological activities. The molecular structure of RSV can be modified to synthesize RSV derivatives through hydroxylation, amination/amidation/imination, methylation, prenylation, halogenation, oligomerization, and glycosylation [ 125 ]. A summary of the main RSV derivatives is provided in Table 2 along with the most distinctive biological activities, followed by a detailed analysis of the structure and function of these derivatives.

2.2.1. Hydroxylated RSV Derivatives

Adding a hydroxyl group at the 4- and 4′-positions in the trans conformation of the stilbenic structure might increase the versatility of the original RSV compound and increase its water solubility. For example, polyhydroxylated RSV derivatives with fewer than three hydroxyl groups exhibit low oral bioavailability [ 136 ]. On the other hand, polyhydroxylated derivatives that contain four hydroxyl groups have better water solubility and, in turn, faster absorption, greater bioavailability, and greater metabolic stability than the parent RSV compound [ 136 ]. In addition, the number and position of hydroxyl groups increase the metabolic activity of some RSV derivatives. For example, the RSV analogs 3,4-dihydroxtrans-stilbene and 4,4-dihydroxytrans-stilben are more effective antioxidants than the parent RSV compound [ 137 ]. Figure 2 shows some of the hydroxylated derivatives that are derived from natural compounds such as oxyRSV (tetrahydroxystilbene), piceatannol, dihydroxystilbene, and hexahydroxystilbene.

Plants that have potential for antioxidant and anti-inflammatory activities are good sources for oxyRSV ( trans -3,3′,4,5′-tetrahydroxystilbene) [ 138 ]. Piceatannol (3′,4′,3,5-tetrahydroxy- trans -stilbene), on the other hand, is the most studied hydroxylated RSV derivative and has an additional hydroxyl group compared to that of RSV [ 139 ]. Piceatannol has shown to possess antioxidative, anti-inflammatory, anticancer, and immunomodulatory effects [ 140 ]. Dihydroxystilbene (4,4′-dihydroxy- trans -stilbene) has two hydroxyl groups at the 4′- and 4-positions, which make it more active than the parental RSV component, which has an aqueous solubility barrier that can be resolved by solubilizing it with hydroxypropyl-β-cyclodextrin [ 137 ]. Tetrahydroxystilbene ( trans -3,3′,4,5′-tetrahydroxystilbene) is a natural analog of RSV that possesses stronger tumor-suppressing and antioxidant activity than RSV but is still considered a poorly bioavailable compound [ 137 ]. Another synthetic RSV derivative is hexahydroxystilbene (3,3′,4,4′,5,5′-hexahydroxy- trans -stilbene), in which additional hydroxy groups improve its biological activity compared to that of the parental RSV compound [ 137 ].

2.2.2. Aminated, Iminated, and Amidated RSV Derivatives

RSV can be modified by the addition of amine groups ( Figure 3 ) and the synthesis of amide and imine RSV derivatives. For example, researchers reported the synthesis of aminoalkyl RSV derivatives by cationic peptide [ 141 ]. On the other hand, the imine RSV derivative 4-(((2-hydroxyphenyl)imino)methyl)benzene-1,2-diol is a very effective agent that acts as a neuroprotectant [ 128 ]. Amidated RSV derivatives are more potent antioxidants than the parent RSV compound. In addition, the allylamine analog trans -3,4-dihydroxy-40-(N-allylaminocarbonyl) stilbene showed enhanced protection against glutamate excitotoxicity in neural cells [ 128 ].

2.2.3. Methoxylated RSV Derivatives

The methoxylation reaction involves the addition of a methoxy group to the chemical structure of RSV ( Figure 4 ), which increases its metabolic stability and the time needed to reach the peak plasma concentration [ 142 ]. The substitution of a methoxy group with a hydroxyl group in an RSV molecule results in an RSV derivative with increased lipophilicity and increased bioavailability [ 134 , 143 ]. For example, pterostilbene 3,5-dimethoxy-4′-hydroxystilbene is an RSV-derived methoxylated molecule in which two of the three hydroxyl groups are substituted with methoxy groups. This modification increases lipophilicity, improves the oral absorption and cellular uptake of pterostilbene, and increases its metabolic stability and bioavailability compared to those of the parent RSV compound [ 131 ]. Trimethoxystilbene trans -3,4′5-trimethoxystilbene is another methylated RSV derivative that exists in two isomers, E and Z [ 134 ]. Another example of a methoxylated RSV derivative is tetramethoxystilbene trans -3,4,5,4′-tetramethoxystilbene, which has more promising pharmacokinetic properties than the parent RSV compound [ 129 ] and has shown low toxicity in animal and human models [ 130 ].

2.2.4. Prenylated RSV Derivatives

Prenylation is the covalent binding of a hydrophobic (lipid) moiety to an RSV molecule to produce a prenylated RSV derivative with increased bioactivity ( Figure 5 ) [ 130 ]. An example of a prenylated RSV derivative is 3,5,40-trihydroxy-4prenylstilbene, which has shown promising results for the development of drugs [ 144 ]. Another example of a prenylated RSV derivative is 5-((E)-2-(3-(3,5-dihydroxy-4-(3-methlbut-2-en-1-yl)phenyl)-2-(4-hydroxyphenyle)-2,3-dihydrobenzofuran-5-yl)vinyl)-2-(3-methylbut-2-en-1-yl)benzene-1,3-diol, which has an increased ability to alter the blood-brain barrier [ 133 ].

2.2.5. Halogenated RSV Derivatives

The addition of a halogen group to RSV might increase its therapeutic potential ( Figure 6 ) [ 145 ]. Interestingly, the (E)-2,6-dibromo-4-(3,5-dibromostyryl)phenol RSV derivative showed greater bioavailability than the parent RSV compound. (E)-3,5-Di-fluoro-4′-acetoxystilbene, a fluorinated halogenated RSV derivative, has greater anticancer activity than its parent compound, and 3,4,5-trimethoxy-4-bromo- cis -stilbene is more effective at suppressing tumor growth [ 134 ]. From an antimicrobial perspective, halogenated RSV derivatives, such as 2-bromo-RSV and 2-chloro-RSV, had lower minimum inhibitory concentrations (MIC) against C. albicans than did the parent RSV compound [ 134 ], indicating the substantial enhancement of the biological activities attained by halogenated derivatives as compared to the parent resveratrol.

2.2.6. Oligomerized RSV Derivatives

RSV oligomerization involves the coupling of monomers via regioselective oxidative coupling ( Figure 7 ) [ 146 ]. At least 92 RSV oligomers with biological activities that greatly depend on their molecular size have been reported, indicating that the addition of more RSV units increases the biological effectiveness and specificity of the oligomer. Furthermore, oligomers have a greater scavenging capacity than the parent RSV compound [ 147 ].

2.2.7. Glycosylated RSV Derivatives

Glycosylation is the addition of one or more glycosidic functional groups to an RSV molecule ( Figure 8 ). The addition of glycosidic moieties to an RSV molecule increases its water solubility and bioavailability [ 148 ]. An example of a glycosylated RSV derivative is polydatin (also known as piceid) 3,4′,5-trihydroxystilbene-3-O-β-D-glucopyranoside. Polydatin has been reported to have greater bioavailability and less susceptibility to enzymatic oxidation [ 149 ]. In addition, polydatin has good oral absorption, antioxidant, and anti-inflammatory properties [ 150 ].

2.3. RSV Nanoparticles

Researchers have increasingly exploited nanotechnology to encapsulate RSV, aiming to enhance tissue-specific or targeted delivery [ 151 ]. Encapsulation is a technique in which RSV, which is the active molecule, is trapped within some form of matrix called the “shell” or the “wall”. Encapsulating RSV improves its water dispersibility, so it can be added to different food products. It also improves its chemical stability, which protects it from environmental factors such as UV light and oxygen. Furthermore, encapsulation can enhance RSV bioavailability by increasing its solubility in gastrointestinal fluids, allowing its absorption by enterocytes and reducing its metabolism before its absorption [ 103 ]. There is a large variety of different delivery systems available for the encapsulation of RSV, such as liposomes, niosomes, nanoemulsions, nanoparticles (NPs), and dendrimers [ 152 ]. However, in this section, we focus on the different types of NPs that are increasingly used as drug delivery systems to overcome the limitations associated with the use of standard drug formulations. Table 3 summarizes the most relevant nanocarrier systems for RSV and related compounds linked to their biological outcomes.

2.3.1. Polymer Nanoparticles

Polymer NPs are a type of drug delivery system in which the drug is either conjugated or dispersed within the polymer matrix, which protects the drug from degradation, enables continuous release, and enhances its bioavailability. There are various techniques for the preparation of polymer NPs, such as desolvation, dialysis, ionic gelation, nanoprecipitation, solvent evaporation, salting out, spray drying, and supercritical fluid [ 164 ]. On the other hand, biopolymer-based systems can be produced using numerous techniques, including extrusion, coacervation, thermodynamic incompatibility, antisolvent precipitation, and emulsion templating [ 103 , 165 ]. However, the choice of an appropriate method depends upon various factors. One of the advantages of polymer-based systems is that they provide high encapsulation and retention efficiency of RSV. In addition, they can be made from natural biomolecules; thus, they are called biopolymers such as proteins and polysaccharides, and they can often be easily made on a laboratory scale. However, problems often arise when scaling up to industrial levels [ 103 ]. Several studies have shown that biopolymer nanoparticle-mediated delivery can be a useful approach for improving the bioavailability of RSV. For example, Sarma et al. encapsulated RSV in chitosan–pectin core-shell NPs, which resulted in enhanced RSV bioavailability (almost 30 h) and better in vitro radical scavenging activity than that of free RSV [ 166 ]. Sanna et al. developed chitosan-alginate-coated poly(D,L-lactide-co-glycolide) nanoparticles loaded with RSV that provided significant protection against light-induced degradation [ 167 ]. Similarly, another study by Detoni et al., showed that encapsulating RSV in NPs provided protection from UV radiation by improving its bioavailability to various targets [ 168 ].

Other researchers encapsulated RSV in gelatin NPs, which increased the rate of cellular uptake of the RSV-loaded NPs compared to that of free RES and showed antiproliferative effects on NCI-H460 lung cancer cells [ 169 ].

Many studies have shown that the nanoencapsulation of RSV is expected to provide controlled delivery. For example, polymeric NPs encapsulating RSV showed significantly greater cytotoxicity in human prostate cancer than free RSV-induced programmed cell death [ 170 , 171 ]. Furthermore, Zheng et al. (ref) obtained enhanced RSV bioavailability by loading NPs with curcumin and RSV in a successful attempt to target hepatoma cells. These NPs loaded with anticancer drugs reduced the drug dosage and delayed the rate of drug release. They are also highly concentrated in the vicinity of the tumor, which allows them to be considered as potential chemotherapeutic candidates [ 172 ].

Protein-based nanoparticles have been used as potential materials for developing delivery systems; nonetheless, there is not a large variety of proteins capable of producing viable nanostructures [ 173 ]. Zein is a water-insoluble protein generated from corn. It is used as a coating material, stabilizing polymer and extended-release agent [ 174 ]. Zein nanoparticles and modified zein nanoparticles loaded with RSV have been used to enhance the drug loading content (30–57%), improve the antioxidant capacity and stability of RSV [ 175 ], and prevent and treat chronic intestinal diseases [ 176 , 177 ]. Moreover, zein-pectin core/shell nanoparticles loaded with RSV have been shown to significantly increase RSV bioavailability and anti-inflammatory activity [ 178 ]. The effect of casein-based NPs loaded with RSV on increasing RSV bioavailability to one hundred times greater than that of oral administration of RSV-NPs without casein [ 179 ].

Another type of protein-based nanoparticle is silk fibroin (SF). SF is a natural protein polymer with remarkable biocompatibility, biodegradability and low immunogenicity [ 180 ]. SF-coated nanoparticles loaded with RSV demonstrated better anti-inflammatory effects and enhanced intestinal barrier function than free RSV in rats with inflammatory bowel disease. The results obtained in rats treated with RSV-loaded NPs revealed decreased expression of inflammatory markers (TNF-α, IL-1β, IL-6, and IL-12) and increased expression of mucins, which are markers of epithelial integrity in the mucosa [ 181 ].

Moreover, beta -lactoglobin, the major whey protein in bovine milk, is used to prepare protein-based nanoparticles loaded with RSV. These RSV-loaded NPs promoted antioxidant activity against oxidative stress generated by hydrogen peroxide by inducing the cellular uptake of RSV in human lung cancer cells (A549 cells) [ 182 ].

Additionally, human serum album (HSA) nanoparticles loaded with RSV were tested in vitro (human liver tumor HepG2 cells) and in vivo (H22 tumor-bearing mice). The coupling of HSA to folic acid (FA) and then encapsulating RSV increased the accumulation of RSV in tumor sites as compared to free HSA encapsulated RSV. A possible explanation could be that HepG2 cells selectively captured FA conjugated HSA and thus increased the uptake of RSV in these NPs. In addition, RSV-loaded HSA NPs combined with folic acid were 5.95-fold more bioavailable than free RSV [ 183 , 184 , 185 ].

In an in vivo study, RSV-loaded NPs were prepared from poly(ε-caprolactone) and tested against murine melanoma. The results of the present study revealed an increase in the stability of RSV and a significant reduction in the tumor volume in the RSV-treated group compared with the group of mice that received free RSV. Moreover, the nanoencapsulation of RSV led to increased necrosis and inflammation in the cancer area and prevented metastasis [ 186 ]. In another study, RSV-loaded polyethylene glycol (PEG)–polylactic acid polymer (PLA) NPs were tested for their in vitro and in vivo anticancer effects. Researchers found that treatment of CT26 colon cancer cells with 40 or 20 μM RSV-NPs for three days significantly reduced the cell number (by 5.6%) and colony-forming capacity (by 6.3%) while enhancing apoptotic cell death and reducing ROS levels. Additionally, when CT26 tumor-bearing mice received 100 mg/kg RSV-NPs intravenously twice per week for three weeks, there was a reduction in tumor growth compared to that in the group receiving free RSV [ 187 ].

Few studies have investigated the possibility of RSV delivery into the brain via encapsulation in polymeric NPs. RSV-loaded NPs based on poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) demonstrated greater neuroprotection than did an equivalent dose of free RSV and a protective effect against ROS in rat cortical cell culture [ 188 ]. Moreover, the in vivo encapsulation of RSV in polysorbate 80-coated poly(lactide) NPs also exerted a neuroprotective effect on a neurotoxin that damages dopaminergic neurons and induces Parkinson’s disease-related symptoms in mice [ 189 ]. In fact, this polysorbate 80 coating enabled plasma-mediated adsorption of apolipoprotein E (Apo E) to the NP surface, facilitating its recognition by LDL receptors in brain capillary endothelial cells. In addition, compared with free RSV, transferrin-modified PEG-PLA NPs for RSV encapsulation resulted in a high concentration of RSV and a significant reduction in brain tumor volume in glioma-bearing rats [ 190 ].

