Exploring the multimodal health‐promoting properties of resveratrol: A comprehensive review

Abstract Resveratrol, a natural polyphenol in various plants, has gained significant attention for its potential health‐promoting properties. It has been demonstrated, after reviewing various clinical and in vitro studies, that resveratrol possesses potent antioxidant potential. Resveratrol demonstrates cellular component protection by directly neutralizing free radicals (FRs) and enhancing the expression of natural antioxidant enzymes, thereby mitigating oxidative damage to proteins, lipids, and nucleic acids. Clinical trials have shown promising results, indicating that resveratrol supplementation can enhance antioxidant defenses and reduce oxidative damage markers in various populations. In addition to its antioxidant effects, resveratrol exhibits potent anti‐inflammatory properties. It can modulate key inflammatory pathways, such as nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinases (MAPKs), thereby suppressing the production of pro‐inflammatory cytokines and chemokines. Furthermore, resveratrol's multimodal effects extend beyond its antioxidant and anti‐inflammatory properties. It has been discovered to exert regulatory effects on various cellular processes, including apoptosis, cell cycle progression, angiogenesis, and immunological responses. The primary aim of this review paper is to provide a thorough overview of the current knowledge on resveratrol, including its chemical composition, bioaccessibility, clinical effectiveness, and utilization in nanotechnology to enhance its bioavailability. From future perspectives, revising the administration methods for certain contexts and understanding the underlying systems responsible for resveratrol's effects will require further inquiry. For the highest potential health results, advanced trial‐based research is necessary for combinational nano‐delivery of resveratrol.


| INTRODUC TI ON
Resveratrol (RESV) (3,5,4′-trans-trihydroxystilbene) is a naturally occurring bioactive compound that belongs to the stilbene family, basically a dietary plant substance that is mostly found in the skin and seeds of grapes, although it has been found in various kinds of plant foods, particularly in the tea plant, berries, and peanuts (Bryl et al., 2022).Japanese scientist Takaoka discovered and extracted RESV for the first time from a white hellebore in 1939 (Tsekovska et al., 2023).RESV became popular in 1991 on the "60 Minutes" CBS show when Drs. Michel de Lorgeril and Serge Renaud were featured about the study nicknamed the French Paradox or Red Wine Paradox.
Based on the study, the French population exhibited a comparatively low prevalence of coronary heart disease due to their practice of consuming red wine, which hypothetically hinders the process of lipid peroxidation.Subsequently, RESV quickly gained widespread attention and sparked a significant amount of media coverage (Silva et al., 2022).
The scientific studies discussed in the posts examined here reveal a wide range of bioactivities and significant potential health benefits of RESV.This finding appeared to contradict the prevailing notion that their diet, characterized by high fat intake, would contribute to adverse health outcomes (Ditano-Vázquez et al., 2019).
RESV is predominantly present in the skin of red grapes and can be obtained through red wine as well.It is naturally synthesized by plants as a phytoalexin, which serves as a defensive mechanism against fungal infection, damage, stress, pathogens, and environmental stressors (Pannu & Bhatnagar, 2019).The levels of RESV in plants can vary depending on factors such as the plant species, climate, and growing conditions, although, RESV naturally exists as both cis and trans isomeric forms, the trans isomer is of particular interest due to its favorable health-promoting properties, compared to the cis form, the trans form has a relatively higher bioavailability (Lubin et al., 2022).
Fresh grape skin is particularly rich in RESV, and during the past three decades, RESV has drawn a lot of attention for its favorable health effects, as it has attracted noteworthy interest in contemporary times owing to its plausible health advantages, such as its antioxidant, anti-inflammatory, and anticancer attributes (Miguel et al., 2021).RESV is a promising compound for therapeutic interventions for cardiovascular diseases (CVDs), and neurodegenerative disorders.Its therapeutic ability to modulate several cellular pathways and affect various biological processes makes it a desirable bioactive compound against different chronic disorders (Thirumalaisamy et al., 2022).According to a number of studies, there is evidence to suggest that RESV may possess potential protective effects against a range of chronic diseases, including cancer (Honari et al., 2019), diabetes (Nowak et al., 2022), CVDs (Zhang et al., 2021), obesity (Thadhani, 2019), metabolic syndromes (Singh et al., 2019), kidney disorders (Alvarenga et al., 2022), and Alzheimer's disease (Tang et al., 2019).Moreover, previous preclinical investigations have demonstrated the potential of this intervention to augment cognitive abilities and attenuate the progression of aging (Terracina et al., 2022).
RESV being a potential antioxidant has been demonstrated to scavenge FRs and protect cells from oxidative damage.Various studies have investigated the possibility of encapsulating RESV in nanoparticles or using it as a nanocarrier.RESV has been proven as a promising choice for nutraceutical administration and functional food applications as studies have demonstrated that using it in nanoparticle formulations increases its bioavailability, absorption, and stability (Ahuja et al., 2020;Nguyen et al., 2022).This review paper aims to provide an overview of the current state of knowledge regarding RESV, including its chemical nature, bioavailability, biological properties, health benefits based on clinical trials, and application of RESV in nanotechnology to enhance its bioavailability.Furthermore, this discussion will focus on the ongoing research about the potential therapeutic uses of RESV, while highlighting the specific areas that demand additional study.

| CHEMI C AL NATURE OF RE S V
Natural polyphenolic antioxidant, RESV, is synthesized from 3 malonyl-CoA molecules and 1 coumaric-CoA molecule, as the method is catalyzed via stilbene synthase (Huang et al., 2020).
Stilbene molecules are composed of an aromatic carbon skeleton of C 6 -C 2 -C 6 (1,2-diphenylethylene), of which RESV is a hydroxylated substance (Vestergaard & Ingmer, 2019).The trans-RESV is the most abundant and has the greatest therapeutic potential because of its lower steric interruption (Shaito et al., 2020).During exposure to ultraviolet or solar radiation at wavelengths of 254 and 366 nm, trans may lose its stability and become cis-isomeric (Fiod Riccio et al., 2020).RESV possesses a similar chemical structure to estrogen diethylstilbestrol, in which a styrene double bond links two phenol rings to form 3,4,5-trihydroxystilbene (Yang et al., 2015).Ring A includes two hydroxyl (-OH) groups at C 3 and C 5 , whereas ring B possesses one hydroxyl group at C 4 .The structure of RESV consists of m-hydroxyquinone and 4′-hydroxystyryl moieties including rings A and B (Chan et al., 2019).
In RESV, hydroxyl groups are unstable, since the double bond between C and C makes it sensitive to light, pH, and temperature (Tian & Liu, 2020).RESV shows stability at room temperature in acidic pH but rapidly degrades in the alkaline pH whereas, trans-RESV in a liquid state could be stabilized by reducing pH, temperature, and limiting oxygen exposure (Zupančič et al., 2015).There are two monomers formed when RESV is decomposed, including resorcinol and phenol.When RESV is heated to its decomposition temperature (380°C), an additional reaction occurs which produces a new product.Analysis of the product structure reveals that it is mainly present among C-C double bonds and the hydroxyl group (da Silva et al., 2017).

