Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico-Chemical Properties.

The targeted compounds in this research, resveratrol analogs 1-14, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 µM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

Computation-guided asymmetric total syntheses of resveratrol dimers.

Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (-)-malibatol A, (-)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (-)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.

Imine resveratrol analogs (IRAs): The strong antioxidant that can protect lymphocytes from oxidative damage.

Imine resveratrol analogs (IRAs) are promising new agents that can have higher positive effects and, simultaneously, lower negative properties than resveratrol. In this study, three imine hydroxy derivatives (2-((4-hydroxyphenylimino) methyl) phenol [IRA1], 3-((4-hydroxyphenylimino) methyl) phenol [IRA2], and 4-((4-hydroxyphenylimino) methyl) phenol [IRA3]) were prepared and tested in several biological assays. They performed superior to resveratrol in several antioxidant and biological assays, showing high antioxidant capacity and low genotoxicity. Ferric reducing antioxidant power assay (FRAP) and hydroxyl radicals scavenging assay revealed good Fe3+ to Fe2+ reduction and strong inhibition of hydroxyl radical formation, respectively. High dosage (1 mmol/dm3 ) of IRA2 and IRA3 did not cause genotoxicity in human lymphocytes. Moreover, lymphocytes pretreated with all three IRAs accumulated only very few DNA breaks induced by H2 O2 than lymphocytes pretreated with resveratrol. Additionally, the number of detected DNA breaks appearing after removal of damaged DNA bases, 8-oxo-7,8-dihydroguanine (8-oxoG), did not dramatically increase in lymphocytes treated with IRA2. Thus, we concluded that IRAs, especially IRA2, are strong antioxidants with the ability to protect lymphocytes from oxidative damage.

Formulation design, optimization and in vivo evaluation of oral co-encapsulated resveratrol-humic acid colloidal polymeric nanocarriers.

The study aims at formulation and optimization of resveratrol and humic acid co-encapsulated colloidal polymeric nanocarriers to improve stability, oral bioavailability, and antiradical activity of water-insoluble, resveratrol. The eudragit E100 polymeric material was used to fabricate resveratrol and humic acid co-encapsulated oral colloidal polymeric nanocarriers (Res-HA-co-CPNs) using emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for oral bioavailability as well as for antiradical potential. Optimized Res-HA-co-CPNs demonstrated spherical and smooth surface including mean particle size, 120.56 ± 18.8 nm; polydispersity index, 0.122; zeta potential, +38.25 mV; and entrapment efficiency, 82.37 ± 1.49%. Solid-state characterization confirmed the amorphous characteristic of optimized Res-HA-co-CPNs. In vitro release profile of Res-HA-co-CPNs showed sustained release behavior up to 48 h and CPNs were found to remain stable at the refrigerated condition for 6 months. In vivo pharmacokinetic studies revealed significant (p < 0.05) improvement of ∼62.76-fold in oral bioavailability. The radical-scavenging activity was found to be increased with time and after 72 h, it was analogous to pure Res. IC50 values were reported to be decreased with time. Henceforth, developed Res-HA-co-CPNs was proven to be a proficient dosage form to increase stability, oral bioavailability, and antiradical activity of resveratrol.HighlightsResveratrol-humic acid co-encapsulated colloidal polymeric nanocarriers (Res-HA-co-CPNs) were fabricated by emulsification-diffusion-evaporation method and optimized by Taguchi orthogonal array design.The Res-HA-co-CPNs revealed favorable mean particle size and percent encapsulation efficiency with a spherical and smooth surface.The Res-HA-co-CPNs showed diffusion-controlled release of Res and were found to be stable at the refrigerated condition for 6 months.The optimized Res-HA-co-CPNs demonstrated significantly (p < 0.05) higher oral bioavailability with respect to pure Res and PM.The optimized Res-HA-co-CPNs demonstrated higher radical-scavenging activity with respect to time.

Design and identification of two novel resveratrol derivatives as potential LSD1 inhibitors.

Background: Overexpression of LSD1 is associated with the occurrence of many diseases, including cancers, which makes LSD1 a significant target for anticancer drug research. Methodology & Results: With the aid of 3D quantitative structure-activity relationship models established with 34 reported resveratrol derivative LSD1 inhibitors, derivatives 35-40 were designed. Absorption, distribution, metabolism and excretion calculations showed that they may have good bioavailability and drug likeness. Additionally, 35 and 37 presented good antitumor effects in an in vitro antiproliferative assay. Molecular docking and molecular dynamics simulation results indicated that 35 and 37 can establish extensive interactions with LSD1. Conclusion: The results of computational prediction and experimental validation suggest that 35 and 37 are effective antitumor inhibitors, which provides some ideas and directions for the development of new anticancer LSD1 inhibitors.

New Hybrids Based on Curcumin and Resveratrol: Synthesis, Cytotoxicity and Antiproliferative Activity against Colorectal Cancer Cells.