RSV encapsulated in NPs functionalized with phenylboronic acid has been used to accelerate infected wound healing by targeting bacteria and solving the water-insoluble problem of RSV. Compared with free RSV, the RSV NPs inhibited the expression of inflammatory cytokines and reduced the amount of excessive ROS inside the cells. The application of a gel embedded with RSV NPs enhanced the formation of granulation tissue, collagen deposition, and re-epithelialization, smoothing wound healing [ 191 ].

2.3.2. Metal Nanoparticles

Metal NPs are multipurpose agents. For example, they can be used in photothermal cancer therapy [ 192 , 193 ]. Metal nanoparticles are synthesized via different methods, such as spray pyrolysis, the colloidal gel technique, chemical vapor deposition, electrodeposition, and rapid solidification processing [ 194 ]. The advantage of these nanocarriers is the ability to control drug release depending on environmental factors, such as pH. The delivery performance and anticancer efficacy of RSV were enhanced when RSV was conjugated with gold nanoparticles (Au SNPs) using polyvinylpyrrolidone as a cross-linker. Compared with free RSV, these RSV-loaded NPs reduced the proportion of necrotic cells by activating the mitochondrial intrinsic apoptotic pathway in human pancreatic cancer cells [ 195 ]. Other studies on the encapsulation of RSV in AuNPs have shown that RSV induces cell cycle arrest in MCF-7 cancer cell lines [ 196 ] and has better anti-invasive effects on human breast cancer cells than RSV alone [ 197 ].

In another study, hollow Au NPs coated with RSV were fabricated to improve the photothermal activity and cytotoxicity against melanoma. These NPSs could block the cell cycle, inhibit cell division, and induce apoptosis after 808 nm laser irradiation in A375 melanoma cells. Because these NPs contain no surfactants, surfactant separation procedures and surface modification procedures are not needed for most theragnostic materials [ 198 ].

To identify a treatment for diabetic retinopathy, which is an important cause of acquired blindness, Dong et al. developed AuNPs coated with RSV through an ecofriendly synthetic process and tested their effects on rats with induced diabetic retinopathy. RSV was used as both a stabilizing agent and a reducing agent. RSV-loaded AuNPs reduced the permeability of the blood–retinal barrier and reduced retinal inflammation by repressing the nuclear factor NF-kB. This latter process is known to promote the development of exacerbated oxidative stress and proinflammatory cytokines and leads to apoptosis. In conclusion, RSV-coated AuNPs have demonstrated anti-inflammatory properties for the treatment of retinal diseases [ 199 , 200 ].

Moreover, RSV encapsulated in metallic NPs has shown potential for application as a nanoantibacterial agent with improved activity. Park et al. developed RSV-AuNPs and RSV-silver NPs (AgNPs) using green procedures, where RSV was used as a reducing agent to chemically reduce gold and silver ions to AuNPs and AgNPs, and it also played a role as a capping agent in RSV-AuNPs. This study showed that both types of metallic NPs had greater antibacterial activity against gram-positive and gram-negative bacteria than did RSV alone. Among the tested strains, the greatest antibacterial activity of the RSV-AuNPs was observed against Streptococcus pneumoniae [ 201 ].

2.3.3. Lipid-Based Nanoparticles

Nanomicelles

Micelles are self-assembling nano-sized constructs (10–100 nm) with a hydrophobic core and hydrophilic shell. They provide an improved solubility and, therefore, a better intestinal permeability of micelles. Polymeric micelles are formed of amphiphilic block copolymers and can range in size up to 200 nm [ 202 ]. They are of important use in tumor targeting due to their prolonged circulation time after systemic injection and their accumulation at tumor sites. Polymeric micelles tend to be more stable than surfactant micelles because they have lower critical micelle concentrations (CMC), slower dissociation rates, and reach a high drug concentration at the target site [ 203 ]. Due to its cost-effectiveness and good bioavailability, pluronic F68 is a popular material for the synthesis of micelles. However, its high CMC significantly can decrease the drug encapsulation efficiency, and, thus, it is crucial to balance cost effectiveness and encapsulation abilities for many polymeric nanomicelles. In fact, pluronics alone have insufficient drug encapsulation capacity and high critical micelle concentration (CMC), leading to the dissociation of micelles after intravenous injections. To overcome this, pluronics are often used with other micelle copolymers to increase drug loading capacity. For instance, Gregoriou A et al. showed that the encapsulation of RSV in polymeric micelles (with dominant size of 179 ± 22 nm) using pluronic F127 block copolymer and Vitamin E-TPGS was highly efficient (73 ± 0.9%) and the drug loading content was of 6.2 ± 0.1. These RSV-loaded micelles reduced the viability of breast cancer cells with no effect on the control cells [ 204 ].

In addition, Radeva et al. developed double-loaded mixed pluronic micelles with doxorubicin and resveratrol using the film hydration method. The nanomicelles size were less than 200 nm and the loading efficiency for both drugs was high (83.4% for doxorubicin and 78% for resveratrol). In vitro tests of drug release were performed in two different media with pH 7.4 and 5.0. Results showed that in both release media, there was a faster release of doxorubicin compared with resveratrol, and it was even more marked in the acidic than the alkaline medium. The study demonstrated that the simultaneous delivery of doxorubicin and resveratrol in pluronic micelles enhanced the cytotoxicity of doxorubicin in lymphoma cells and lowered its cardiotoxicity in cardiac cells [ 156 ]. Yet, another study by Kamenova et al. reported the development of a micellar system based on a poly(methacrylic acid)-b-poly(ε-caprolactone)-b-poly(methacrylic acid) triblock copolymer for the oral delivery of resveratrol. The 100 nm micelles were first formed in an aqueous media via the solvent evaporation method and then loaded with resveratrol (72% encapsulation efficiency). A pH-sensitive release strategy was adopted (pH of 1.2 and 6.8 similar to those of the gastrointestinal tract), and results showed that approximately 86% of RSV was released in the medium resembling the intestines’ pH (6.8), while at the gastric pH (1.2), the released drug was 74%. In addition, the micellar RSV shielded epithelial cells from damage due to inflammatory cytokines which makes it useful in the treatment of inflammatory gastrointestinal diseases [ 205 ].

Nanoemulsions

Nanoemulsions, lipid-based pharmaceutical systems provide a versatile method for delivering drugs through lipophilic barriers. These systems consist of two immiscible liquids (oil and water); one in the dispersed phase and the other in the continuous phase. These nanoformulations are typically stabilized by emulsifiers such as surfactants and co-surfactants [ 206 ]. Usually, the preparation of an emulsion is carried out using high-pressure homogenizers, high shear stirring, or ultrasound generators as external forces to promote the release and absorption of the drug after digestion while improving targeted drug delivery [ 207 ]. For example, RSV nanoemulsion-based gels have been developed for the topical delivery of the antioxidant RSV for the prevention of UV-induced oxidative skin damage due to the RSV-enhanced skin permeability and retention effect [ 208 ].

RSV-nanoemulsions have been used in the treatment of diseases such as cancer, autoimmune disease, parasitic infections, and others. For instance, methotrexate-RSV loaded nanoemulsions have been developed to surmount the bioavailability problems and the adverse effects of rheumatoid arthritis monotherapy. This nanoformulation loaded with RSV showed 79% inhibition in inflammation and better anti-arthritic effects [ 209 ].

In another study, RSV-based oil-in-water nanoemulsions were shown to be effective against bladder cancer. By facilitating rapid intracellular drug uptake, RSV-nanoemulsions reduced the viability of bladder T24 cancer cells and intensified the cytotoxic activity of RSV. These results strongly indicate that the utilization of nanoemulsions can effectively enhance the bioavailability of RSV [ 210 ].

Resveratrol nanoemulsions were also used as an anti-leishmanial therapeutic against Leishmania major , the parasite that causes leishmaniasis. RSV-loaded nanoemulsions were prepared using the probe ultra-sonication method and tested for anti-leishmanial activity using different concentrations. This study showed that, in comparison to the control group, both RSV and RSV-nanoemulsions at all concentrations demonstrated significant inhibitory effects against leishmania and that both are safe for mammalian cells. However, there were no significant differences between the anti-leishmanial effects of RSV and RSV-nanoemulsions [ 211 ].

Furthermore, Kotta et al. prepared coconut oil-based resveratrol nanoemulsion using pluronic-107 and cremphor EL as surfactants. The nanoemulsion exhibited superior drug release properties in comparison to an RES suspension in 0.5% ( w / v ) sodium carboxymethyl cellulose, and demonstrated an effective brain-targeting effect upon intranasal administration in rats. Additionally, the nanoemulsion remained stable at room temperature for a period of 3 months [ 212 ].

Liposomes

Liposomes are traditional models of lipid-based formulations which were invented in 1965. They are defined as stable spherical vesicles made of amphiphilic lipids. They can be easily made in an aqueous environment by controlling the temperature, the pH, and the ionic strength, to allow lipids and phospholipids to assemble into spherical bilayers [ 213 ]. There are several methods for liposome preparation such as thin-film hydration, reverse-phase evaporation, and microfluidic mixing [ 214 ]. Several studies have used liposomes as a biocompatible and smart delivery system to carry RSV.

Liposomal encapsulation of resveratrol has been shown to improve the solubility, stability, and bioavailability of RSV, enhancing its therapeutic effects, such as the anti-cancer properties [ 215 ], antibacterial properties [ 216 ], wound healing properties [ 217 ], reduction in induced nephrotoxicity [ 218 ], among others properties, by protecting it from degradation and facilitating its delivery to targeted cells or tissues.

Zhu et al. synthesized RSV-loaded liposomes modified with folate (FA-RSV-liposomes) in order to evaluate antitumoral activity against the human osteosarcoma cell 143B. According to the findings, the FA-RSV-liposomes increased apoptosis while inhibiting tumor cell growth. Folate-modified liposomes had significant antitumor efficacy in comparison to free RSV [ 219 ].

Xu et al. encapsulated RSV in a liposomal nanoparticle of 333 ± 50 nm; the encapsulation efficiency was about 85%. The encapsulated material showed a stronger ability to reduce reactive oxygen species when compared with free RSV which demonstrate their potential ability to deliver poor bioavailable nutrients [ 220 ].

In addition, Huang et al. used the thin-film hydration technique of egg yolk phosphatidylcholine and Tween 80 to make liposomes loaded with both RSV and curcumin. The liposomes had a diameter ranging from 75 to 90 nm. When compared to their individually loaded counterparts, co-encapsulated liposomes demonstrated greater antioxidant and lipid peroxidation inhibitory characteristics, as well as improved stability [ 221 ].

Moreover, Peng et al. studied the use of pH-driven techniques paired with high-pressure homogenization to create polyphenol-loaded liposomes containing curcumin, quercetin, and RSV. Each polyphenol had a distinct encapsulation efficiency depending on its stability in alkaline environments, with the highest for liposome-loaded curcumin at 100% efficiency, RSV at 93% efficiency, and quercetin at only 54% efficiency. Thus, the aforementioned findings demonstrate that adopting pH-driven techniques to encapsulate lipophilic polyphenols is dependent on the impact of pH on the stability and solubility of the bioactive molecules [ 222 ].

Cadena et al. showed that encapsulation of quercetin and RSV into elastic liposomes was highly efficient (up to a 97%) and liposomes presented a mean diameter of 149 nm with a polydispersion index of 0.3 which makes them suitable for subcutaneous injection used for reducing subcutaneous fat [ 223 ].

Despite the advantages of liposomes, many of their applications are limited due to their high production costs, short shelf life, poor stability, rapid removal by the reticuloendothelial system, and cell interactions.

2.3.4. Solid Lipid Nanoparticles (SLNPs)

SLNPs are another carrier system that combines the benefits of both polymeric NPs and lipid emulsions. The spherical vesicles contain a solid lipid core surrounded by hydrophilic surfaces. Although they can transport both hydrophobic and hydrophilic agents, they are especially useful in the delivery of hydrophobic drugs due to their high affinity for the core [ 224 ], so RSV, a hydrophobic drug, can be easily incorporated into the lipid core. The fabrication of SLNPs can be achieved through the hot homogenization method or the solvent emulsification and diffusion technique [ 225 ]. The advantage of using SLNPs is their easy uptake by cells, which makes them good nanodevices for the delivery of transdermal drugs [ 226 , 227 ]. For example, RSV-loaded SLNPs cross the phospholipid bilayer in less than 15 min [ 228 ]. Additionally, when tested for their potential use in skin disorder therapies, it was shown that RSV-loaded SLNPs were more effective than kojic acid, a melanin inhibitor, at inhibiting tyrosinase and proved to be nontoxic to HaCaT keratinocytes [ 229 ]. The same effect was produced by RSV-loaded SLNPs prepared with polyoxyethylene 40 (POE40) stearate lipid. These compounds even showed greater encapsulation efficiency and greater inhibition of tyrosinase than did RSV-loaded SLNPs alone or those prepared with glyceryl behenate, which is more hydrophobic than POE40 stearate [ 230 ].

Moreover, these lipid nanocarriers have been shown to be effective RSV delivery systems that could be used to improve the treatment of brain diseases such as glioma. Few studies have reported the delivery of RSV to the brain through the blood–brain barrier when it is loaded in SLNPs. The results showed that RSV-loaded nonfunctionalized SLNPs significantly increased the RSV concentration in the brain compared to that of free RSV but had a lower RSV concentration than that obtained with RSV-loaded nonfunctionalized SLNPs [ 231 , 232 ]. It can be concluded that the functionalization of SLNPs with ApoE indeed improved the permeability of RSV-loaded SLNPs across the BBB and thus increased RSV delivery to the brain.

The ability of RSV-loaded SLNPs to attenuate doxorubicin-induced cardiotoxicity was analyzed. In fact, RSV is known to attenuate the cardiotoxicity of doxorubicin, a chemotherapeutic drug that is clinically used to treat breast and lung cancer. However, the poor water solubility of RSV makes it difficult to achieve a satisfactory effect after oral administration. Thus, its encapsulation in SLNPs was found to improve the bioavailability of RSV to better protect the myocardium and inhibit doxorubicin-induced cardiac toxicity [ 233 ].

RSV-loaded SLNPs were also analyzed for the delivery of RSV to human breast cancer cells. An in vitro study on the delivery of RSV to human breast cancer cells using RSV-loaded SLNPs showed that the latter blocked the cell cycle and reduced metastasis to a greater extent than free RSV. In addition, RSV-loaded SLNPs were more effective than free RSV at inducing cell apoptosis, probably because the water solubility of RSV improved when RSV was incorporated into SLNPs [ 234 ]. These results suggest that RSV-SLNPs may be potential therapeutic agents for breast cancer treatment.