| B I OAVAIL AB ILIT Y OF RE S V
The lipophilic properties of RESV contribute to its high absorption (Gambini et al., 2015).It has been identified that approximately 75% of RESV is orally absorbed when ingested by humans (Walle, 2011), and is primarily absorbed through transepithelial diffusion.The biosynthesis of trans-RESV-3-O-glucuronide and trans-RESV-3-sulfate occurs extensively in the intestine and liver through glucuronic acid conjugation and sulfation, respectively, its bioavailability is less than 1% (Summerlin et al., 2015).The effectiveness of RESV may be diminished by its low bioavailability (Gambini et al., 2015).When given orally, RESV has poor bioavailability, which represents one of the main obstacles in translating its therapeutic properties.It is very difficult to sustain a therapeutic level of RESV in blood circulation as it is removed by the body in an immensely rapid manner (Kemper et al., 2022).
The bioavailability of RESV is limited as it metabolizes rapidly.A maximum plasma concentration of 1.48-2.48ng/mL has been observed between 0.8 and 1.3 h following the first administration of 25, 50, 100, and 150 mg of RESV (Almeida et al., 2009).Oral administration of 400 mg RESV results in a plasma concentration of 47 mg/ mL (Vaz-da-Silva et al., 2008), whereas 500 mg results in 71 mg/mL (Sergides et al., 2016).
The process of active transport facilitates the absorption of RESV metabolites, subsequently leading to their presence in the circulatory system, where they exhibit binding affinity toward lipoproteins and albumin.Upon interaction with cells possessing receptors for lipoproteins and albumin, these complexes facilitate the release of RESV into the cell.Subsequently, upon dissociation, RESV gains unhindered entry into the cell.Thus, these complexes serve as RESV reservoirs and aid in the distribution of the active compound (Pannu & Bhatnagar, 2019).Despite the rapid metabolism of RESV, the oral administration method is usually preferred, although plasma concentrations of RESV that do not undergo metabolism depend on the dosage (Chimento et al., 2019).The major metabolism of RESV occurs in the intestines and liver, where UDP-glucuronosyltransferases and sulfotransferases are responsible for converting the compound into glucuronide and sulfate forms (Pannu & Bhatnagar, 2019;Sergides et al., 2016).After oral administration of RESV, the major RESV metabolites encountered are dihydro RESV, RESV-3-O-sulfate, and RESV-3-O-glucuronide conjugates that cause the low bioavailability of RESV (Peñalva et al., 2018).

| HE ALTH B ENEFITS OF RE S V
RESV has attracted great attention worldwide as it has been demonstrated to be one of the key components that contribute to human health.Potent antioxidants like RESV can help the body fight off dangerous FRs, which are known to speed up aging and cause several ailments (Lucarini et al., 2021;Pastor et al., 2019).As presented in Figure 1, RESV consumption can provide different health benefits.
RESV has been demonstrated to enhance heart health by lowering oxidative stress (OS) and inflammation in the body, consequently, the risk of cancer, inflammatory diseases, heart disease, and stroke may also be reduced (Zhang et al., 2021).In addition to preventing the synthesis of pro-inflammatory cytokines including tumor necrosis factor and interleukin-1 (IL-1), RESV also reduced inflammation by stimulating the anti-inflammatory enzymes (Ghanbari et al., 2021).
Additionally, as an estrogen receptor (ER) ligand and an ER coregulator, sirtuin 1 (SIRT1) mediates the modulation of inflammatory responses by suppressing the transcription of interleukin-6 (IL-6).It has been demonstrated that RESV is able to upregulate SIRT1, decrease NF-κB and the related cascades, and block PYD domains containing protein 3 (NALP3) activation.This allows it to manage both pro-and anti-inflammatory cytokines and chemokines, as well as avoid inflammation (Banez et al., 2020;Battineni et al., 2021).
The immune system's reaction to pathogens like bacteria, viruses, and some harmful substances may also be modulated by RESV F I G U R E 1 Reported health benefits associated with RESV consumption.(Abedini et al., 2021).RESV has also been observed to decrease the survival of bacteria and decrease contagious pulmonary inflammation without observable host harm in vivo, resulting in attenuated diarrhea and inflammation in rotavirus-infected piglets (Meng et al., 2023).Remarkably, it has been shown that RESV significantly increased immunological function in immunosuppressed animals, demonstrating a bidirectional regulatory influence on immunity (Song et al., 2022).
RESV has also been shown to have anticancer effects, which may aid in limiting the development and spread of cancer cells.
Additionally, RESV has shown a significant reduction in fasting blood sugar, triglycerides (TGs), and heart rate, all of which are CVD risk factors (Battineni et al., 2021).Moreover, it has been demonstrated to enhance cognitive performance and shield the brain against deterioration brought on by aging.In addition to this, RESV has been observed to lessen brain inflammation and may influence antiaging properties by enhancing mitochondrial function and activating specific genes that increase durability (Yanez et al., 2019).RESV is useful in preventing several diseases, including kidney problems, Alzheimer's disease, and Parkinson's disease, according to several epidemiological investigations (Battineni et al., 2021;Donia & Khamis, 2021;Rana et al., 2022).Owing to the encouraging outcomes from experimental research, numerous clinical studies have also revealed RESV's effectiveness against a variety of disorders as presented in Table 1.A few of RESV's health-promoting potentials are discussed below.