We synthesized twelve hybrids based on curcumin and resveratrol, and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, along with the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 3e and 3i (for SW480) and 3a, 3e and 3k (for SW620) displayed the best cytotoxic activity with IC50 values ranging from 11.52 ± 2.78 to 29.33 ± 4.73 µM for both cell lines, with selectivity indices (SI) higher than 1, after 48 h of treatment. Selectivity indices were even higher than those reported for the reference drug, 5-fluorouracil (SI = 0.96), the starting compound resveratrol (SI = 0.45) and the equimolar mixture of curcumin plus resveratrol (SI = 0.77). The previous hybrids showed good antiproliferative activity.

Microparticle prepared by chitosan coating on the extruded mixture of corn starch, resveratrol, and α-amylase controlled the resveratrol release.

Microcapsule was developed by chitosan coating on the microparticle which was prepared by smashing the extruded mixture of corn starch, resveratrol, and α-amylase. In the preparation process, the low-temperature extrusion and α-amylase were employed to overcome the disadvantages of low gelatinization, dissolution, and poor hydration of extruded starch. Chitosan-coating retarded starch aging, improved the stability of microcapsules, delayed the release of resveratrol. Considering the bioactive functions of chitosan, microcapsules also obtained the functions of chitosan by chitosan coating. The chitosan coating and α-amylase addition improved the release ratio of resveratrol. CESRA (chitosan solution (2%) coating on the extruded mixture of corn starch, resveratrol, and α-amylase) released 86.8% resveratrol at 25 °C in six days chasing, and 85.3% resveratrol at 37 °C in 48 h chasing. Chitosan coating slightly improved the free radical scavenging activity of ABTS+. The particle size variation, SEM, XRD, and FT-IR were also employed to investigate the variation of morphology, crystal structure, and chemical composition.

Poly(Vinyl Alcohol) Cryogel Membranes Loaded with Resveratrol as Potential Active Wound Dressings.

Hydrogel wound dressings are highly effective in the therapy of wounds. Yet, most of them do not contain any active ingredient that could accelerate healing. The aim of this study was to prepare hydrophilic active dressings loaded with an anti-inflammatory compound - trans-resveratrol (RSV) of hydrophobic properties. A special attention was paid to select such a technological strategy that could both reduce the risk of irritation at the application site and ensure the homogeneity of the final hydrogel. RSV dissolved in Labrasol was combined with an aqueous sol of poly(vinyl) alcohol (PVA), containing propylene glycol (PG) as a plasticizer. This sol was transformed into a gel under six consecutive cycles of freezing (-80 °C) and thawing (RT). White, uniform and elastic membranes were successfully produced. Their critical features, namely microstructure, mechanical properties, water uptake and RSV release were studied using SEM, DSC, MRI, texture analyser and Franz-diffusion cells. The cryogels made of 8 % of PVA showed optimal tensile strength (0.22 MPa) and elasticity (0.082 MPa). The application of MRI enabled to elucidate mass transport related phenomena in this complex system at the molecular (detection of PG, confinement effects related to pore size) as well as at the macro level (swelling). The controlled release of RSV from membranes was observed for 48 h with mean dissolution time of 18 h and dissolution efficiency of 35 %. All in all, these cryogels could be considered as a promising new active wound dressings.

The Synergistic Cytotoxic and Apoptotic Effect of Resveratrol and Naringenin on Y79 Retinoblastoma Cell Line.

BACKGROUND: Resveratrol is a phenolic natural product, which is found in red grapes and in Japanese knotweed root (Polygonum cuspidatum). Naringenin is one of the flavonoid compounds found in landing grape and other citrus fruits. Both agents exert antioxidant and anti-inflammatory properties. OBJECTIVE: In this study, the effect of Resveratrol and Naringenin in an in vitro model of retinoblastoma of the eye has been investigated. METHODS: XTT and trypan blue assays were used to evaluate the anti-proliferative/cytotixic effect of resveratrol and naringenin in Y79 cells. With the aid of AnnexinV/PI flow cytometry, the kind of cell death was investigated. To assess important gene expression levels at mRNA level involved in apoptosis, Real-time PCR was utilized. RESULTS: Naringenin and resveratrol significantly decreased proliferation and stimulated cell death (mostly apoptosis) in Y79 cells at 50 and 100 (µg/ml) after 24 and 48 hours. Additional cytotoxic effect was observed after 48 hours. Furthermore expression level of Bax and Bcl2 mRNAs altered significantly in all samples treated with 50 (µg/ml) of naringenin, resveratrol, or simultaneously with both. P21 mRNAs expression altered in all mentioned samples except those treated with 50 (µg/ml) of resveratrol. CONCLUSION: Based on the results, it can be concluded that resveratrol and naringenin can decrease cell viability in retinoblastoma cells in an in vitro dose/time-dependent manner. Albeit more studies are needed to shed the light on the mechanism of action, our data reveal a potential synergistic cytotoxic effect of naringenin and resveratrol on Y79 cells in 48 hours.