Another promising tool against cancer is the co-encapsulation of a cytostatic drug such as docetaxel with a natural chemosensitizer such as RSV in epidermal growth factor-conjugated SLNPs. In vitro and in vivo studies have shown that these SLPNs have significant synergistic effects, the greatest extent of tumor inhibition, and the lowest systemic toxicity in comparison to free docetaxel; thus, these SLPNs can be used for the treatment of non-small cell lung cancer [ 235 ]. The advantage of the simultaneous administration of docetaxel and RSV is that it can overcome multidrug resistance, which often impairs the efficacy of traditional chemotherapy [ 236 ].

2.3.5. Nanostructured Lipid Carriers

Nanostructured lipid carriers (NLCs) are the second generation of SLNPs. They are composed of a mixture of solid lipids and liquid lipids in the nanocore, usually in a ratio of 7:3 to 9:1 and have an average size between 10 and 500 nm [ 237 ]. NLCs are thought to be an upgraded version of SLNPs, with the same distinctive features but an optimized core composition, resulting in a higher drug loading capacity, greater stability, and the ability to work at lower temperatures. It is worth noting that NLCs remain solid even at body temperature [ 238 ]. Just like SLNPs, NLCs are prepared using the high-pressure homogenization (most commonly used), solvent emulsification/evaporation, supercritical fluid extraction of emulsions, ultrasonication and spray drying [ 239 ]. Recent studies have shown that RSV-loaded NLCs prepared using interfacial polymer deposition can improve acute lung injury [ 240 ],protect blood vessels, and improve the antihypertensive effects of RSV [ 241 ].

NLCs (composed of the lipids trimyristin and triolein) loaded with RSV were prepared via probe sonication. The particle sizes were less than 100 nm, the encapsulation efficiency was as high of 97%, and the drug loading was about 3.4%. The release of RSV from NLCs was retained with the maximal release of RV observed after 12 h (27.7%) which confirms the ability of NLCs to protect the entrapped drug, reducing its release and degradation in the outer media.

This study showed the ability of RSV-loaded NLCs to restore vasodilator responses in an ex vivo model of acute hypertension [ 241 ].

NLCs have also demonstrated the capacity to protect the skin by delivering RSV to the epidermis. A nanostructured lipid carrier gel loaded with RSV was prepared in an average particle size of 175.6 ± 11.2 nm and with an RSV encapsulation efficiency of 97.76%. Results showed improved stability of RSV under ultraviolet irradiation and its accumulation in the epidermis. This RSV-loaded NLC gel could scavenge free radicals effectively and protect human keratinocyte from UV irradiation by inhibiting the generation of ROS [ 242 ].

To conclude, there is no doubt that RSV encapsulated in nanocarriers overcomes the hurdle of physicochemical characteristics and has shown promising results in preclinical studies in terms of its therapeutic efficacy. However, the suitability of RES nanocarriers still needs to be investigated in human trials. In addition to the above-discussed RSV nanoformualtions, Figure 9 brings together the more common RSV-based nanoformulations.

3. Discussion and Future Directions

Inflammation and inflammation-associated disorders such as cancer have been treated with natural compounds derived from plants for the longest time. Extensive studies have aimed to investigate the efficacy of natural compounds as anti-inflammatory, antitumor, and other therapeutic agents. Two important concepts are generally connected to RSV: the French paradox and calorie restriction. The first was introduced approximately 30 years ago and describes the epidemiological observation that French people have a relatively low rate of cardiovascular diseases even though their diets are rich in fats. The observation may not be fully scientifically validated, but one implication has gained much interest; a component of the French diet must have a protective role against coronary complications. In fact, it was shown later that RSV protected against plaque formation in different animal models of atherogenesis and enhanced nitric oxide production to improve vasodilatation. This provided a possible partial explanation for the French paradox.

The concept of calorie restriction refers to the moderate intake of food and thus a reduction in calorie intake without leading to malnutrition. It is one of the most reliable nonpharmacological applications that increases life span in model organisms, including rats, insects, fish, and mammals. The link between RSV and caloric restriction effects emerged with the discovery that the protein Sir2 (silent information regulator 2) is involved in the regulation of aging in yeast.

In general, preclinical studies have yielded promising results on the benefits of RSV for the management of a variety of diseases related to inflammation as well as for cancer treatment. It is important to know that the treatment and/or prevention of most diseases in animals do not always translate to human studies, so care should be taken in our interpretation of the effectiveness of RSV in treating humans.

One of the greatest challenges associated with RSV is its low bioavailability. RSV is highly absorbed when given orally, and it has very low bioavailability due to the rapid metabolism of its glucuronide and sulfate conjugates. Although this latter concept may explain the in vivo results observed for RSV and for the treatment of disease in humans, whether appropriate target cells can also transport the sulfated conjugates of RSV into the cell to be metabolized back to the parent compound needs to be investigated.

Due to the poor bioavailability of RSV, it is unclear which dose should be used for clinical studies. This dose is particularly important because several effects of RSV are dose dependent. Furthermore, since RSV may exhibit a hormetic dose-response effect, this further complicates dose selection for clinical studies. Another important and related question is what method of administration should be chosen.

Although RSV is poorly soluble in aqueous solutions, some preclinical studies have administered RSV in drinking water, which may create dose variability issues. How this hurdle will be overcome in clinical trials has yet to be addressed, but the poor solubility of RSV may be enhanced by increasing its aqueous solubility via microparticulate systems, cyclodextrin complexes, nanocarrier systems, or even vesicular systems. However, whether this approach can improve the effectiveness of RSV in clinical studies is yet to be tested. For the aforementioned reasons, the bioavailability of RSV derivatives needs to be fully investigated for clinical use. Our previous results provide in vitro and in vivo insights into these RSV derivatives, but further usefulness will require extensive pharmacokinetic analysis and bioavailability determination before human clinical trials are attempted [ 7 ].

In summary, given the valuable health benefits of RSV, novel methods involving the use of “modified” RSV in clinical trials are urgently needed. Combinatorial therapy including polyphenols such as RSV can be a mechanism to lower chemotherapy-associated toxicity. In fact, catechins, which constitute another class of polyphenols, are reportedly used among classical antitumor drugs [ 243 ]. Combination treatment including polyphenols are well reported for their synergistic outcomes. RSV, containing a free hydroxyl group, can interact with a plethora of other drugs to enhance their therapeutic ability. However, the reactivity of the hydroxyl group needs to be carefully monitored for potential conjugation with cellular components such as protein and lipids. In fact, RSV has been described in several reports as a hormetic drug, showing protective outcomes at lower doses and more toxic ones at higher doses. This can be further attributed to the fact that the RSV acts as an antioxidant at low doses and a prooxidant at higher doses [ 244 ].

The rise of nanoparticles and delivery systems has perhaps reignited the hype around RSV, by enhancing the physiochemical properties. Increasing the half-life of RSV and its association with serum albumin can be promising in ensuring better biodistribution and bioavailability. A key point which remains to be answered in pre-clinical and clinical research with RSV is how long a course of RSV treatment should be. As noted in Table 1 , the time frame of treatment for most existing clinical trials is quite different. An interesting speculation would be whether a low dose (antioxidant) and long-term supplementation of RSV will be tolerable in humans. In fact, an interesting observation in middle-aged primates fed on RSV for 2 years showed reductions in brain inflammation [ 245 ]. That being said, there is need for ongoing research to elucidate the best delivery system and the optimal treatment duration with detailed analysis of any possible adverse effects.

Cancer is on the rise as a global threat, and the conventional tools we are utilizing are not the most effective. Therefore, “cocktail” approaches, including multicomponent delivery drugs and natural products, can be alternative nonclassical approaches. Polyphenols, including RSV, have been shown to act in synergy with classical drugs such as cisplatin, doxorubicin, paclitaxel, and 5-FU. In addition, derivatizing RSV remains an interesting option for enhancing its efficacy and delivery. For instance, the addition of methyl groups can increase the bio affinity of RSV, increasing its lipophilicity and improving its delivery to cells and tissues. Methylation and other derivatizing mechanisms can also protect the parent RSV from the detoxification machinery, which is considered a “xenobiotic”. As chemical derivatizing may remain costly, it would be interesting to challenge certain naturally modified systems (plants) to produce the desired derivative after genetic engineering. Considering the limitations of bioavailability and target specificity, the above-suggested derivatives and combination therapies can be loaded into nanoparticles, liposomes, nanocarriers, and micelles to overcome these limitations.

On the other hand, it is imperative to carefully characterize any off-target effects of RSV combinations, derivatives, or loaded therapeutics, including RSV. RSV, as a parent compound, has multiple molecular targets; RSV modifications can only add a plethora of targets that need to be characterized.

In addition to the biological efficacy still being extensively investigated for potentially effective modifications, as discussed in this report, the transition of RSV into clinical usage if furthered hurdled by several factors. Being a nutraceutical, various regulatory bodies impose different standards to ensure safety and compliance. The FDA issued, in the past, an advisory (FDA Advisory No. 2020-029) against purchase of some RESV supplements (PIPING ROCK Resveratrol Defense + C Dietary Supplement) for the lack of sufficient labelling and evaluation information. On the other side, the European Food Safety Authority (EFSA) concluded an intake of 150 mg/day for adults does not raise safety concerns [ 246 ].

Acknowledgments

The authors would like to thank Fatima El Khatib for drawing the chemical structure of RSV and the different derivatives.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

All authors contributed significantly to the manuscript. M.S., N.K., B.E.K., A.J.A., S.Y., M.N.A.C., S.B. and S.E.K. wrote the article and edited it. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

1. Salehi B. Mishra A.P. Nigam M. Sener B. Kilic M. Sharifi-Rad M. Fokou P.V.T. Martins N. Sharifi-Rad J. Resveratrol: A Double-Edged Sword in Health Benefits Biomedicines 2018 6 91 10.3390/biomedicines6030091 30205595 PMC6164842

2. Zhang L.-X. Li C.-X. Kakar M.U. Khan M.S. Wu P.-F. Amir R.M. Dai D.-F. Naveed M. Li Q.-Y. Saeed M. Resveratrol (RV): A Pharmacological Review and Call for Further Research Biomed. Pharmacother. 2021 143 112164 10.1016/j.biopha.2021.112164 34649335

3. Koushki M. Amiri-Dashatan N. Ahmadi N. Abbaszadeh H.-A. Rezaei-Tavirani M. Resveratrol: A Miraculous Natural Compound for Diseases Treatment Food Sci. Nutr. 2018 6 2473 10.1002/fsn3.855 30510749 PMC6261232

4. Arbo B.D. André-Miral C. Nasre-Nasser R.G. Schimith L.E. Santos M.G. Costa-Silva D. Muccillo-Baisch A.L. Hort M.A. Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease Front. Aging Neurosci. 2020 12 103 10.3389/fnagi.2020.00103 32362821 PMC7180342

5. He S. Yan X. From Resveratrol to Its Derivatives: New Sources of Natural Antioxidant Curr. Med. Chem. 2013 20 1005 1017 23210785

6. Lin M.-H. Hung C.-F. Sung H.-C. Yang S.-C. Yu H.-P. Fang J.-Y. The Bioactivities of Resveratrol and Its Naturally Occurring Derivatives on Skin J. Food Drug Anal. 2021 29 15 10.38212/2224-6614.1151 35696226 PMC9261849

7. Salla M. Pandya V. Bhullar K.S. Kerek E. Wong Y.F. Losch R. Ou J. Aldawsari F.S. Velazquez-Martinez C. Thiesen A. Resveratrol and Resveratrol-Aspirin Hybrid Compounds as Potent Intestinal Anti-Inflammatory and Anti-Tumor Drugs Molecules 2020 25 3849 10.3390/molecules25173849 32847114 PMC7503224

8. Nawaz W. Zhou Z. Deng S. Ma X. Ma X. Li C. Shu X. Therapeutic Versatility of Resveratrol Derivatives Nutrients 2017 9 1188 10.3390/nu9111188 29109374 PMC5707660

9. Chachay V.S. Kirkpatrick C.M.J. Hickman I.J. Ferguson M. Prins J.B. Martin J.H. Resveratrol—Pills to Replace a Healthy Diet? Br. J. Clin. Pharmacol. 2011 72 27 38 10.1111/j.1365-2125.2011.03966.x 21410504 PMC3141184

10. Ruivo J. Francisco C. Oliveira R. Figueiras A. The Main Potentialities of Resveratrol for Drug Delivery Systems Braz. J. Pharm. Sci. 2015 51 499 513 10.1590/S1984-82502015000300002

11. Hecker A. Schellnegger M. Hofmann E. Luze H. Nischwitz S.P. Kamolz L.-P. Kotzbeck P. The Impact of Resveratrol on Skin Wound Healing, Scarring, and Aging Int. Wound J. 2022 19 9 28 10.1111/iwj.13601 33949795 PMC8684849

12. Gülçin I. Beydemir Ş. Phenolic Compounds as Antioxidants: Carbonic Anhydrase Isoenzymes Inhibitors Mini Rev. Med. Chem. 2013 13 408 430 10.2174/138955713804999874 23190033

13. Papuc C. Goran G. Durdun C. Nicorescu V. Stefan G. Plant Polyphenols as Antioxidant and Antibacterial Agents for Shelf-Life Extension of Meat and Meat Products: Classification, Structures, Sources, and Action Mechanisms Compr. Rev. Food Sci. Food Saf. 2017 16 1243 1268 10.1111/1541-4337.12298 33371586

14. Bhullar K.S. Hubbard B.P. Lifespan and Healthspan Extension by Resveratrol Biochim. Biophys. Acta 2015 1852 1209 1218 10.1016/j.bbadis.2015.01.012 25640851

15. Konyalioglu S. Armagan G. Yalcin A. Atalayin C. Dagci T. Effects of Resveratrol on Hydrogen Peroxide-Induced Oxidative Stress in Embryonic Neural Stem Cells Neural Regen. Res. 2013 8 485 10.3969/j.issn.1673-5374.2013.06.001 25206691 PMC4146049

16. Means J.C. Gerdes B.C. Koulen P. Distinct Mechanisms Underlying Resveratrol-Mediated Protection from Types of Cellular Stress in C6 Glioma Cells Int. J. Mol. Sci. 2017 18 1521 10.3390/ijms18071521 28708069 PMC5536011

17. Yang T. Wang L. Zhu M. Zhang L. Yan L. Properties and Molecular Mechanisms of Resveratrol: A Review Pharmazie 2015 70 501 506 26380517

18. Marumo M. Ekawa K. Wakabayashi I. Resveratrol Inhibits Ca 2+ Signals and Aggregation of Platelets Environ. Health Prev. Med. 2020 25 70 10.1186/s12199-020-00905-1 33160329 PMC7648989

19. Hao E. Lang F. Chen Y. Zhang H. Cong X. Shen X. Su G. Resveratrol Alleviates Endotoxin-Induced Myocardial Toxicity via the Nrf2 Transcription Factor PLoS ONE 2013 8 e69452 10.1371/journal.pone.0069452 23894482 PMC3718737