| Antioxidant potential
The potential health benefits of RESV have garnered significant attention in recent years, particularly its antioxidant properties.The potential of RESV to scavenge FRs and alleviate OS has been proven, highlighting its significance in the development and progression of several chronic diseases including cancer, CVDs, and neurological disorders.Moreover, research has shown that RESV can activate various cellular signaling pathways, which promote cellular health and longevity (Hu et al., 2019).
In a study conducted in 2018, Fu et al. demonstrated the antioxidative properties of RESV.Impact of RESV was studied on the suppression of inducible nitric oxide synthase (iNOS) expression and the mitogen-activated protein kinase (p38-MAPK) signaling pathway.Additionally, the study aimed to assess the potential protective effects of RESV administration against spinal cord reperfusion injury caused by heightened oxidative stress resulting from ischemia.
After administering RESV therapy, the investigators observed a noteworthy reduction in plasma concentrations of nitrite and nitrate, as well as diminished mRNA and protein expressions of iNOS.
Additionally, there was a significant drop in the phosphorylation of p38MAPK.Furthermore, the study provided evidence that the administration of RESV can effectively mitigate ischemic injury to the spinal cord.This protective effect is achieved through the inhibition of the iNOS/p38MAPK pathway, hence reducing the likelihood of organ dysfunction resulting from ischemia-reperfusion injury (Fu et al., 2018).
Deficiencies in wound healing arise from a multitude of intrinsic and extrinsic factors that contribute to the pathophysiology of the wound, culminating in significant morbidity and mortality rates globally (Oguntibeju, 2019).The process of wound healing is subject to perturbation by OS-induced injuries, which have the potential to modify the entire healing course.Zhou et al. used human umbilical vein endothelial cells (HUVEC) for in vitro experiments to evaluate the effect of RESV on OS and cell proliferation.The findings of the study revealed that hydrogen peroxide-induced OS undermines the ability of HUVEC to proliferate and migrate, whereas pretreatment with RESV mitigates this deleterious impact.In vivo experiments utilizing wound models demonstrated that RESV accelerated the wound healing process, conceivably via the attenuation of OSinduced damage through the activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and manganese superoxide dismutase (Zhou et al., 2021).obtained from the investigation, it was observed that both HPIMBD and TIMBD analogs exhibited no discernible indications of cytotoxicity toward nontumorigenic breast epithelial cells.Furthermore, it has been found that these analogs elicit activation of the antioxidant defense system through the nuclear factor erythroid 2 (Nrf2)dependent signaling pathway.This finding implies that these analogs may have potential use in regulating cellular antioxidant responses in the context of combating breast cancer (Chatterjee et al., 2018).Santos et al. conducted a study to ascertain the antioxidant impact of RESV on human mononuclear cells (PBMC) under oxidative stress.The PBMCs were sourced from donors of different age groups.The chemiluminescence assay employed RESV at a dose of 5 micromolar, together with a stimulus containing 0.64% hydrogen peroxide, and inhibitors targeting the PKA, AkT/PKB, and MAPK signaling pathways.The senior group had a greater baseline generation of ROS compared to the middle-aged group.RESV was effective in reducing ROS in both groups, but the middle-aged group experienced a more pronounced decrease in ROS (Santos et al., 2021).
RESV can immediately eliminate peroxynitrite when it is exposed to authentic peroxynitrite in a system without cells.This strongly inhibits the nitration of bovine serum albumin by a factor of twenty, surpassing the effectiveness of N-acetyl-l-cysteine.
RESV inhibits the oxidation of LDL caused by peroxynitrite, as well as the cytotoxic effects created by peroxynitrite (Holthoff et al., 2010).RESV has been shown to greatly enhance the activation of eNOS via stimulating the membrane estrogen receptor.RESV facilitates the augmentation of endothelial nitric oxide (NO) production through various mechanisms, with this being just one of them.Moreover, outside the direct protective effects of TA B L E 1 Clinical studies on RESV supplementation to target different health issues.

References
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| Anti-inflammatory potential
The inflammatory reaction is a multistage process that involves various cell types and mediator signals (Lugrin et al., 2014).Damaged tissues or pathogenic infections trigger inflammation, which is the body's normal and crucial response to such signals (Tu et al., 2022).It is interesting to note that the protective effects of RESV were accompanied by a decrease in the pro-inflammatory members of p38-MAPK and ERK1/2, demonstrating that the control of these pro-inflammatory pathways may be a factor in the therapeutic effects of RESV in cardiac disorders (Riba et al., 2017).In astrocytes exposed to lipopolysaccharides (LPS), RESV might in fact activate  et al., 2017).Moreover, these anti-inflammatory effects of RESV can indirectly downregulate both respiratory and skeletal muscle damage in COPD patients (Beijers et al., 2018).RESV exerts its antiinflammatory properties through several pathways and intermediaries, thereby mitigating the pathophysiological effects of SARS-CoV-2 infection.It seems to have the capacity to inhibit the production of interleukins such as IL-6, IL-1β, and IL-8, therefore decreasing inflammation (Akhondzadeh et al., 2020).RESV functions as a stimulator of the SIRT1 gene.SIRT1 is an enzyme associated with COVID-19 due to its possession of the regulator NAD + .With advancing age, there is a decline in the levels of NAD + in individuals.As the activation of SIRT1 relies on the presence of NAD + , reduced levels of NAD + are likewise associated with lower SIRT1 activity.Consequently, the administration of nutritional supplements containing SIRT1 activators such as RESV has the potential to decrease the intensity of the disease (Miller et al., 2020).

| Anti-allergic potential
Allergy is a hyperactive response of the immune system to typically innocuous exogenous substances, primarily proteins, resulting in symptoms such as skin rash, sneezing, or mucous membrane inflammation.The global incidence of allergic disorders is substantial, with nearly 30% of the world's population experiencing one or more forms of allergic conditions.Clemens von Pirquet devised the word, "allergy" in the early 1900s.It refers to a group of diseases, such as allergic rhinitis, atopic dermatitis, asthma, food allergy, drug allergy, and anaphylaxis, a potentially fatal systemic response caused by mast cells (MCs) (Sikdar et al., 2023).MCs are a component of the innate immune system and play a pivotal role in acute allergic and inflammatory reactions by discharging inflammatory mediators such as histamine, cytokines, chemotactic factors, proteases, and arachidonic acid metabolites (AAMs), which act on a variety of inflammatory cells (Civelek et al., 2022).
Secondary plant substances, such as RESV, are natural compounds that have gained attention as potential nutraceuticals.
Furthermore, in vitro and in vivo studies have demonstrated its antiallergic effects (Chen et al., 2020;Zhang et al., 2019).In a research study, the effect of RESV on mast cells was investigated in vivo using ovalbumin-induced allergic enteritis and experimental colitis in IL- (IL-4), and leukotriene C4 (LTC4).Additionally, there was a reduction in the number of inflammatory cells, including leucocytes, eosinophils, lymphocytes, and neutrophils, as well as a decrease in the secretion of various cytokines, such as tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-5 (IL-5), interleukin-13 (IL-13), and interleukin-17 (IL-17).The data presented in this study offer compelling evidence for the possible use of RESV as a therapeutic agent for the management of allergic rhinitis (Li et al., 2020).

| Antidiabetic potential
Diabetes mellitus is classified as a persistent metabolic condition characterized by elevated levels of blood glucose.This condition arises from impaired insulin function and/or secretion, occurring during periods of fasting as well as after meals (Faisal et al., 2022).
Extensive research has been conducted on the antidiabetic effects of RESV in both human and animal models with diabetes.It has been observed that by enhancing glucose metabolism and increasing insulin sensitivity, RESV may aid in lowering blood sugar levels (Hoca et al., 2023).The potential for managing diabetes mellitus using RESV, either in combination with antidiabetic medications or as a standalone treatment, is noteworthy.glucose and HbA1c levels.Furthermore, this combination of factors also mitigated lipid abnormalities and the subsequent increase in atherogenic indicators (Tamimi et al., 2023).
The objective of another study project was to assess the potential of RESV to induce favorable modifications in the Goto-Kakizaki

| Anti-obesity potential
The global prevalence of obesity has reached epidemic proportions, with a steady increase observed annually.The observed phenomenon is strongly associated with a decrease in physical activity and the adoption of bad dietary practices driven by the process of modernization.Obesity significantly contributes to the development and advancement of metabolic syndrome within the human body (Faisal et al., 2022).The aim of this study was to examine the potential correlation between the anti-obesity properties of RESV and alterations in the gut microbiota and metabolic processes.The research findings indicated that the administration of RESV resulted in positive changes in the composition and function of the gut microbiota, as well as improvements in the oxidative status of the intestinal tract.These effects suggested that RESV may have prebiotic properties that can impact the overall health of the host.Furthermore, it was observed that RESV underwent biotransformation by gut bacteria, resulting in the production of 3-hydroxyphenyl propionic acid and 4-hydroxyphenyl acetic acid.These metabolites were found to possess the ability to mitigate fat storage (Wang et al., 2020).

Carpéné et al. conducted a study to examine the potential of
RESV to restrict glucose utilization within the gut-adipose tissue axis.
The study revealed that RESV demonstrated a higher level of inhibitory efficacy against α-glucosidase compared to pancreatic lipase activity.The administration of RESV resulted in a fast attenuation of glucose transport in fully developed adipocytes, achieved by antagonizing the actions of insulin and insulin-like lipogenic substances.
In a time frame of two hours, it demonstrated that RESV effectively hindered the process of glucose integration into lipids within adipocytes.Notably, this inhibitory effect remained unchanged even when the depletion of membrane cholesterol was taken into consideration (Carpéné et al., 2019).A comprehensive review incorporating meta-analysis was conducted to examine the impact of RESV on weight loss.RESV leads to a considerable reduction in body weight, body mass index (BMI), waist circumference, and fat mass (Tabrizi et al., 2020).

| Anticancer potential
Cancer poses the most severe threat to human life and well-being, ranking as the second most deadly ailment after cardiovascular disease.Globally, cancer accounts for approximately 16% of all deaths.
Regrettably, all currently available anticancer medications have exhibited limitations, including resistance and unwanted effects.
Hence, it is imperative to devise novel anticancer medications that have been meticulously refined.RESV has generated significant interest as a potential and versatile anticancer medication due to its potential use in chemotherapy and chemoprevention for several types of cancers (Ahmadi & Ebrahimzadeh, 2020).
By comparing the effects of RESV on normal cell lines and cancer cell lines, Wu et al. found that RESV had a higher level of toxicity against cancer cells.RESV can induce apoptosis in cancer cells, and this impact is influenced by the duration and dosage of the treatment.Following an extensive analysis of transcriptome sequencing data, a total of 330 genes exhibiting substantial differences from each other were identified.Out of these genes, 103 genes were identified as being upregulated, while 227 genes were identified as being downregulated.Analysis of the transcriptome and quantitative real-time PCR data revealed that the administration of RESV led to a substantial alteration in the expression of numerous genes linked to the cell cycle.The modifications in the stages of the cell cycle at different time intervals after treatment with RESV were revealed through further inquiry.It was determined that the cells were arrested in the S phase as evidenced by a rise in the proportion of cells in the S phase and a decrease in the proportion of cells in the G1/G0 phase.RESV can effectively hinder the growth of 4T1 cancer cells by impeding the cell cycle and inducing apoptosis (Wu et al., 2019).
To examine the impact and underlying mechanism of RESV on In addition, administration of oral RESV at a dosage of 100 mg/kg/ day in a mouse model of melanoma showed significant inhibition of tumor growth by effectively reducing the expression of surviving (Habibie et al., 2014).The prostate cancer cell lines PC3 and DU145 exhibited a decline in their ability to store Ca 2+ in the endoplasmic reticulum (ER) and a decrease in store-operated Ca 2+ entry (SOCE) when treated with 100 μM RSV for 24 h.Consequently, ER stress was triggered, leading to autophagic cell death (Selvaraj et al., 2016).