20. Voloshyna I. Hussaini S.M. Reiss A.B. Resveratrol in Cholesterol Metabolism and Atherosclerosis J. Med. Food 2012 15 763 773 10.1089/jmf.2012.0025 22856383

21. Baczkó I. Light P.E. Resveratrol and Derivatives for the Treatment of Atrial Fibrillation Ann. N. Y. Acad. Sci. 2015 1348 68 74 10.1111/nyas.12843 26205342

22. Delucchi F. Berni R. Frati C. Cavalli S. Graiani G. Sala R. Chaponnier C. Gabbiani G. Calani L. Rio D.D. Resveratrol Treatment Reduces Cardiac Progenitor Cell Dysfunction and Prevents Morpho-Functional Ventricular Remodeling in Type-1 Diabetic Rats PLoS ONE 2012 7 e39836 10.1371/journal.pone.0039836 22768138 PMC3387239

23. Riba A. Deres L. Sumegi B. Toth K. Szabados E. Halmosi R. Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model Oxid. Med. Cell Longev. 2017 2017 6819281 10.1155/2017/6819281 29109832 PMC5646324

24. Rauf A. Imran M. Suleria H.A.R. Ahmad B. Peters D.G. Mubarak M.S. A Comprehensive Review of the Health Perspectives of Resveratrol Food Funct. 2017 8 4284 4305 10.1039/C7FO01300K 29044265

25. Wahab A. Gao K. Jia C. Zhang F. Tian G. Murtaza G. Chen J. Significance of Resveratrol in Clinical Management of Chronic Diseases Molecules 2017 22 1329 10.3390/molecules22081329 28820474 PMC6152193

26. Sun A.Y. Wang Q. Simonyi A. Sun G.Y. Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases Mol. Neurobiol. 2010 41 375 383 10.1007/s12035-010-8111-y 20306310 PMC3076208

27. Andrade S. Ramalho M.J. Pereira M.D.C. Loureiro J.A. Resveratrol Brain Delivery for Neurological Disorders Prevention and Treatment Front. Pharmacol. 2018 9 1261 10.3389/fphar.2018.01261 30524273 PMC6262174

28. Bonsack F. Alleyne C.H. Sukumari-Ramesh S. Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice Front. Cell. Neurosci. 2017 11 228 10.3389/fncel.2017.00228 28848394 PMC5550718

29. Cai J.-C. Liu W. Lu F. Kong W.-B. Zhou X.-X. Miao P. Lei C.-X. Wang Y. Resveratrol Attenuates Neurological Deficit and Neuroinflammation Following Intracerebral Hemorrhage Exp. Ther. Med. 2018 15 4131 4138 10.3892/etm.2018.5938 29725362 PMC5920231

30. Zhou Z.-X. Mou S.-F. Chen X.-Q. Gong L.-L. Ge W.-S. Anti-Inflammatory Activity of Resveratrol Prevents Inflammation by Inhibiting NF-κB in Animal Models of Acute Pharyngitis Mol. Med. Rep. 2018 17 1269 1274 10.3892/mmr.2017.7933 29115472

31. Meng T. Xiao D. Muhammed A. Deng J. Chen L. He J. Anti-Inflammatory Action and Mechanisms of Resveratrol Molecules 2021 26 229 10.3390/molecules26010229 33466247 PMC7796143

32. Ding S. Jiang H. Fang J. Liu G. Regulatory Effect of Resveratrol on Inflammation Induced by Lipopolysaccharides via Reprograming Intestinal Microbes and Ameliorating Serum Metabolism Profiles Front. Immunol. 2021 12 777159 10.3389/fimmu.2021.777159 34868045 PMC8634337

33. Berman A.Y. Motechin R.A. Wiesenfeld M.Y. Holz M.K. The Therapeutic Potential of Resveratrol: A Review of Clinical Trials NPJ Precis. Oncol. 2017 1 35 10.1038/s41698-017-0038-6 28989978 PMC5630227

34. Patel K.R. Scott E. Brown V.A. Gescher A.J. Steward W.P. Brown K. Clinical Trials of Resveratrol Ann. N. Y. Acad. Sci. 2011 1215 161 169 10.1111/j.1749-6632.2010.05853.x 21261655

35. Fang X. Zhang J. Zhao J. Wang L. Effect of Resveratrol Combined with Donepezil Hydrochloride on Inflammatory Factor Level and Cognitive Function Level of Patients with Alzheimer’s Disease J. Health Eng. 2022 2022 9148650 10.1155/2022/9148650 35368930 PMC8975642

36. Anton S.D. Ebner N. Dzierzewski J.M. Zlatar Z.Z. Gurka M.J. Dotson V.M. Kirton J. Mankowski R.T. Marsiske M. Manini T.M. Effects of 90 Days of Resveratrol Supplementation on Cognitive Function in Elders: A Pilot Study J. Altern. Complement. Med. 2018 24 725 732 10.1089/acm.2017.0398 29583015 PMC6065512

37. Kuršvietienė L. Stanevičienė I. Mongirdienė A. Bernatonienė J. Multiplicity of Effects and Health Benefits of Resveratrol Medicina 2016 52 148 155 10.1016/j.medici.2016.03.003 27496184

38. Sharifi-Rad J. Quispe C. Mukazhanova Z. Knut E. Turgumbayeva A. Kipchakbayeva A. Seitimova G. Mahomoodally M.F. Lobine D. Koay A. Resveratrol-Based Nanoformulations as an Emerging Therapeutic Strategy for Cancer Front. Mol. Biosci. 2021 8 649395 10.3389/fmolb.2021.649395 34540888 PMC8440914

39. Tian Y. Song W. Li D. Cai L. Zhao Y. Resveratrol As A Natural Regulator Of Autophagy For Prevention And Treatment Of Cancer OncoTargets Ther. 2019 12 8601 8609 10.2147/OTT.S213043 PMC6802539 31802896

40. Elshaer M. Chen Y. Wang X.J. Tang X. Resveratrol: An Overview of Its Anti-Cancer Mechanisms Life Sci. 2018 207 340 349 10.1016/j.lfs.2018.06.028 29959028

41. Zhang H. Inhibitory Effect of Resveratrol on the Expression of the VEGF Gene and Proliferation in Renal Cancer Cells Mol. Med. Rep. 2011 4 981 983 10.3892/mmr.2011.511 21687947

42. Trapp V. Parmakhtiar B. Papazian V. Willmott L. Fruehauf J.P. Anti-Angiogenic Effects of Resveratrol Mediated by Decreased VEGF and Increased TSP1 Expression in Melanoma-Endothelial Cell Co-Culture Angiogenesis 2010 13 305 315 10.1007/s10456-010-9187-8 20927579 PMC2980626

43. Sun Y. Zhou Q.-M. Lu Y.-Y. Zhang H. Chen Q.-L. Zhao M. Su S.-B. Resveratrol Inhibits the Migration and Metastasis of MDA-MB-231 Human Breast Cancer by Reversing TGF-Β1-Induced Epithelial-Mesenchymal Transition Molecules 2019 24 1131 10.3390/molecules24061131 30901941 PMC6471699

44. Varoni E.M. Lo Faro A.F. Sharifi-Rad J. Iriti M. Anticancer Molecular Mechanisms of Resveratrol Front. Nutr. 2016 3 8 10.3389/fnut.2016.00008 27148534 PMC4828556

45. Pezzuto J.M. Resveratrol as an Inhibitor of Carcinogenesis Pharm. Biol. 2008 46 443 573 10.1080/13880200802116610

46. Ko J.-H. Sethi G. Um J.-Y. Shanmugam M.K. Arfuso F. Kumar A.P. Bishayee A. Ahn K.S. The Role of Resveratrol in Cancer Therapy Int. J. Mol. Sci. 2017 18 2589 10.3390/ijms18122589 29194365 PMC5751192

47. Cheng L. Yan B. Chen K. Jiang Z. Zhou C. Cao J. Qian W. Li J. Sun L. Ma J. Resveratrol-Induced Downregulation of NAF-1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways Oxid. Med. Cell Longev. 2018 2018 9482018 10.1155/2018/9482018 29765509 PMC5885341

48. Li L. Qiu R.-L. Lin Y. Cai Y. Bian Y. Fan Y. Gao X.-J. Resveratrol Suppresses Human Cervical Carcinoma Cell Proliferation and Elevates Apoptosis via the Mitochondrial and P53 Signaling Pathways Oncol. Lett. 2018 15 9845 9851 10.3892/ol.2018.8571 29928358 PMC6004645

49. de Sá Coutinho D. Pacheco M.T. Frozza R.L. Bernardi A. Anti-Inflammatory Effects of Resveratrol: Mechanistic Insights Int. J. Mol. Sci. 2018 19 1812 10.3390/ijms19061812 29925765 PMC6032205

50. Sinha D. Sarkar N. Biswas J. Bishayee A. Resveratrol for Breast Cancer Prevention and Therapy: Preclinical Evidence and Molecular Mechanisms Semin. Cancer Biol. 2016 40–41 209 232 10.1016/j.semcancer.2015.11.001 26774195

51. Alamolhodaei N.S. Tsatsakis A.M. Ramezani M. Hayes A.W. Karimi G. Resveratrol as MDR Reversion Molecule in Breast Cancer: An Overview Food Chem. Toxicol. 2017 103 223 232 10.1016/j.fct.2017.03.024 28315369

52. Verna F.D. Resveratrol as a Chemopreventive Agent in Lung Cancer Therapy Biosci. Med. J. Biomed. Transl. Res. 2022 6 2173 2182 10.37275/bsm.v6i9.557

53. Chen Y. Tseng S.-H. Lai H.-S. Chen W.-J. Resveratrol-Induced Cellular Apoptosis and Cell Cycle Arrest in Neuroblastoma Cells and Antitumor Effects on Neuroblastoma in Mice Surgery 2004 136 57 66 10.1016/j.surg.2004.01.017 15232540

54. Singh A.P. Singh R. Verma S.S. Rai V. Kaschula C.H. Maiti P. Gupta S.C. Health Benefits of Resveratrol: Evidence from Clinical Studies Med. Res. Rev. 2019 39 1851 1891 10.1002/med.21565 30741437

55. Khattar S. Khan S.A. Zaidi S.A.A. Darvishikolour M. Farooq U. Naseef P.P. Kurunian M.S. Khan M.Z. Shamim A. Khan M.M.U. Resveratrol from Dietary Supplement to a Drug Candidate: An Assessment of Potential Pharmaceuticals 2022 15 957 10.3390/ph15080957 36015105 PMC9412308

56. Hussain S.A. Marouf B.H. Ali Z.S. Ahmmad R.S. Efficacy and Safety of Co-Administration of Resveratrol with Meloxicam in Patients with Knee Osteoarthritis: A Pilot Interventional Study Clin. Interv. Aging 2018 13 1621 1630 10.2147/CIA.S172758 30233159 PMC6130538

57. Ibrahim R.S. Ibrahim S.S. El-Naas A. Koklesová L. Kubatka P. Büsselberg D. Could Metformin and Resveratrol Support Glioblastoma Treatment? A Mechanistic View at the Cellular Level Cancers 2023 15 3368 10.3390/cancers15133368 37444478 PMC10340608

58. Anwar M. Altaf A. Imran M. Amir M. Alsagaby S. Alabdulmonem W. Mujtaba A. El-Ghorab A. Ghoneim M. Hussain M. Anti-Cancer Perspectives of Resveratrol: A Comprehensive Review Food Agric. Immunol. 2023 34 2265686 10.1080/09540105.2023.2265686

59. Brockmueller A. Sajeev A. Koklesova L. Samuel S.M. Kubatka P. Büsselberg D. Kunnumakkara A.B. Shakibaei M. Resveratrol as Sensitizer in Colorectal Cancer Plasticity Cancer Metastasis Rev. 2023 43 55 85 10.1007/s10555-023-10126-x 37507626 PMC11016130

60. Song B. Wang W. Tang X. Goh R.M.W.-J. Thuya W.L. Ho P.C.L. Chen L. Wang L. Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy Cancers 2023 15 2758 10.3390/cancers15102758 37345095 PMC10216034

61. Najafiyan B. Bokaii Hosseini Z. Esmaelian S. Firuzpour F. Rahimipour Anaraki S. Kalantari L. Hheidari A. Mesgari H. Nabi-Afjadi M. Unveiling the Potential Effects of Resveratrol in Lung Cancer Treatment: Mechanisms and Nanoparticle-Based Drug Delivery Strategies Biomed. Pharmacother. 2024 172 116207 10.1016/j.biopha.2024.116207 38295754

62. Bhattacharya S. Perris A. Jawed J.J. Hoda M. Therapeutic Role of Resveratrol against Hepatocellular Carcinoma: A Review on Its Molecular Mechanisms of Action Pharmacol. Res.-Mod. Chin. Med. 2023 6 100233 10.1016/j.prmcm.2023.100233

63. Izzo C. Annunziata M. Melara G. Sciorio R. Dallio M. Masarone M. Federico A. Persico M. The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials Nutrients 2021 13 933 10.3390/nu13030933 33805795 PMC7999728

64. Patel K.R. Brown V.A. Jones D.J.L. Britton R.G. Hemingway D. Miller A.S. West K.P. Booth T.D. Perloff M. Crowell J.A. Clinical Pharmacology of Resveratrol and Its Metabolites in Colorectal Cancer Patients Cancer Res. 2010 70 7392 7399 10.1158/0008-5472.CAN-10-2027 20841478 PMC2948608

65. Howells L.M. Berry D.P. Elliott P.J. Jacobson E.W. Hoffmann E. Hegarty B. Brown K. Steward W.P. Gescher A.J. Phase I Randomized, Double-Blind Pilot Study of Micronized Resveratrol (SRT501) in Patients with Hepatic Metastases--Safety, Pharmacokinetics, and Pharmacodynamics Cancer Prev. Res. 2011 4 1419 1425 10.1158/1940-6207.CAPR-11-0148 21680702 PMC3173869

66. Nguyen A.V. Martinez M. Stamos M.J. Moyer M.P. Planutis K. Hope C. Holcombe R.F. Results of a Phase I Pilot Clinical Trial Examining the Effect of Plant-Derived Resveratrol and Grape Powder on Wnt Pathway Target Gene Expression in Colonic Mucosa and Colon Cancer Cancer Manag. Res. 2009 1 25 37 21188121 PMC3004662

67. Chow H.-H.S. Garland L.L. Heckman-Stoddard B.M. Hsu C.-H. Butler V.D. Cordova C.A. Chew W.M. Cornelison T.L. A Pilot Clinical Study of Resveratrol in Postmenopausal Women with High Body Mass Index: Effects on Systemic Sex Steroid Hormones J. Transl. Med. 2014 12 223 10.1186/s12967-014-0223-0 25115686 PMC4243716