Li et al. demonstrated that RESV can hinder the proliferation of
HeLa cells and enhance apoptosis by acting through the intrinsic and p53 pathways.The researchers showed that when HeLa cells were treated with a concentration of 20 μmol/L of RESV, it caused the activation of caspase −3 and −9, an increase in BAX levels, and a decrease in the production of Bcl-XL and Bcl-2 proteins.Furthermore, cells that had been subjected to RESV exhibited elevated levels of the protein p53 (Li et al., 2018).Liu et al. conducted a separate investigation that showed RESV's capacity to hinder the survival of colorectal cancer cells and enhance the expression of p53 and its target genes, including BAX and PUMA.These genes play a crucial role in p53-dependent apoptosis.Furthermore, it was discovered that cells subjected to RESV treatment had augmentation in the expression of SET domain-containing lysine methyltransferase 7/9 (SET7/9), a protein that positively regulates p53 (Liu et al., 2019).
Another research study was conducted to ascertain whether MCF-7 cells, which were treated with RESV before being exposed to heat or radiotherapy, were more prone to undergoing apoptosis.
Various doses of RESV were administered to MCF-7 cancer cells to achieve an IC50% result.Subsequently, the cells exposed to the specific concentration of RESV were then exposed to either radiation or heat.The viability of MCF-7 cells may be reduced when they are subjected to either irradiation or heat.In terms of additional details, there was an increase in the regulation of the Bax and caspase genes, whereas the expression of the Bcl-2 gene dropped.The addition of RESV greatly enhanced the impact of radiation and heat on MCF-7 cells.According to the findings of this study, RESV can activate the regulation of genes that promote cell death and decrease the viability of MCF-7 cells (Amini et al., 2021).

| RE S V AND G UT MI CROB I OTA
RESV's limited absorption has led to the belief that its possible therapeutic benefits are attributed to its interaction with the gut.There is a notion suggesting that RESV may exert its health benefits by altering the composition of the gut microbiota as several mechanisms have been proposed to explain this phenomenon (Bird et al., 2017).
The ingestion of RESV has been found to cause changes in the gut microbiota and enhance glucose homeostasis in obese and diabetic mice (Chaplin et al., 2018).In another study, it was postulated that RESV possesses antiobesity advantages, mostly through the modulation of gut microbiota, leading to enhanced fat storage and metabolism.After administering RESV, the gut microbes, as well as glucose and lipid metabolism, are examined in live mice that were given a high-fat diet factor through its physiological actions (Qiao et al., 2014).
The study conducted by Most et al. examined the impact of RESV and epigallocatechin-3-gallate supplementation on the microbiota composition in the human gut.The researchers found that administering a supplement containing RESV and epigallocatechin-3-gallate concurrently for a duration of twelve weeks had the potential to significantly decrease the abundance of Bacteroidetes and exhibited a tendency to decrease the abundance of Faecalibacterium prausnitzii in overweight individuals.Nevertheless, the same patterns were not observed in females (Most et al., 2017).Sung and colleagues discovered that administering RESV to obese mice has the potential to reduce the prevalence of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia, while simultaneously increasing the prevalence of Bacteroides and Parabacteroides (Sung, Byrne, et al., 2017).
Furthermore, the improved regulation of glucose levels, resulting from the transfer of fecal matter from healthy mice treated with RESV, gave further proof that the modification of the gut microbiota was the cause of the compound's antidiabetic effects (Sung, Kim, et al., 2017).
Several research studies have also reported the effect of gut microbiota on RESV, that is, its bioconversion.Etxeberria et al. employed liquid chromatography (LC) in conjunction with high-resolution mass spectrometry (MS) to detect and analyze the microbial metabolites found in the fecal samples of Wistar rats that were given trans-RESV as a supplement.Two primary metabolites, dihydro RESV and lunularin, were identified in these samples (Etxeberria et al., 2015).
Bode and colleagues conducted controlled intervention research to investigate the bioconversion of trans-RESV by the human gut flora.
The subjects consisted of individuals in good health who received a single oral administration of 0.5 mg.In addition, the team performed in vitro fermentation studies.LC-ultraviolet-MS/MS detection revealed the presence of three metabolites: dihydroresveratrol, lunularin, and 3,4-dihydroxy-trans-stilbene (Bode et al., 2013).

| NANOPARTICLE S -BA S ED RE S V DELIVERY
The science of nano-delivery systems is rapidly developing and involves the use of nanoscale materials to provide diagnostic tools and therapeutic agents in a controlled manner to specific targeted sites (Patra et al., 2018).The field of nanotechnology exhibits considerable promise due to its capability to enhance the stability and solubility of naturally insoluble or less soluble materials.Additionally, the enhancement of oral bioavailability of the composites can be achieved by the promotion of their stability within biological systems (De Vries et al., 2018).Nanotechnology enhances the bioavailability of RESV by reducing the compound's size to the nanoscale.This reduction in size leads to an increased surface area of the compound, allowing for more efficient interaction with biological processes.
Nanoparticles can protect RESV from degradation and metabolism, hence enhancing its targeted delivery.Furthermore, nanoparticles can be manipulated to control the discharge of RESV, leading to a sustained therapeutic impact.The utilization of nanotechnology in the administration of RESV enhances the bioavailability of the substance, mostly as a result of the synergistic impact of these components (Gowd et al., 2022).
As an artificial vesicle with nanometer particle sizes and biocompatible nature, liposomes are a promising delivery system for drug delivery, allowing for increased drug solubility and bioavailability due to their size, amphiphilic nature, and biocompatibility (Yao et al., 2020).As shown in Figure 3, RESV has been delivered through different kinds of nanoparticles to obtain positive health outcomes.
In addition to maintaining an intact membrane structure during digestion, RESV-Liposomes were also capable of replicating intestinal conditions during hydrolysis.Furthermore, RESV-LPS digests exhibited higher efficiency of cellular absorption and reduced ROS when compared with free RESV in the Caco-2 cell uptake study (Xu et al., 2023).Different applications of RESV in nano-encapsulation are presented in Table 2.A study found that RESV loaded in liposomes was released at slower rates than free RESV at pH 6.8 and pH 7.4, suggesting that its prolonged release profile could be enhanced by encapsulation.However, the pH 6.8 condition resulted in a significantly longer release than the pH 7.4 condition.According to this outcome, the liposomal formulation of RESV is useful in an acidic environment within the microenvironment compartment of the tumor (Dana et al., 2022).
Mesoporous silica nanoparticles (MSNs) possess a variety of beneficial morphological characteristics, including extensive precise surface area and pore volume, symmetrical shapes and sizes, colloidal stability, abundant surface chemistry, and a high dispersion (Kankala et al., 2020).Their distinctive structural characteristics make it easier to load the drug and then deliver it in a controlled manner to the target site (Mehmood et al., 2017).The RESV loading in MSN facilitated its amorphous transformation, which is a desired outcome aimed at enhancing the drug's solubility (Marinheiro et al., 2021).The antitumor impact of RESV-loaded MSN indicated that they had a more effective anticancer effect than RESV alone treatment on gastric cancer therapy both in vivo and in vitro (Lin et al., 2021).RESV-loaded MSN particles inhibited breast cancer progression more effectively than RESV alone by hindering the NF-κB signaling pathway, indicating that MSN-RESV can be used as adjuvant management for breast cancer with an improved efficacy.
Phytochemicals can be used as a safe and new adjuvant treatment method to treat breast cancer, which is a very promising way of using phytochemicals in combination treatment (Gu & Fei, 2022).
By facilitating targeted delivery to specific tissues, polymeric nanoparticles have enormous potential to improve treatment efficacy.A biodegradable polymer could be used as a nanocarrier, as its properties can be intended to degrade in physiological conditions, and it can be engineered to exhibit prompted functionality when activated by an external source or at a particular site (Karlsson et al., 2018).Among these polymers, polyethylene glycol (PEG) and polylactic acid (PLA) were identified as harmless and practical F I G U R E 3 An overview of RESV sources, applications, and the types of nanoformulations used to deliver it, and their certain health benefits.elements for developing nano-delivery systems and have received FDA approval for clinical usage (Mahapatro & Singh, 2011).A dosedependent suppression of CT26 colon cancer cell proliferation by RESV-loaded polymeric nanoparticles was demonstrated in sulforhodamine B (SRB) assays, whereas minimal effects were found from empty polymeric nanoparticles.As a result of treatment with 20 and 40 mM of RESV-encapsulated polymeric nanoparticles, the colony formation capacity of CT26 cells was significantly inhibited and apoptotic cell death was induced.The potential for inhibiting colony development and triggering apoptosis was even greater than that of free RESV (Jung et al., 2015).Studies on the pharmacokinetics and brain distribution in mice showed that polymeric nanoparticles considerably enhanced the bioavailability of paclitaxel and RESV polymeric nanoparticles compared to pure paclitaxel and RESV (Hussain et al., 2021).