68. Ávila-Gálvez M.Á. García-Villalba R. Martínez-Díaz F. Ocaña-Castillo B. Monedero-Saiz T. Torrecillas-Sánchez A. Abellán B. González-Sarrías A. Espín J.C. Metabolic Profiling of Dietary Polyphenols and Methylxanthines in Normal and Malignant Mammary Tissues from Breast Cancer Patients Mol. Nutr. Food Res. 2019 63 e1801239 10.1002/mnfr.201801239 30690879

69. Zhu W. Qin W. Zhang K. Rottinghaus G.E. Chen Y.-C. Kliethermes B. Sauter E.R. Trans-Resveratrol Alters Mammary Promoter Hypermethylation in Women at Increased Risk for Breast Cancer Nutr. Cancer 2012 64 393 400 10.1080/01635581.2012.654926 22332908 PMC3392022

70. Kjaer T.N. Ornstrup M.J. Poulsen M.M. Jørgensen J.O.L. Hougaard D.M. Cohen A.S. Neghabat S. Richelsen B. Pedersen S.B. Resveratrol Reduces the Levels of Circulating Androgen Precursors but Has No Effect on, Testosterone, Dihydrotestosterone, PSA Levels or Prostate Volume. A 4-Month Randomised Trial in Middle-Aged Men Prostate 2015 75 1255 1263 10.1002/pros.23006 25939591

71. Paller C.J. Rudek M.A. Zhou X.C. Wagner W.D. Hudson T.S. Anders N. Hammers H.J. Dowling D. King S. Antonarakis E.S. A Phase I Study of Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: Safety, Tolerability, and Dose Determination Prostate 2015 75 1518 1525 10.1002/pros.23024 26012728 PMC4537354

72. van Die M.D. Williams S.G. Emery J. Bone K.M. Taylor J.M.G. Lusk E. Pirotta M.V. A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer Prostate 2017 77 765 775 10.1002/pros.23317 28181675 PMC5444299

73. Popat R. Plesner T. Davies F. Cook G. Cook M. Elliott P. Jacobson E. Gumbleton T. Oakervee H. Cavenagh J. A Phase 2 Study of SRT501 (Resveratrol) with Bortezomib for Patients with Relapsed and or Refractory Multiple Myeloma Br. J. Haematol. 2013 160 714 717 10.1111/bjh.12154 23205612

74. Fu Y. Zhang L. Lin Y. Zhao X. Chen H. Zhong Y. Jiang W. Wu X. Lin X. Unveiling the Antibacterial Mechanism of Resveratrol against Aeromonas Hydrophila through Proteomics Analysis Front. Cell. Infect. Microbiol. 2024 14 1378094 10.3389/fcimb.2024.1378094 38510959 PMC10951904

75. Wu S. Huang J. Resveratrol Alleviates Staphylococcus Aureus Pneumonia by Inhibition of the NLRP3 Inflammasome Exp. Ther. Med. 2017 14 6099 10.3892/etm.2017.5337 29285164 PMC5740584

76. Yang S.-C. Tseng C.-H. Wang P.-W. Lu P.-L. Weng Y.-H. Yen F.-L. Fang J.-Y. Pterostilbene, a Methoxylated Resveratrol Derivative, Efficiently Eradicates Planktonic, Biofilm, and Intracellular MRSA by Topical Application Front. Microbiol. 2017 8 1103 10.3389/fmicb.2017.01103 28659908 PMC5468402

77. Weber K. Schulz B. Ruhnke M. Resveratrol and Its Antifungal Activity against Candida Species Mycoses 2011 54 30 33 10.1111/j.1439-0507.2009.01763.x 19703269

78. Houillé B. Papon N. Boudesocque L. Bourdeaud E. Besseau S. Courdavault V. Enguehard-Gueiffier C. Delanoue G. Guérin L. Bouchara J.-P. Antifungal Activity of Resveratrol Derivatives against Candida Species J. Nat. Prod. 2014 77 1658 1662 10.1021/np5002576 25014026

79. Abba Y. Hassim H. Hamzah H. Noordin M.M. Antiviral Activity of Resveratrol against Human and Animal Viruses Adv. Virol. 2015 2015 184241 10.1155/2015/184241 26693226 PMC4676993

80. Zhao X. Tong W. Song X. Jia R. Li L. Zou Y. He C. Liang X. Lv C. Jing B. Antiviral Effect of Resveratrol in Piglets Infected with Virulent Pseudorabies Virus Viruses 2018 10 457 10.3390/v10090457 30150559 PMC6164078

81. Lephart E.D. Resveratrol, 4′ Acetoxy Resveratrol, R-Equol, Racemic Equol or S-Equol as Cosmeceuticals to Improve Dermal Health Int. J. Mol. Sci. 2017 18 1193 10.3390/ijms18061193 28587197 PMC5486016

82. Farris P.K. Innovative Cosmeceuticals: Sirtuin Activators and Anti-Glycation Compounds Semin. Cutan. Med. Surg. 2011 30 163 166 10.1016/j.sder.2011.05.004 21925370

83. Gal R. Praksch D. Kenyeres P. Rabai M. Toth K. Halmosi R. Habon T. Hemorheological Alterations in Patients with Heart Failure with Reduced Ejection Fraction Treated by Resveratrol Cardiovasc. Ther. 2020 2020 7262474 10.1155/2020/7262474 32695229 PMC7350166

84. Gonçalinho G.H.F. Roggerio A. Goes M.F.d.S. Avakian S.D. Leal D.P. Strunz C.M.C. Mansur A.d.P. Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial Molecules 2021 26 3168 10.3390/molecules26113168 34073163 PMC8199010

85. Dzator J.S.A. Howe P.R.C. Coupland K.G. Wong R.H.X. A Randomised, Double-Blind, Placebo-Controlled Crossover Trial of Resveratrol Supplementation for Prophylaxis of Hormonal Migraine Nutrients 2022 14 1763 10.3390/nu14091763 35565731 PMC9100551

86. Mahjabeen W. Khan D.A. Mirza S.A. Role of Resveratrol Supplementation in Regulation of Glucose Hemostasis, Inflammation and Oxidative Stress in Patients with Diabetes Mellitus Type 2: A Randomized, Placebo-Controlled Trial Complement. Ther. Med. 2022 66 102819 10.1016/j.ctim.2022.102819 35240291

87. Ali Sangouni A. Abdollahi S. Mozaffari-Khosravi H. Effect of Resveratrol Supplementation on Hepatic Steatosis and Cardiovascular Indices in Overweight Subjects with Type 2 Diabetes: A Double-Blind, Randomized Controlled Trial BMC Cardiovasc. Disord. 2022 22 212 10.1186/s12872-022-02637-2 35538431 PMC9088077

88. Rabbani N. Xue M. Weickert M.O. Thornalley P.J. Reversal of Insulin Resistance in Overweight and Obese Subjects by Trans-Resveratrol and Hesperetin Combination-Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation Nutrients 2021 13 2374 10.3390/nu13072374 34371884 PMC8308792

89. Pecoraro L. Zoller T. Atkinson R.L. Nisi F. Antoniazzi F. Cavarzere P. Piacentini G. Pietrobelli A. Supportive Treatment of Vascular Dysfunction in Pediatric Subjects with Obesity: The OBELIX Study Nutr. Diabetes 2022 12 2 10.1038/s41387-021-00180-1 35013093 PMC8748969

90. Marouf B.H. Hussain S.A. Ali Z.S. Correlation between Serum pro Inflammatory Cytokines and Clinical Scores of Knee Osteoarthritic Patients Using Resveratrol as a Supplementary Therapy with Meloxicam Indian. J. Pharmacol. 2021 53 270 277 10.4103/ijp.IJP_493_20 34414904 PMC8411958

91. Wong R.H. Thaung Zaw J.J. Xian C.J. Howe P.R. Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo-Controlled Trial J. Bone Min. Res. 2020 35 2121 2131 10.1002/jbmr.4115 32564438 PMC7689937

92. Samaei A. Moradi K. Bagheri S. Ashraf-Ganjouei A. Alikhani R. Mousavi S.B. Rezaei F. Akhondzadeh S. Resveratrol Adjunct Therapy for Negative Symptoms in Patients With Stable Schizophrenia: A Double-Blind, Randomized Placebo-Controlled Trial Int. J. Neuropsychopharmacol. 2020 23 775 782 10.1093/ijnp/pyaa006 33372679 PMC7770519

93. Kawamura K. Fukumura S. Nikaido K. Tachi N. Kozuka N. Seino T. Hatakeyama K. Mori M. Ito Y.M. Takami A. Resveratrol Improves Motor Function in Patients with Muscular Dystrophies: An Open-Label, Single-Arm, Phase IIa Study Sci. Rep. 2020 10 20585 10.1038/s41598-020-77197-6 33239684 PMC7688653

94. Malaguarnera G. Pennisi M. Bertino G. Motta M. Borzì A.M. Vicari E. Bella R. Drago F. Malaguarnera M. Resveratrol in Patients with Minimal Hepatic Encephalopathy Nutrients 2018 10 329 10.3390/nu10030329 29522439 PMC5872747

95. Zhang Q. Xu S. Xu W. Zhou Y. Luan H. Wang D. Resveratrol Decreases Local Inflammatory Markers and Systemic Endotoxin in Patients with Aggressive Periodontitis Medicine 2022 101 e29393 10.1097/MD.0000000000029393 35758374 PMC9276133

96. Murillo Ortiz B.O. Fuentes Preciado A.R. Ramírez Emiliano J. Martínez Garza S. Ramos Rodríguez E. de Alba Macías L.A. Recovery Of Bone And Muscle Mass In Patients With Chronic Kidney Disease And Iron Overload On Hemodialysis And Taking Combined Supplementation With Curcumin And Resveratrol Clin. Interv. Aging 2019 14 2055 2062 10.2147/CIA.S223805 31819387 PMC6873966

97. Bo S. Togliatto G. Gambino R. Ponzo V. Lombardo G. Rosato R. Cassader M. Brizzi M.F. Impact of Sirtuin-1 Expression on H3K56 Acetylation and Oxidative Stress: A Double-Blind Randomized Controlled Trial with Resveratrol Supplementation Acta Diabetol. 2018 55 331 340 10.1007/s00592-017-1097-4 29330620 PMC5851693

98. Murtaza G. Latif U. Najam-Ul-Haq M. Sajjad A. Karim S. Akhtar M. Hussain I. Resveratrol: An Antiaging Active Natural Product for Cancer J. Food Drug Anal. 2013 21 12 10.6227/jfda.2013210101

99. Szymkowiak I. Kucinska M. Murias M. Between the Devil and the Deep Blue Sea—Resveratrol, Sulfotransferases and Sulfatases—A Long and Turbulent Journey from Intestinal Absorption to Target Cells Molecules 2023 28 3297 10.3390/molecules28083297 37110530 PMC10140952

100. Davidov-Pardo G. McClements D.J. Nutraceutical Delivery Systems: Resveratrol Encapsulation in Grape Seed Oil Nanoemulsions Formed by Spontaneous Emulsification Food Chem. 2015 167 205 212 10.1016/j.foodchem.2014.06.082 25148980

101. Amri A. Chaumeil J. Sfar S. Charrueau C. Administration of Resveratrol: What Formulation Solutions to Bioavailability Limitations? J. Control. Release 2012 158 182 193 10.1016/j.jconrel.2011.09.083 21978644

102. Radko Y. Christensen K.B. Christensen L.P. Semi-Preparative Isolation of Dihydroresveratrol-3-O-β-d-Glucuronide and Four Resveratrol Conjugates from Human Urine after Oral Intake of a Resveratrol-Containing Dietary Supplement J. Chromatogr. B 2013 930 54 61 10.1016/j.jchromb.2013.05.002 23727867

103. Davidov-Pardo G. McClements D.J. Resveratrol Encapsulation: Designing Delivery Systems to Overcome Solubility, Stability and Bioavailability Issues Trends Food Sci. Technol. 2014 38 88 103 10.1016/j.tifs.2014.05.003

104. Baur J.A. Sinclair D.A. Therapeutic Potential of Resveratrol: The In Vivo Evidence Nat. Rev. Drug Discov. 2006 5 493 506 10.1038/nrd2060 16732220

105. Planas J.M. Alfaras I. Colom H. Juan M.E. The Bioavailability and Distribution of Trans-Resveratrol Are Constrained by ABC Transporters Arch. Biochem. Biophys. 2012 527 67 73 10.1016/j.abb.2012.06.004 22750234

106. Mudshinge S.R. Deore A.B. Patil S. Bhalgat C.M. Nanoparticles: Emerging Carriers for Drug Delivery Saudi Pharm. J. 2011 19 129 141 10.1016/j.jsps.2011.04.001 23960751 PMC3744999

107. Alcindor T. Beauger N. Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy Curr. Oncol. 2011 18 18 25 10.3747/co.v18i1.708 21331278 PMC3031353

108. Huang H. Aladelokun O. Ideta T. Giardina C. Ellis L.M. Rosenberg D.W. Inhibition of PGE2/EP4 Receptor Signaling Enhances Oxaliplatin Efficacy in Resistant Colon Cancer Cells through Modulation of Oxidative Stress Sci. Rep. 2019 9 4954 10.1038/s41598-019-40848-4 30894570 PMC6427013

109. Wang D. DuBois R.N. An Inflammatory Mediator, Prostaglandin E2, in Colorectal Cancer Cancer J. 2013 19 502 510 10.1097/PPO.0000000000000003 24270349 PMC4797645

110. Feng M. Zhong L.-X. Zhan Z.-Y. Huang Z.-H. Xiong J.-P. Resveratrol Treatment Inhibits Proliferation of and Induces Apoptosis in Human Colon Cancer Cells Med. Sci. Monit. 2016 22 1101 1108 10.12659/MSM.897905 27040803 PMC4822945

111. Kaminski B.M. Weigert A. Scherzberg M.-C. Ley S. Gilbert B. Brecht K. Brüne B. Steinhilber D. Stein J. Ulrich-Rückert S. Resveratrol-Induced Potentiation of the Antitumor Effects of Oxaliplatin Is Accompanied by an Altered Cytokine Profile of Human Monocyte-Derived Macrophages Apoptosis 2014 19 1136 1147 10.1007/s10495-014-0988-x 24715262

112. Dasari S. Bernard Tchounwou P. Cisplatin in Cancer Therapy: Molecular Mechanisms of Action Eur. J. Pharmacol. 2014 740 364 378 10.1016/j.ejphar.2014.07.025 25058905 PMC4146684

113. Liu Z. Peng Q. Li Y. Gao Y. Resveratrol Enhances Cisplatin-Induced Apoptosis in Human Hepatoma Cells via Glutamine Metabolism Inhibition BMB Rep. 2018 51 474 479 10.5483/BMBRep.2018.51.9.114 30103844 PMC6177506