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research investigation was conducted to assess the efficacy of two newly discovered analogs of RESV, specifically 4-(E)-(p-tolylimin o)-methylbenzene-1,2-diol (TIMBD) and 4-(E)-(4-hydroxyphenylimin o)-methylbenzene-1,2-diol (HPIMBD), in terms of their antioxidative properties in relation to breast cancer.Both of these chemicals are commonly referred to as HPIMBD and TIMBD.Based on the results Downregulation of inflammatory responses is one of RESV's potential protective mechanisms as shown in Figure2.Through downregulation of the toll-like receptors (TLR-4), NF-κB, signal transducers and activators of transcription (STAT) signaling pathway, RESV exhibits anti-inflammatory action both in vitro and in vivo compared to prompted microglial activation.By inhibiting these multiple mechanisms, RESV reduces the inflammation in rat models.Anti-inflammatory properties of RESV include suppressing p38-MAPK and NF-κB pathways and lowering the serum levels of tumor necrosis factor-alpha (TNFα), IL-1, and IL-6, which are primarily responsible for its positive benefits(Hsu et al., 2021).RESV was found to have a potent anti-inflammatory effect in cell culture studies by reducing the synthesis of prostaglandin E2 (PGE2), TNFα, NO, IL-1, and IL-6, encouraging the release of IL-10, repressing the TLR4 expression, and preventing the initiation of extracellular signal-regulated protein kinases 1 & 2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and MAPK(Liu et al., 2020).Additionally, RESV blocks the activity of cyclooxygenases (COX), through which arachidonic acid converts to prostaglandins.As a result of this pathway's regulation, inflammation is reduced, raising the prospect that RESV may be used to treat inflammatory diseases(Berman et al., 2017).Inflammatory response plays a significant role in the progression of acute kidney injury (AKI)(Inoue et al., 2017).Pro-inflammatory cytokines (TNFα, IL-1, IL-6, and IL-18) play an important role in the development and progression of ischemic AKI (Sharfuddin & F I G U R E 2 RESV and inflammatory parameters.Numerous cell signaling pathways are activated by inflammation.RESV directly inhibits the phosphoinositide 3-kinases (PI3K)/Akt, mitogen-activated protein kinases (MAPKs) signaling pathways which lead to NF-κB activation that stimulate the production of several inflammatory markers.It suppresses the activation of NF-κB directly through the facilitation of the degradation and phosphorylation of IκBα, one of the proteins associated with IκB.A downregulation of Janus kinase (JAK) is one of the effects of RESV on signal transducers and activators of transcription (STAT) protein phosphorylation and activation.The overall STAT signaling pathway could potentially be impacted by resveratrol by suppressing the activation of JAKs or other signaling molecules upstream of STAT proteins.Molitoris, 2011).Studies showed a substantial correlation between RESV and decreased levels of IL-1, and IL-6.Clinical medications depend heavily on the effects of dose and time response.No animal studies on the dose-response and time-response effects of RESV in the treatment of AKI were reported(Cao et al., 2022).To reduce AKI induced by sepsis in a rat model, RESV upregulated SIRT1 expression, reduced the release of inflammatory molecules, and promoted NF-κB-P65 deacetylation(Gan et al., 2017).The treatment with RESV inhibited the intercellular adhesion molecule 1 (ICAM-1), IL-1, iNOS, and mRNA expression in human coronary arterial endothelial cells stimulated by TNFα, was one of the results of numerous in vitro studies that demonstrated the antiinflammatory effects of RESV in cardiac tissue(Huang et al., 2017).RESV's anti-inflammatory potential on CVDs attributed to several mechanisms, including reduction of monocyte adhesion to endothelial cells, suppression of NF-кB and JAK (Janus kinase)/STAT signal pathways, upregulation of anti-inflammatory cytokines, and inhibition of the production of pro-inflammatory mediators like TNFα, IL-1, and IL-6(Gal et al., 2021).Additionally, RESV administration for eight weeks was cardioprotective against myocardial infarction in rats inoculated with isoproterenol, a robust sympathetic agent.
phosphatidylinositol 3-kinase (PI3K)/Akt and Nrf2 pathways and inhibit NF-κB and p38 MAPK(Bobermin et al., 2019).Espinoza et al. investigated  the influence of RESV on immunological cells. 1 g of RESV capsules were given daily to nine healthy men and women for twenty-eight days.The outcomes of the research indicated that the administration of RESV directed to an elevation in the number of T cells present in the bloodstream, eventually resulting in a reduction in the levels of TNFα and monocyte chemoattractant protein 1, which are both pro-inflammatory cytokines found in the plasma.Additionally, RESV increased plasma antioxidant capacity and subsequently reduced DNA damage-causing OS markers(Espinoza et al., 2017).According to research, the treatment of RESV in a Crohn's disease (CD) rat model reduced inflammation and attenuated fibrosis.With the downregulation of insulin-like growth factor 1 (IGF-1) and procollagen mRNA expression, RESV significantly decreased the expression of inflammatory cytokines (IL-1, IL-6, and TNFα), profibrotic factors like transforming growth factor beta (TGF-β1)(Rahal et al., 2012).Chronic obstructive pulmonary disease (COPD) is pathogenetically influenced by inflammation.RESV was administered by oral gavage to ten Wistar rats for 20 days (50 mg/kg) prior to smoking.Following a 30-day investigative study, the researchers observed a reduction in inflammation and a reconstructed appearance of the small airways in the lungs.Treatment with RESV reduced IL-6 and IL-8 serum levels.The SIRT1/peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) signaling pathways may have been activated and upgraded as part of the mechanism(Wang 10 −/− mice.RESV was administered to the mice via drinking water, and its effects were analyzed.The research discovered that RESV demonstrated inhibitory effects on the process of IgE-dependent degranulation and the expression of pro-inflammatory cytokines, including TNFα, in both IgE/2,4-dinitrophenyl (DNP)-activated and LPS-activated mast cells generated from bone marrow.The results of this study indicate that RESV has anti-allergic and anti-inflammatory properties and could be beneficial in the prevention or treatment of ailments linked with mast cells(Bilotta et al., 2022).Allergic rhinitis is a type I hypersensitivity reaction mediated by IgE in the nasal passages.ROS production is a key process in which thioredoxin-interacting protein (TXNIP) plays a vital role.RESV is a known inhibitor of TXNIP, and therefore, Zhang et al. aimed to investigate the effect and mechanism of RESV on an ovalbumin-induced mouse model of allergic rhinitis.The study revealed significant changes in sneezing, nasal rubbing, inflammatory cytokine levels, eosinophil counts, TXNIP expression, and the levels of OS markers such as malondialdehyde and superoxide dismutase in RESV-treated mice compared to untreated allergic rhinitis mice.The findings suggest that RESV may effectively alleviate allergic rhinitis by inhibiting the TXNIP-mediated OS pathway (Zhang et al., 2020).Zhang et al. provided evidence that RESV exhibited a reduction in the discharge of β-hexosaminidase and histamine within rat basophilic leukemia-2H3 cells.These observations implied that RESV mitigated these reactions through a dual mechanism, involving the downregulation of serum ovalbumin-specific IgE, histamine, mouse mast cell proteinase, and the depletion of dendritic cells, B cells, and mast cells in the spleen or mesenteric lymph node (Zhang et al., 2019).The investigation conducted by Li et al. examined the possible protective properties of RESV against allergic rhinitis and elucidated the associated signaling pathways.The formation of an effective mouse model of allergic rhinitis was achieved by administering ovalbumin by intraperitoneal injection.The animals were administered different doses of RESV (5, 30, and 50 mg/kg) via their dietary intake.Based on the results, it was observed that therapy involving RESV exhibited a reduction in the frequency of sneezing and nasal rubbing in mice afflicted with allergic rhinitis.Consequently, there was a decrease in the synthesis of histamine, ovalbumin-specific immunoglobulin E (IgE) and immunoglobulin G1 (IgG1), interleukin-4

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GK) rat, a naturally occurring model of diabetes that exhibits certain similarities to individuals with type 2 diabetes.GK rats were administered RESV orally at a dosage of 20 milligrams per kilogram of body weight every day for a duration of 10 weeks.Subsequently, an assessment of the patient's glucose tolerance was conducted.The implementation of RESV administration resulted in enhanced glucose tolerance, decreased fat formation in skeletal muscle, notable improvement in the morphology of pancreatic islets, and partial restoration of adiponectin and leptin levels in the bloodstream.Based on the results obtained from the study, the administration of RESV to GK rats exhibited a significant decrease in the prevalence of key indicators associated with diabetes(Szkudelska et al., 2019).The study conducted byMovahed et al. aimed  to assess the effectiveness of RESV in reducing hyperglycemia among individuals diagnosed with type 1 diabetes.A total of 13 patients diagnosed with Type 1 Diabetes, comprising individuals of both genders, took part in this clinical trial.Each patient was administered 500 mg capsules of RESV, twice daily, for a duration of 60 days.The findings of the study revealed that the administration of RESV for a duration of 60 days led to a noteworthy reduction in fasting blood glucose and hemoglobin A1c levels when compared to the initial measurements(Movahed et al., 2020).
Research conducted on animals has demonstrated that RESV can replicate the physiological consequences of calorie restriction by activating a protein called SIRT1.SIRT1 is a significant contributor to the control of cellular energy balance and the generation of new mitochondria.Previous research conducted on rodents has demonstrated the advantageous impacts of RESV administration on various physiological aspects, including mitochondrial function, glucose metabolism, body composition, and liver fat storage (de Ligt et al., 2015).The study conducted by Wang et al. explored the potential of RESV as an anti-obesity agent in mice that were fed a high-fat diet.