114. Ghafouri-Fard S. Abak A. Tondro Anamag F. Shoorei H. Fattahi F. Javadinia S.A. Basiri A. Taheri M. 5-Fluorouracil: A Narrative Review on the Role of Regulatory Mechanisms in Driving Resistance to This Chemotherapeutic Agent Front. Oncol. 2021 11 658636 10.3389/fonc.2021.658636 33954114 PMC8092118

115. Buhrmann C. Shayan P. Kraehe P. Popper B. Goel A. Shakibaei M. Resveratrol Induces Chemosensitization to 5-Fluorouracil through up-Regulation of Intercellular Junctions, Epithelial-to-Mesenchymal Transition and Apoptosis in Colorectal Cancer Biochem. Pharmacol. 2015 98 51 68 10.1016/j.bcp.2015.08.105 26310874

116. Chung S.S. Dutta P. Austin D. Wang P. Awad A. Vadgama J.V. Combination of Resveratrol and 5-Flurouracil Enhanced Anti-Telomerase Activity and Apoptosis by Inhibiting STAT3 and Akt Signaling Pathways in Human Colorectal Cancer Cells Oncotarget 2018 9 32943 32957 10.18632/oncotarget.25993 30250641 PMC6152483

117. Wu S.-L. Effect of Resveratrol and in Combination with 5-FU on Murine Liver Cancer World J. Gastroenterol. 2004 10 3048 10.3748/wjg.v10.i20.3048 15378791 PMC4576270

118. Amrutkar M. Gladhaug I. Pancreatic Cancer Chemoresistance to Gemcitabine Cancers 2017 9 157 10.3390/cancers9110157 29144412 PMC5704175

119. Harikumar K.B. Kunnumakkara A.B. Sethi G. Diagaradjane P. Anand P. Pandey M.K. Gelovani J. Krishnan S. Guha S. Aggarwal B.B. Resveratrol, a Multitargeted Agent, Can Enhance Antitumor Activity of Gemcitabine In Vitro and in Orthotopic Mouse Model of Human Pancreatic Cancer Int. J. Cancer 2010 127 257 268 10.1002/ijc.25041 19908231 PMC3090706

120. Yang Y. Tian W. Yang L. Zhang Q. Zhu M. Liu Y. Li J. Yang L. Liu J. Shen Y. Gemcitabine Potentiates Anti-Tumor Effect of Resveratrol on Pancreatic Cancer via down-Regulation of VEGF-B J. Cancer Res. Clin. Oncol. 2021 147 93 103 10.1007/s00432-020-03384-7 32897433 PMC11802043

121. Marinello J. Delcuratolo M. Capranico G. Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives Int. J. Mol. Sci. 2018 19 3480 10.3390/ijms19113480 30404148 PMC6275052

122. Jin X. Wei Y. Liu Y. Lu X. Ding F. Wang J. Yang S. Resveratrol Promotes Sensitization to Doxorubicin by Inhibiting Epithelial-Mesenchymal Transition and Modulating SIRT1/β-Catenin Signaling Pathway in Breast Cancer Cancer Med. 2019 8 1246 1257 10.1002/cam4.1993 30697969 PMC6434195

123. Xu J. Liu D. Niu H. Zhu G. Xu Y. Ye D. Li J. Zhang Q. Resveratrol Reverses Doxorubicin Resistance by Inhibiting Epithelial-Mesenchymal Transition (EMT) through Modulating PTEN/Akt Signaling Pathway in Gastric Cancer J. Exp. Clin. Cancer Res. 2017 36 19 10.1186/s13046-016-0487-8 28126034 PMC5270306

124. Mirzapur P. Khazaei M.R. Moradi M.T. Khazaei M. Apoptosis Induction in Human Breast Cancer Cell Lines by Synergic Effect of Raloxifene and Resveratrol through Increasing Proapoptotic Genes Life Sci. 2018 205 45 53 10.1016/j.lfs.2018.04.035 29705353

125. De Amicis F. Giordano F. Vivacqua A. Pellegrino M. Panno M.L. Tramontano D. Fuqua S.A.W. Andò S. Resveratrol, through NF-Y/P53/Sin3/HDAC1 Complex Phosphorylation, Inhibits Estrogen Receptor Alpha Gene Expression via p38MAPK/CK2 Signaling in Human Breast Cancer Cells FASEB J. 2011 25 3695 3707 10.1096/fj.10-178871 21737614 PMC3177579

126. Jang Y.-G. Go R.-E. Hwang K.-A. Choi K.-C. Resveratrol Inhibits DHT-Induced Progression of Prostate Cancer Cell Line through Interfering with the AR and CXCR4 Pathway J. Steroid Biochem. Mol. Biol. 2019 192 105406 10.1016/j.jsbmb.2019.105406 31185279

127. Breitenbach J. Fischer A. von Dalwigk K. Sevelda F. Goldhahn K. Galardon E. Tögel S. Steiner G. Klösch B. Resveratrol Derivatives for the Treatment of Inflammatory and Degenerative Joint Diseases. Effects on Fibroblast-like Synoviocytes and Chondrocytes Osteoarthr. Cartil. 2020 28 S501 10.1016/j.joca.2020.02.786

128. Ksila M. Ghzaiel I. Pires V. Ghrairi T. Masmoudi-Kouki O. Latruffe N. Vervandier-Fasseur D. Vejux A. Lizard G. Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle Molecules 2023 28 3178 10.3390/molecules28073178 37049947 PMC10096382

129. Sale S. Verschoyle R.D. Boocock D. Jones D.J.L. Wilsher N. Ruparelia K.C. Potter G.A. Farmer P.B. Steward W.P. Gescher A.J. Pharmacokinetics in Mice and Growth-Inhibitory Properties of the Putative Cancer Chemopreventive Agent Resveratrol and the Synthetic Analogue Trans 3,4,5,4′-Tetramethoxystilbene Br. J. Cancer 2004 90 736 744 10.1038/sj.bjc.6601568 14760392 PMC2409587

130. Riche D.M. McEwen C.L. Riche K.D. Sherman J.J. Wofford M.R. Deschamp D. Griswold M. Analysis of Safety from a Human Clinical Trial with Pterostilbene J. Toxicol. 2013 2013 463595 10.1155/2013/463595 23431291 PMC3575612

131. Wang H.L. Gao J.P. Han Y.L. Xu X. Wu R. Gao Y. Cui X.H. Comparative Studies of Polydatin and Resveratrol on Mutual Transformation and Antioxidative Effect In Vivo Phytomedicine Int. J. Phytother. Phytopharm. 2015 22 553 559 10.1016/j.phymed.2015.03.014 25981921

132. Chen X. Mukwaya E. Wong M.S. Zhang Y. A Systematic Review on Biological Activities of Prenylated Flavonoids Pharm. Biol. 2014 52 655 660 10.3109/13880209.2013.853809 24256182

133. Tang Y.W. Shi C.J. Yang H.L. Cai P. Liu Q.H. Yang X.L. Kong L.Y. Wang X.B. Synthesis and Evaluation of Isoprenylation-Resveratrol Dimer Derivatives against Alzheimer’s Disease Eur. J. Med. Chem. 2019 163 307 319 10.1016/j.ejmech.2018.11.040 30529634

134. Liu Y. Liu Y. Chen H. Yao X. Xiao Y. Zeng X. Zheng Q. Wei Y. Song C. Zhang Y. Synthetic Resveratrol Derivatives and Their Biological Activities: A Review Open J. Med. Chem. 2015 5 97 105 10.4236/ojmc.2015.54006

135. Fabris S. Momo F. Ravagnan G. Stevanato R. Antioxidant Properties of Resveratrol and Piceid on Lipid Peroxidation in Micelles and Monolamellar Liposomes Biophys. Chem. 2008 135 76 83 10.1016/j.bpc.2008.03.005 18420333

136. Chimento A. De Amicis F. Sirianni R. Sinicropi M.S. Puoci F. Casaburi I. Saturnino C. Pezzi V. Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol Int. J. Mol. Sci. 2019 20 1381 10.3390/ijms20061381 30893846 PMC6471659

137. Fan G.-J. Liu X.-D. Qian Y.-P. Shang Y.-J. Li X.-Z. Dai F. Fang J.-G. Jin X.-L. Zhou B. 4,4′-Dihydroxy-Trans-Stilbene, a Resveratrol Analogue, Exhibited Enhanced Antioxidant Activity and Cytotoxicity Bioorganic Med. Chem. 2009 17 2360 2365 10.1016/j.bmc.2009.02.014 19251420

138. Likhitwitayawuid K. Oxyresveratrol: Sources, Productions, Biological Activities, Pharmacokinetics, and Delivery Systems Molecules 2021 26 4212 10.3390/molecules26144212 34299485 PMC8307110

139. Marko M. Pawliczak R. Resveratrol and Its Derivatives in Inflammatory Skin Disorders—Atopic Dermatitis and Psoriasis: A Review Antioxidants 2023 12 1954 10.3390/antiox12111954 38001807 PMC10669798

140. da Costa F.P. Puty B. Nogueira L.S. Mitre G.P. dos Santos S.M. Teixeira B.J.B. Kataoka M.S.d.S. Martins M.D. Barboza C.A.G. Monteiro M.C. Piceatannol Increases Antioxidant Defense and Reduces Cell Death in Human Periodontal Ligament Fibroblast under Oxidative Stress Antioxidants 2020 9 16 10.3390/antiox9010016 PMC7023480 31878036

141. Cebrián R. Lucas R. Fernández-Cantos M.V. Slot K. Peñalver P. Martínez-García M. Párraga-Leo A. de Paz M.V. García F. Kuipers O.P. Synthesis and Antimicrobial Activity of Aminoalkyl Resveratrol Derivatives Inspired by Cationic Peptides J. Enzym. Inhib. Med. Chem. 2023 38 267 10.1080/14756366.2022.2146685 PMC9828810 36600674

142. Fragopoulou E. Gkotsi K. Petsini F. Gioti K. Kalampaliki A.D. Lambrinidis G. Kostakis I.K. Tenta R. Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives Molecules 2023 28 5547 10.3390/molecules28145547 37513418 PMC10386404

143. Cichocki M. Paluszczak J. Szaefer H. Piechowiak A. Rimando A.M. Baer-Dubowska W. Pterostilbene Is Equally Potent as Resveratrol in Inhibiting 12-O-Tetradecanoylphorbol-13-Acetate Activated NFkappaB, AP-1, COX-2, and iNOS in Mouse Epidermis Mol. Nutr. Food Res. 2008 52 (Suppl. S1) S62 S70 10.1002/mnfr.200700466 18551458

144. Perrone D. Fuggetta M.P. Ardito F. Cottarelli A. Filippis A.D. Ravagnan G. Maria S.D. Muzio L.L. Resveratrol (3,5,4′-Trihydroxystilbene) and Its Properties in Oral Diseases Exp. Ther. Med. 2017 14 3 10.3892/etm.2017.4472 28672886 PMC5488484

145. Faleye O.S. Boya B.R. Lee J.-H. Choi I. Lee J. Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens Pharmacol. Rev. 2024 76 90 141 10.1124/pharmrev.123.000863 37845080

146. Kang J.E. Yoo N. Jeon B.J. Kim B.S. Chung E.-H. Resveratrol Oligomers, Plant-Produced Natural Products With Anti-Virulence and Plant Immune-Priming Roles Front. Plant Sci. 2022 13 885625 10.3389/fpls.2022.885625 35712595 PMC9197177

147. Sy B. Krisa S. Richard T. Courtois A. Resveratrol, ε-Viniferin, and Vitisin B from Vine: Comparison of Their In Vitro Antioxidant Activities and Study of Their Interactions Molecules 2023 28 7521 10.3390/molecules28227521 38005243 PMC10672907

148. Ioannou I. Barboza E. Willig G. Marié T. Texeira A. Darme P. Renault J.-H. Allais F. Implementation of an Enzyme Membrane Reactor to Intensify the α- O-Glycosylation of Resveratrol Using Cyclodextrins Pharmaceuticals 2021 14 319 10.3390/ph14040319 33916212 PMC8065884

149. Karami A. Fakhri S. Kooshki L. Khan H. Polydatin: Pharmacological Mechanisms, Therapeutic Targets, Biological Activities, and Health Benefits Molecules 2022 27 6474 10.3390/molecules27196474 36235012 PMC9572446

150. Chen G. Yang Z. Wen D. Guo J. Xiong Q. Li P. Zhao L. Wang J. Wu C. Dong L. Polydatin Has Anti-Inflammatory and Antioxidant Effects in LPS-Induced Macrophages and Improves DSS-Induced Mice Colitis Immun. Inflamm. Dis. 2021 9 959 970 10.1002/iid3.455 34010516 PMC8342204

151. Ahmadi Z. Mohammadinejad R. Ashrafizadeh M. Drug Delivery Systems for Resveratrol, a Non-Flavonoid Polyphenol: Emerging Evidence in Last Decades J. Drug Deliv. Sci. Technol. 2019 51 591 604 10.1016/j.jddst.2019.03.017

152. Chopra H. Bibi S. Islam F. Ahmad S.U. Olawale O.A. Alhumaydhi F.A. Marzouki R. Baig A.A. Emran T.B. Emerging Trends in the Delivery of Resveratrol by Nanostructures: Applications of Nanotechnology in Life Sciences J. Nanomater. 2022 2022 3083728 10.1155/2022/3083728

153. Kotta S. Aldawsari H.M. Badr-Eldin S.M. Nair A.B. Kaleem M. Dalhat M.H. Thermosensitive Hydrogels Loaded with Resveratrol Nanoemulsion: Formulation Optimization by Central Composite Design and Evaluation in MCF-7 Human Breast Cancer Cell Lines Gels 2022 8 450 10.3390/gels8070450 35877535 PMC9318454

154. Bombelli C. Pagano L. Aiello S. Gkartziou F. Simonis B. Ceccacci F. Sennato S. Ciogli A. Bugli F. Martini C. Resveratrol-Loaded Glycosylated Liposomes for Targeting Bacteria Med. Sci. Forum 2022 14 61 10.3390/ECMC2022-13158

155. Dana P. Thumrongsiri N. Tanyapanyachon P. Chonniyom W. Punnakitikashem P. Saengkrit N. Resveratrol Loaded Liposomes Disrupt Cancer Associated Fibroblast Communications within the Tumor Microenvironment to Inhibit Colorectal Cancer Aggressiveness Nanomaterials 2023 13 107 10.3390/nano13010107 36616017 PMC9824711

156. Radeva L. Yordanov Y. Spassova I. Kovacheva D. Tzankova V. Yoncheva K. Double-Loaded Doxorubicin/Resveratrol Polymeric Micelles Providing Low Toxicity on Cardiac Cells and Enhanced Cytotoxicity on Lymphoma Cells Pharmaceutics 2023 15 1287 10.3390/pharmaceutics15041287 37111772 PMC10143567