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Negative Breast Cancer (TNBC) cells, Liang et al. employed RNA sequencing (RNA-seq).The data demonstrated a consistent decline in the survival rate of MDA-MB-231 cells with increasing concentration of RESV treatment.The RNA-seq investigation demonstrated that the RESV medication largely affected genes involved in apoptosis and the p53 signaling pathway.Moreover, it was shown that POLD1 served as the principal agent of apoptosis in MDA-MB-231 cells subjected to the influence of RESV.The expression levels of full-length PARP1, PCNA, and BCL-2 were significantly decreased upon treatment of the cells with RESV.Conversely, there was a considerable increase in the levels of Cleaved-PARP1 and Cleaved-Caspase3 expression.The results of animal investigations have demonstrated that RESV has a significant inhibitory impact on the formation of live malignancies.The study's findings suggest that RESV has the potential to trigger apoptosis in TNBC cells by suppressing the expression of POLD1, hence activating the apoptotic pathway (Liang et al., 2021).After being exposed to 100 μM of RSV for 24-72 h, this specific process resulted in the release of cytochrome c and caspase activators derived from mitochondria.Additionally, it caused the activation of caspases and the stimulation of calpain, a protease that is activated by calcium.Ultimately, this process led to the demise of breast cancer cells via apoptosis (Madreiter-Sokolowski et al., 2017).Jin et al. conducted a study to assess the effects of RESV and doxorubicin (DOX) on epithelial-mesenchymal transitions (EMTs) and chemoresistance in MCF-7/ADR breast cancer cells that had developed resistance to adriamycin (ADR).The researchers successfully showed that the combination of RESV and DOX had a significant impact on suppressing the proliferation and spread of MCF-7/ ADR cells.By promoting the expression of silent mating type information regulation 2 homolog 1 (SIRT1) and modulating the SIRT1/βcatenin pathway, RESV can reverse the EMT process in MCF-7/ADR cells.The upregulation of ubiquitin-mediated proteolysis facilitated the degradation of β-catenin by promoting the activity of increased SIRT1 (Jin et al., 2019).Habibie et al. discovered that RESV triggers apoptosis in both murine and human melanoma cells, leading to detrimental effects on these cells.The stimulatory action of RESV on apoptosis of cells was attributed to the inhibition of survivin.RESV effectively decreased survivin expression at the transcriptional level by regulating the STAT3/β-catenin pathway, employing a mechanistic method.
Cai et al. investigated  the potential of RESV to regulate the composition of the gut microbiome, intestinal barrier dysfunction, and the inflammatory response in the genetic db/db mice model.The aim was to identify if RESV has any beneficial effects in preventing diabetic nephropathy.RESV enhanced the functionality of the intestinal barrier, while also decreasing intestinal permeability and inflammation.The gut microbiota composition in db/db persons was found to be significantly distinct from that of the control group of db/m mice(Cai et al., 2020).

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HF).When given to HF mice at a dosage of 200 milligrams per kilogram per day, RESV significantly reduces both body and visceral adipose weights, as well as lowers blood glucose and cholesterol levels.RESV can mitigate the imbalance of the gut microbiota induced by the high-fat diet by increasing the proportion of Bacteroidetes compared to Firmicutes, which leads to a significant decrease in the proliferation of Enterococcus faecalis while promoting the growth of Lactobacillus and Bifidobacterium.Furthermore, RESV has been demonstrated to significantly increase the fasting-induced adipose Zhang et al. synthesized PEGylated nano-liposomes for the simultaneous delivery of docetaxel (Doc) and RESV.This study aimed to assess the efficacy of combined drugs in the treatment of prostate cancer.Animal studies revealed that the co-encapsulation of Doc/Res in liposomes significantly decreased tumor growth in PC3bearing Balb/c nude mice.This was evidenced by alterations in the parameters of cellular growth and apoptosis(Zhang et al., 2022).Rapamycin (RAP) and RESV coloaded liposomes (RAP-RSV-LIP)were developed as potential therapies for breast cancer.In vitro experiments revealed that RAP-RSV-LIP was infused in an estrogen receptor-positive human breast cancer cell line (MCF-7) at a rate of 34.2%.Furthermore, it exhibited enhanced cytotoxicity relative to free medications (DosReis et al., 2023).7 | CON CLUS I ON AND FUTURE DIREC TIONSResveratrol (RESV) demonstrates promising health benefits, particularly its antioxidant and anti-inflammatory effects, as supported by clinical trials.Its ability to combat OS and inflammation suggests its potential in the prevention and management of several diseases.Nonetheless, RESV has shown significant attributes as a multimodal curative substance in promoting health and preventing chronic illnesses.RESV has been suggested to possess potential protective properties against various chronic ailments, including diabetes, CVDs, cancer, obesity, metabolic syndrome, kidney disorders, and Alzheimer's disease.The targeted delivery of RESV through nanoparticles has been utilized to address these ailments by targeting different inflammatory and oxidation pathways, immunomodulation, and neuro and cardiovascular protection.An additional comprehensive clinical study is necessary to validate the therapeutic advantages of RESV and ascertain its optimal dosage, potential long-term consequences, and safety profile in various health conditions.It is highly recommended that both researchers and clinicians strengthen their attention to advancing targeted investigations, with a particular focus on novel nanodelivery systems, to further improve the therapeutic effectiveness of resveratrol and make significant contributions to the field of health.Further investigation is necessary to elucidate the underlying processes accountable for the effects of RESV and to refine the administration protocols for certain contexts.Trial-based advanced research is required in combinational nano-delivery of RESV for the best possible health outcomes.
(Xia et al., 2017)ly traverse mitochondrial membranes and disperse into the cytoplasm.Notably, treatment with RESV results in reduced cytoplasmic levels of H 2 O 2 .This could be due to enhanced H 2 O 2 detoxification by GPx1 within the mitochondria and/or increased H 2 O 2 inactivation by GPx1 and catalase in the cytoplasm.RESV possesses the capacity to enhance the activity of both antioxidant enzymes(Xia et al., 2017).
Tamimi et al. intendedto investigate the potential synergistic effects of combining RESV and pioglitazone (PGZ) in the treatment of streptozotocin (STZ)induced diabetes.The findings of the study demonstrate that the combination of PGZ + RESV delivered the most favorable outcomes, as evidenced by statistically significant reductions in fasting blood Application of RESV in Nano-encapsulation.
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