157. Al Fatease A. Shah V. Nguyen D.X. Cote B. LeBlanc N. Rao D.A. Alani A.W. Chemosensitization and Mitigation of Adriamycin-Induced Cardiotoxicity Using Combinational Polymeric Micelles for Co-Delivery of Quercetin/Resveratrol and Resveratrol/Curcumin in Ovarian Cancer Nanomed. Nanotechnol. Biol. Med. 2019 19 39 48 10.1016/j.nano.2019.03.011 31022465

158. Anwar D.M. Khattab S.N. Helmy M.W. Kamal M.K. Bekhit A.A. Elkhodairy K.A. Elzoghby A.O. Lactobionic/Folate Dual-Targeted Amphiphilic Maltodextrin-Based Micelles for Targeted Codelivery of Sulfasalazine and Resveratrol to Hepatocellular Carcinoma Bioconjugate Chem. 2018 29 3026 3041 10.1021/acs.bioconjchem.8b00428 30110148

159. Wang W. Zhou M. Xu Y. Peng W. Zhang S. Li R. Zhang H. Zhang H. Cheng S. Wang Y. Resveratrol-Loaded TPGS-Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer: In Vivo and In Vitro Study Front. Bioeng. Biotechnol. 2021 9 762489 10.3389/fbioe.2021.762489 34950642 PMC8688991

160. Zhang D. Zhang J. Zeng J. Li Z. Zuo H. Huang C. Zhao X. Nano-Gold Loaded with Resveratrol Enhance the Anti-Hepatoma Effect of Resveratrol In Vitro and In Vivo J. Biomed. Nanotechnol. 2019 15 288 300 10.1166/jbn.2019.2682 30596551

161. Sudha T. El-Far A.H. Mousa D.S. Mousa S.A. Resveratrol and Its Nanoformulation Attenuate Growth and the Angiogenesis of Xenograft and Orthotopic Colon Cancer Models Molecules 2020 25 1412 10.3390/molecules25061412 32244860 PMC7144556

162. Katila N. Duwa R. Bhurtel S. Khanal S. Maharjan S. Jeong J.-H. Lee S. Choi D.-Y. Yook S. Enhancement of Blood-Brain Barrier Penetration and the Neuroprotective Effect of Resveratrol J. Control. Release Off. J. Control. Release Soc. 2022 346 1 19 10.1016/j.jconrel.2022.04.003 35398173

163. Liang M. Guo M. Saw P.E. Yao Y. Fully Natural Lecithin Encapsulated Nano-Resveratrol for Anti-Cancer Therapy Int. J. Nanomed. 2022 17 2069 2078 10.2147/IJN.S362418 PMC9091702 35571257

164. Mahalingam M. Krishnamoorthy K. Selection of a Suitable Method for the Preparation of Polymeric Nanoparticles: Multi-Criteria Decision Making Approach Adv. Pharm. Bull. 2015 5 57 67 10.5681/APB.2015.008 25789220 PMC4352224

165. Matalanis A. Jones O.G. McClements D.J. Structured Biopolymer-Based Delivery Systems for Encapsulation, Protection, and Release of Lipophilic Compounds Food Hydrocoll. 2011 25 1865 1880 10.1016/j.foodhyd.2011.04.014

166. Sarma S. Agarwal S. Bhuyan P. Hazarika J. Ganguly M. Resveratrol-Loaded Chitosan–Pectin Core–Shell Nanoparticles as Novel Drug Delivery Vehicle for Sustained Release and Improved Antioxidant Activities R. Soc. Open Sci. 2022 9 210784 10.1098/rsos.210784 35127111 PMC8808105

167. Sanna V. Roggio A.M. Silvia S. Piccinini M. Salvatore M. Mariani A. Sechi M. Development of Novel Cationic Chitosan- and Anionic Alginate–Coated Poly(D,L-Lactide-Co-Glycolide) Nanoparticles for Controlled Release and Light Protection of Resveratrol Int. J. Nanomed. 2012 7 5501 5516 10.2147/IJN.S36684 PMC3477887 23093904

168. Detoni C.B. Souto G.D. da Silva A.L.M. Pohlmann A.R. Guterres S.S. Photostability and Skin Penetration of Different E-Resveratrol-Loaded Supramolecular Structures Photochem. Photobiol. 2012 88 913 921 10.1111/j.1751-1097.2012.01147.x 22443373

169. Karthikeyan S. Prasad N.R. Ganamani A. Balamurugan E. Anticancer Activity of Resveratrol-Loaded Gelatin Nanoparticles on NCI-H460 Non-Small Cell Lung Cancer Cells Biomed. Prev. Nutr. 2013 3 64 73 10.1016/j.bionut.2012.10.009

170. Sanna V. Siddiqui I.A. Sechi M. Mukhtar H. Nanoformulation of Natural Products for Prevention and Therapy of Prostate Cancer Cancer Lett. 2013 334 142 151 10.1016/j.canlet.2012.11.037 23201598 PMC3890375

171. Nassir A.M. Shahzad N. Ibrahim I.A.A. Ahmad I. Md S. Ain M.R. Resveratrol-Loaded PLGA Nanoparticles Mediated Programmed Cell Death in Prostate Cancer Cells Saudi Pharm. J. 2018 26 876 885 10.1016/j.jsps.2018.03.009 30202231 PMC6128707

172. Zheng Y. Jia R. Li J. Tian X. Qian Y. Curcumin- and Resveratrol-Co-Loaded Nanoparticles in Synergistic Treatment of Hepatocellular Carcinoma J. Nanobiotechnol. 2022 20 339 10.1186/s12951-022-01554-y PMC9301856 35858935

173. Yin L. Yuvienco C. Montclare J.K. Protein Based Therapeutic Delivery Agents: Contemporary Developments and Challenges Biomaterials 2017 134 91 116 10.1016/j.biomaterials.2017.04.036 28458031 PMC5513498

174. Rowe R.C. Sheskey P. Quinn M. Handbook of Pharmaceutical Excipients Libros Digitales-Pharmaceutical Press Chicago, IL, USA 2009 1-58212-135-4

175. Xing M. Zhao H. Ahmed R. Wang X. Liu J. Wang J. Guo A. Wang M. Fabrication of Resveratrol-Loaded Zein Nanoparticles Based on Flash Nanoprecipitation Colloids Surf. A Physicochem. Eng. Asp. 2022 654 129829 10.1016/j.colsurfa.2022.129829

176. Contado C. Caselotto L. Mello P. Maietti A. Marvelli L. Marchetti N. Dalpiaz A. Design and Formulation of Eudragit-Coated Zein/Pectin Nanoparticles for the Colon Delivery of Resveratrol Eur. Food Res. Technol. 2020 246 2427 2441 10.1007/s00217-020-03586-w

177. Nunes R. Baião A. Monteiro D. das Neves J. Sarmento B. Zein Nanoparticles as Low-Cost, Safe, and Effective Carriers to Improve the Oral Bioavailability of Resveratrol Drug Deliv. Transl. Res. 2020 10 826 837 10.1007/s13346-020-00738-z 32207071

178. Liu Y. Liang X. Zou Y. Peng Y. McClements D.J. Hu K. Resveratrol-Loaded Biopolymer Core–Shell Nanoparticles: Bioavailability and Anti-Inflammatory Effects Food Funct. 2020 11 4014 4025 10.1039/D0FO00195C 32322856

179. Peñalva R. Morales J. González-Navarro C. Larrañeta E. Quincoces G. Peñuelas I. Irache J. Increased Oral Bioavailability of Resveratrol by Its Encapsulation in Casein Nanoparticles Int. J. Mol. Sci. 2018 19 2816 10.3390/ijms19092816 30231546 PMC6163610

180. Zhao Z. Li Y. Xie M.-B. Silk Fibroin-Based Nanoparticles for Drug Delivery Int. J. Mol. Sci. 2015 16 4880 4903 10.3390/ijms16034880 25749470 PMC4394455

181. Galvez J. Rodriguez-Nogales A. Ortiz V. Algieri F. Zorrilla P. Rodriguez-Cabezas M.E. Garrido-Mesa N. Utrilla M.P. Matteis L. Garrido-Mesa J. Silk Fibroin Nanoparticles Constitute a Vector for Controlled Release of Resveratrol in an Experimental Model of Inflammatory Bowel Disease in Rats Int. J. Nanomed. 2014 9 4507 4520 10.2147/IJN.S68526 PMC4181735 25285004

182. Kim J.-H. Park E.-Y. Ha H.-K. Jo C.-M. Lee W.-J. Lee S.S. Kim J.W. Resveratrol-Loaded Nanoparticles Induce Antioxidant Activity against Oxidative Stress Asian Australas. J. Anim. Sci. 2016 29 288 298 10.5713/ajas.15.0774 26732454 PMC4698710

183. Ackova D.G. Smilkov K. Bosnakovski D. Contemporary Formulations for Drug Delivery of Anticancer Bioactive Compounds Recent Pat. Anti-Cancer Drug Discov. 2019 14 19 31 10.2174/1574892814666190111104834 30636616

184. Lian B. Wu M. Feng Z. Deng Y. Zhong C. Zhao X. Folate-Conjugated Human Serum Albumin-Encapsulated Resveratrol Nanoparticles: Preparation, Characterization, Bioavailability and Targeting of Liver Tumors Artif. Cells Nanomed. Biotechnol. 2019 47 154 165 10.1080/21691401.2018.1548468 30686050

185. Santos A.C. Pereira I. Magalhães M. Pereira-Silva M. Caldas M. Ferreira L. Figueiras A. Ribeiro A.J. Veiga F. Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence AAPS J. 2019 21 57 10.1208/s12248-019-0325-y 31016543

186. Carletto B. Berton J. Ferreira T.N. Dalmolin L.F. Paludo K.S. Mainardes R.M. Farago P.V. Favero G.M. Resveratrol-Loaded Nanocapsules Inhibit Murine Melanoma Tumor Growth Colloids Surf. B Biointerfaces 2016 144 65 72 10.1016/j.colsurfb.2016.04.001 27070053

187. Jung K.-H. Lee J.H. Park J.W. Quach C.H.T. Moon S.-H. Cho Y.S. Lee K.-H. Resveratrol-Loaded Polymeric Nanoparticles Suppress Glucose Metabolism and Tumor Growth In Vitro and In Vivo Int. J. Pharm. 2015 478 251 257 10.1016/j.ijpharm.2014.11.049 25445992

188. Lu X. Xu H. Sun B. Zhu Z. Zheng D. Li X. Enhanced Neuroprotective Effects of Resveratrol Delivered by Nanoparticles on Hydrogen Peroxide-Induced Oxidative Stress in Rat Cortical Cell Culture Mol. Pharm. 2013 10 2045 2053 10.1021/mp400056c 23534345

189. da Rocha Lindner G. Bonfanti Santos D. Colle D. Gasnhar Moreira E.L. Daniel Prediger R. Farina M. Khalil N.M. Mara Mainardes R. Improved Neuroprotective Effects of Resveratrol-Loaded Polysorbate 80-Coated Poly(Lactide) Nanoparticles in MPTP-Induced Parkinsonism Nanomedicine 2015 10 1127 1138 10.2217/nnm.14.165 25929569

190. Guo W. Li A. Jia Z. Yuan Y. Dai H. Li H. Transferrin Modified PEG-PLA-Resveratrol Conjugates: In Vitro and In Vivo Studies for Glioma Eur. J. Pharmacol. 2013 718 41 47 10.1016/j.ejphar.2013.09.034 24070814

191. Tang L. Chen X. Tong Q. Ran Y. Ma L. Tan Y. Yi Z. Li X. Biocompatible, Bacteria-Targeting Resveratrol Nanoparticles Fabricated by Mannich Molecular Condensation for Accelerating Infected Wound Healing J. Mater. Chem. B 2022 10 9280 9294 10.1039/D2TB01697D 36342467

192. Karaki N. Hajj Ali H. El Kak A. Gold Nanoparticles as Promising Agents for Cancer Therapy Nanoparticle Drug Delivery Systems for Cancer Treatment Gali-Muhtasib H. Chouaib R. Jenny Stanford Publishing Pte. Ltd. Boca Raton, FL, USA 2020 Volume 1

193. Neshastehriz A. Tabei M. Maleki S. Eynali S. Shakeri-Zadeh A. Photothermal Therapy Using Folate Conjugated Gold Nanoparticles Enhances the Effects of 6 MV X-Ray on Mouth Epidermal Carcinoma Cells J. Photochem. Photobiol. B Biol. 2017 172 52 60 10.1016/j.jphotobiol.2017.05.012 28527427

194. Wijesinghe W.P.S.L. Mantilaka M.M.M.G.P.G. Ruparathna K.A.A. Rajapakshe R.B.S.D. Sameera S.A.L. Thilakarathna M.G.G.S.N. Filler Matrix Interfaces of Inorganic/Biopolymer Composites and Their Applications Interfaces in Particle and Fibre Reinforced Composites Elsevier Amsterdam, The Netherlands 2020 95 112 978-0-08-102665-6

195. Lee D.G. Lee M. Go E.B. Chung N. Resveratrol-Loaded Gold Nanoparticles Enhance Caspase-Mediated Apoptosis in PANC-1 Pancreatic Cells via Mitochondrial Intrinsic Apoptotic Pathway Cancer Nano 2022 13 34 10.1186/s12645-022-00143-w

196. Lee D.G. Go E.B. Lee M. Pak P.J. Kim J.-S. Chung N. Gold Nanoparticles Conjugated with Resveratrol Induce Cell Cycle Arrest in MCF-7 Cell Lines Appl. Biol. Chem. 2019 62 33 10.1186/s13765-019-0440-6

197. Park S.Y. Chae S.Y. Park J.O. Lee K.J. Park G. Gold-Conjugated Resveratrol Nanoparticles Attenuate the Invasion and MMP-9 and COX-2 Expression in Breast Cancer Cells Oncol. Rep. 2016 35 3248 3256 10.3892/or.2016.4716 27035791

198. Wang W. Tang Q. Yu T. Li X. Gao Y. Li J. Liu Y. Rong L. Wang Z. Sun H. Surfactant-Free Preparation of Au@Resveratrol Hollow Nanoparticles with Photothermal Performance and Antioxidant Activity ACS Appl. Mater. Interfaces 2017 9 3376 3387 10.1021/acsami.6b13911 28098974

199. Dong Y. Wan G. Yan P. Qian C. Li F. Peng G. Fabrication of Resveratrol Coated Gold Nanoparticles and Investigation of Their Effect on Diabetic Retinopathy in Streptozotocin Induced Diabetic Rats J. Photochem. Photobiol. B Biol. 2019 195 51 57 10.1016/j.jphotobiol.2019.04.012 31082734

200. Scheive M. Yazdani S. Hajrasouliha A.R. The Utility and Risks of Therapeutic Nanotechnology in the Retina Ophthalmol. Eye Dis. 2021 13 251584142110033 10.1177/25158414211003381 PMC7989128 33817552

201. Park S. Cha S.-H. Cho I. Park S. Park Y. Cho S. Park Y. Antibacterial Nanocarriers of Resveratrol with Gold and Silver Nanoparticles Mater. Sci. Eng. C 2016 58 1160 1169 10.1016/j.msec.2015.09.068 26478416

202. Tawfik S.M. Azizov S. Elmasry M.R. Sharipov M. Lee Y.-I. Recent Advances in Nanomicelles Delivery Systems Nanomaterials 2021 11 70 10.3390/nano11010070 PMC7823398 33396938

203. Bose A. Roy Burman D. Sikdar B. Patra P. Nanomicelles: Types, Properties and Applications in Drug Delivery IET Nanobiotechnol. 2021 15 19 27 10.1049/nbt2.12018 34694727 PMC8675821

204. Gregoriou Y. Gregoriou G. Yilmaz V. Kapnisis K. Prokopi M. Anayiotos A. Strati K. Dietis N. Constantinou A.I. Andreou C. Resveratrol Loaded Polymeric Micelles for Theranostic Targeting of Breast Cancer Cells Nanotheranostics 2021 5 113 124 10.7150/ntno.51955 33391978 PMC7738945

205. Kamenova K. Radeva L. Konstantinov S. Petrov P.D. Yoncheva K. Copolymeric Micelles of Poly(ε-Caprolactone) and Poly(Methacrylic Acid) as Carriers for the Oral Delivery of Resveratrol Polymers 2023 15 3769 10.3390/polym15183769 37765623 PMC10537763

206. Bonferoni M. Rossi S. Sandri G. Ferrari F. Gavini E. Rassu G. Giunchedi P. Nanoemulsions for “Nose-to-Brain” Drug Delivery Pharmaceutics 2019 11 84 10.3390/pharmaceutics11020084 30781585 PMC6409749

207. Choradiya B.R. Patil S.B. A Comprehensive Review on Nanoemulsion as an Ophthalmic Drug Delivery System J. Mol. Liq. 2021 339 116751 10.1016/j.molliq.2021.116751

208. Sharma B. Iqbal B. Kumar S. Ali J. Baboota S. Resveratrol-Loaded Nanoemulsion Gel System to Ameliorate UV-Induced Oxidative Skin Damage: From In Vitro to In Vivo Investigation of Antioxidant Activity Enhancement Arch. Dermatol. Res. 2019 311 773 793 10.1007/s00403-019-01964-3 31432208

209. Poonia N. Lather V. Kaur B. Kirthanashri S.V. Pandita D. Optimization and Development of Methotrexate- and Resveratrol-Loaded Nanoemulsion Formulation Using Box–Behnken Design for Rheumatoid Arthritis ASSAY Drug Dev. Technol. 2020 18 356 368 10.1089/adt.2020.989 33052698

210. Rinaldi F. Maurizi L. Forte J. Marazzato M. Hanieh P. Conte A. Ammendolia M. Marianecci C. Carafa M. Longhi C. Resveratrol-Loaded Nanoemulsions: In Vitro Activity on Human T24 Bladder Cancer Cells Nanomaterials 2021 11 1569 10.3390/nano11061569 34203613 PMC8232283

211. Mousavi P. Rahimi Esboei B. Pourhajibagher M. Fakhar M. Shahmoradi Z. Hejazi S.H. Hassannia H. Nasrollahi Omran A. Hasanpour H. Anti-Leishmanial Effects of Resveratrol and Resveratrol Nanoemulsion on Leishmania Major BMC Microbiol. 2022 22 56 10.1186/s12866-022-02455-8 35168553 PMC8845381

212. Kotta S. Mubarak Aldawsari H. Badr-Eldin S.M. Alhakamy N.A. Md S. Coconut Oil-Based Resveratrol Nanoemulsion: Optimization Using Response Surface Methodology, Stability Assessment and Pharmacokinetic Evaluation Food Chem. 2021 357 129721 10.1016/j.foodchem.2021.129721 33866243

213. Hosseini S.F. Ramezanzade L. McClements D.J. Recent Advances in Nanoencapsulation of Hydrophobic Marine Bioactives: Bioavailability, Safety, and Sensory Attributes of Nano-Fortified Functional Foods Trends Food Sci. Technol. 2021 109 322 339 10.1016/j.tifs.2021.01.045

214. Has C. Sunthar P. A Comprehensive Review on Recent Preparation Techniques of Liposomes J. Liposome Res. 2020 30 336 365 10.1080/08982104.2019.1668010 31558079

215. Jagwani S. Jalalpure S. Dhamecha D. Jadhav K. Bohara R. Pharmacokinetic and Pharmacodynamic Evaluation of Resveratrol Loaded Cationic Liposomes for Targeting Hepatocellular Carcinoma ACS Biomater. Sci. Eng. 2020 6 4969 4984 10.1021/acsbiomaterials.0c00429 33455290

216. Pagano L. Gkartziou F. Aiello S. Simonis B. Ceccacci F. Sennato S. Ciogli A. Mourtas S. Spiliopoulou I. Antimisiaris S.G. Resveratrol Loaded in Cationic Glucosylated Liposomes to Treat Staphylococcus Epidermidis Infections Chem. Phys. Lipids 2022 243 105174 10.1016/j.chemphyslip.2022.105174 35038451

217. Pandey S. Shamim A. Shaif M. Kushwaha P. Development and Evaluation of Resveratrol-Loaded Liposomes in Hydrogel-Based Wound Dressing for Diabetic Foot Ulcer Naunyn-Schmiedeberg’s Arch. Pharmacol. 2023 396 1811 1825 10.1007/s00210-023-02441-5 36862150

218. Alhusaini A.M. Fadda L.M. Alanazi A.M. Sarawi W.S. Alomar H.A. Ali H.M. Hasan I.H. Ali R.A. Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR Front. Pharmacol. 2022 13 826908 10.3389/fphar.2022.826908 35281939 PMC8913579

219. Zhu W.T. Zeng X.F. Yang H. Jia M.L. Zhang W. Liu W. Liu S.Y. Resveratrol Loaded by Folate-Modified Liposomes Inhibits Osteosarcoma Growth and Lung Metastasis via Regulating JAK2/STAT3 Pathway Int. J. Nanomed. 2023 18 2677 2691 10.2147/IJN.S398046 37228445 PMC10204760

220. Xu X. Tian M. Deng L. Jiang H. Han J. Zhen C. Huang L. Liu W. Structural Degradation and Uptake of Resveratrol-Encapsulated Liposomes Using an In Vitro Digestion Combined with Caco-2 Cell Absorption Model Food Chem. 2023 403 133943 10.1016/j.foodchem.2022.133943 36191420

221. Huang M. Liang C. Tan C. Huang S. Ying R. Wang Y. Wang Z. Zhang Y. Liposome Co-Encapsulation as a Strategy for the Delivery of Curcumin and Resveratrol Food Funct. 2019 10 6447 6458 10.1039/C9FO01338E 31524893

222. Peng S. Zou L. Zhou W. Liu W. Liu C. McClements D.J. Encapsulation of Lipophilic Polyphenols into Nanoliposomes Using pH-Driven Method: Advantages and Disadvantages J. Agric. Food Chem. 2019 67 7506 7511 10.1021/acs.jafc.9b01602 31184879

223. Cadena P.G. Pereira M.A. Cordeiro R.B. Cavalcanti I.M. Neto B.B. Pimentel M.D.C.C. Filho J.L.L. Silva V.L. Santos-Magalhães N.S. Nanoencapsulation of Quercetin and Resveratrol into Elastic Liposomes Biochim. Biophys. Acta (BBA)-Biomembr. 2013 1828 309 316 10.1016/j.bbamem.2012.10.022 23103506

224. Mishra R.K. Tiwari S.K. Mohapatra S. Thomas S. Efficient Nanocarriers for Drug-Delivery Systems: Types and Fabrication Micro and Nano Technologies Elsevier Amsterdam, The Netherlands 2019 1 41 978-0-12-814033-8

225. Mu H. Holm R. Solid Lipid Nanocarriers in Drug Delivery: Characterization and Design Expert Opin. Drug Deliv. 2018 15 771 785 10.1080/17425247.2018.1504018 30064267

226. Chenthamara D. Subramaniam S. Ramakrishnan S.G. Krishnaswamy S. Essa M.M. Lin F.-H. Qoronfleh M.W. Therapeutic Efficacy of Nanoparticles and Routes of Administration Biomater. Res. 2019 23 20 10.1186/s40824-019-0166-x 31832232 PMC6869321

227. Uchechi O. Ogbonna J.D. Attama A.A. Nanoparticles for Dermal and Transdermal Drug Delivery Appl. Nanotechnol. Drug Deliv. 2014 4 193 227

228. Teskač K. Kristl J. The Evidence for Solid Lipid Nanoparticles Mediated Cell Uptake of Resveratrol Int. J. Pharm. 2010 390 61 69 10.1016/j.ijpharm.2009.10.011 19833178

229. Rigon R. Fachinetti N. Severino P. Santana M. Chorilli M. Skin Delivery and In Vitro Biological Evaluation of Trans-Resveratrol-Loaded Solid Lipid Nanoparticles for Skin Disorder Therapies Molecules 2016 21 116 10.3390/molecules21010116 26805794 PMC6273087

230. Fachinetti N. Rigon R.B. Eloy J.O. Sato M.R. dos Santos K.C. Chorilli M. Comparative Study of Glyceryl Behenate or Polyoxyethylene 40 Stearate-Based Lipid Carriers for Trans-Resveratrol Delivery: Development, Characterization and Evaluation of the In Vitro Tyrosinase Inhibition AAPS PharmSciTech 2018 19 1401 1409 10.1208/s12249-018-0961-z 29404955

231. Jose S. Anju S.S. Cinu T.A. Aleykutty N.A. Thomas S. Souto E.B. In Vivo Pharmacokinetics and Biodistribution of Resveratrol-Loaded Solid Lipid Nanoparticles for Brain Delivery Int. J. Pharm. 2014 474 6 13 10.1016/j.ijpharm.2014.08.003 25102112

232. Neves A.R. Queiroz J.F. Reis S. Brain-Targeted Delivery of Resveratrol Using Solid Lipid Nanoparticles Functionalized with Apolipoprotein E J Nanobiotechnol 2016 14 27 10.1186/s12951-016-0177-x 27061902 PMC4826547

233. Zhang L. Zhu K. Zeng H. Zhang J. Pu Y. Wang Z. Zhang T. Wang B. Resveratrol Solid Lipid Nanoparticles to Trigger Credible Inhibition of Doxorubicin Cardiotoxicity Int. J. Nanomed. 2019 14 6061 6071 10.2147/IJN.S211130 PMC6681569 31534336

234. Wang W. Zhang L. Chen T. Guo W. Bao X. Wang D. Ren B. Wang H. Li Y. Wang Y. Anticancer Effects of Resveratrol-Loaded Solid Lipid Nanoparticles on Human Breast Cancer Cells Molecules 2017 22 1814 10.3390/molecules22111814 29068422 PMC6150230

235. Song Z. Shi Y. Han Q. Dai G. Endothelial Growth Factor Receptor-Targeted and Reactive Oxygen Species-Responsive Lung Cancer Therapy by Docetaxel and Resveratrol Encapsulated Lipid-Polymer Hybrid Nanoparticles Biomed. Pharmacother. 2018 105 18 26 10.1016/j.biopha.2018.05.095 29843041

236. Jurczyk M. Kasperczyk J. Wrześniok D. Beberok A. Jelonek K. Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy Biomedicines 2022 10 1187 10.3390/biomedicines10051187 35625921 PMC9138983

237. Waghule T. Rapalli V.K. Gorantla S. Saha R.N. Dubey S.K. Puri A. Singhvi G. Nanostructured Lipid Carriers as Potential Drug Delivery Systems for Skin Disorders Curr. Pharm. Des. 2020 26 4569 4579 10.2174/1381612826666200614175236 32534562

238. Gordillo-Galeano A. Mora-Huertas C.E. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: A Review Emphasizing on Particle Structure and Drug Release Eur. J. Pharm. Biopharm. 2018 133 285 308 10.1016/j.ejpb.2018.10.017 30463794

239. Naseri N. Valizadeh H. Zakeri-Milani P. Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application Adv Pharm Bull 2015 5 305 313 10.15171/apb.2015.043 26504751 PMC4616893

240. De Oliveira M.T.P. De Sá Coutinho Éverton D. Tenório De Souza É. Stanisçuaski Guterres S. Pohlmann A.R. Silva P.M.R. Martins M.A. Bernardi A. Orally Delivered Resveratrol-Loaded Lipid-Core Nanocapsules Ameliorate LPS-Induced Acute Lung Injury via the ERK and PI3K/Akt Pathways Int. J. Nanomed. 2019 14 5215 5228 10.2147/IJN.S200666 31371957 PMC6636190

241. Astley C. Houacine C. Zaabalawi A. Wilkinson F. Lightfoot A.P. Alexander Y. Whitehead D. Singh K.K. Azzawi M. Nanostructured Lipid Carriers Deliver Resveratrol, Restoring Attenuated Dilation in Small Coronary Arteries, via the AMPK Pathway Biomedicines 2021 9 1852 10.3390/biomedicines9121852 34944670 PMC8699041

242. Miao L. Daozhou L. Ying C. Qibing M. Siyuan Z. A Resveratrol-Loaded Nanostructured Lipid Carrier Hydrogel to Enhance the Anti-UV Irradiation and Anti-Oxidant Efficacy Colloids Surf. B Biointerfaces 2021 204 111786 10.1016/j.colsurfb.2021.111786 33984613

243. Vladu A.F. Ficai D. Ene A.G. Ficai A. Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance Int. J. Mol. Sci. 2022 23 10244 10.3390/ijms231810244 36142147 PMC9499610

244. Posadino A.M. Giordo R. Cossu A. Nasrallah G.K. Shaito A. Abou-Saleh H. Eid A.H. Pintus G. Flavin Oxidase-Induced ROS Generation Modulates PKC Biphasic Effect of Resveratrol on Endothelial Cell Survival Biomolecules 2019 9 209 10.3390/biom9060209 31151226 PMC6628153

245. Bernier M. Wahl D. Ali A. Allard J. Faulkner S. Wnorowski A. Sanghvi M. Moaddel R. Alfaras I. Mattison J.A. Resveratrol Supplementation Confers Neuroprotection in Cortical Brain Tissue of Nonhuman Primates Fed a High-Fat/Sucrose Diet Aging 2016 8 899 916 10.18632/aging.100942 27070252 PMC4931843

246. Safety of Synthetic Trans-Resveratrol as a Novel Food Pursuant to Regulation (EC) No 258/97 Available online: https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2016.4368 (accessed on 1 April 2024)