Resveratrol and other Stilbenes: Effects on Dysregulated Gene Expression in Cancers and Novel Delivery Systems.

Trans-resveratrol (RESV), pterostilbene, trans-piceid and trans-viniferins are bioactive stilbenes present in grapes and other plants. Several groups applied biotechnology to introduce their synthesis in plant crops. Biochemical interaction with enzymes, regulation of non-coding RNAs, and activation of signaling pathways and transcription factors are among the main effects described in literature. However, solubility in ethanol, short half-life, metabolism by gut bacteria, make the concentration responsible for the effects observed in cultured cells difficult to achieve. Derivatives obtained by synthesis, trans-resveratrol analogs and methoxylated stilbenes show to be more stable and allow the synthesis of bioactive compounds with higher bioavailability. However, changes in chemical structure may require testing for toxicity. Thus, the delivery of RESV and its natural analogs incorporated into liposomes or nanoparticles, is the best choice to ensure stability during administration and appropriate absorption. The application of RESV and its derivatives with anti-inflammatory and anticancer activity is presented with description of novel clinical trials.

Protective Effect of Resveratrol against Glioblastoma: A Review.

BACKGROUND: One of the most common tumors of the central nervous system is Glioblastoma (GBM). OBJECTIVE: There is not still an appropriate cure for this malignant tumor. Plant-derived natural products have demonstrated great potential in cancer therapy, and Resveratrol (Res) is among them. Therefore, the current study focused on the protective effect of resveratrol against glioblastoma and its underlying mechanism. METHODS: PubMed, Medline, Scopus, Web of Science, and Google Scholar were searched by using the following keywords: Resveratrol, Glioblastoma, Brain tumor, Cancer therapy, Medicinal herbs to July 2020. RESULTS: Res is a non-flavonoid polyphenol responsible for the protection of plants against pathogen attacks. Res has multiple pharmacological effects, including antioxidant, anti-inflammatory, anti-diabetic, and anti-tumor. Res is capable of penetration into the blood-brain barrier, making it suitable for brain tumor therapy. Besides, Res targets various molecular signaling pathways in cancer therapy. CONCLUSION: In the present review, it was found that Res administration is beneficial in GBM therapy by inhibition of proliferation, viability, and migration via modulation of molecular pathways.

Optimization and Development of Methotrexate- and Resveratrol-Loaded Nanoemulsion Formulation Using Box-Behnken Design for Rheumatoid Arthritis.

Methotrexate (MTX) is the first line of choice for the management of rheumatoid arthritis (RA) and has been reported for its low bioavailability and side effects. Combination therapy has been widely investigated to overcome bioavailability issues and to reduce adverse effects associated with monotherapy. Various phytoconstituents such as resveratrol (RSV) and curcumin have been found to possess potent anti-inflammatory activity via downregulating the signaling of cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor alpha) and nuclear factor kappa B signaling. The prime objective of this study was to develop transdermal gel containing MTX-RSV loaded nanoemulsions (NEs) to overcome bioavailability issues and adverse effects of RA monotherapy. The NEs optimized by using Box-Behnken Design were incorporated within gel, and an in vitro skin permeation study performed on rat skin by using vertical Franz diffusion cells exhibited controlled drug release up to 48 h. Subsequently, anti-inflammatory and potential anti-arthritic activities of the combination in nanocarrier were assessed in rats and showed 78.76 ± 4.16% inhibition in inflammation and better anti-arthritic effects. Consequently, integration of dual delivery with nanotechnology can hopefully produce successful therapeutic options for rheumatic diseases.

Screening of an Endophyte Transforming Polydatin to Resveratrol from Reynoutria Japonica Houtt and the Optimization of Its Transformation Parameters.

Resveratrol showed various kinds of bioactivities, such as antioxidant, antimicrobial, anticancer effects and, therefore, has been used widely as an important ingredient in medication, healthy foods and cosmetics. However, in nature, resveratrol usually exists at low content and more often exists as polydatin. Therefore, it becomes important to find the cost-effective and environmental-friendly way to transform polydatin to resveratrol. In this study, endophytes were isolated from the rhizome tissue of Reynoutria japonica and screened for transforming polydatin to resveratrol using reversed-phase high-performance liquid chromatography (RP-HPLC) and confirmed by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy. A bacterium identified as Bacillus aryabhattai using 16S rRNA phylogenetic tree analysis showed highest transformation rate. The transforming conditions were optimized including substrate concentration, substrate addition time, culture temperature and inoculation ratio. Our results demonstrated that the bacteria isolated from R. japonica rhizome tissue showed high activity in transforming polydatin into resveratrol. Crude extract of R. japonica root and rhizome (RJE) was also tested as substrate and it was found that the transformation was significantly inhibited at 10.0 mg/mL RJE. Emodin at equivalent concentration of 10.0 mg/mL RJE showed no inhibition activity, and glucose content in RJE was trace and far from enough to exhibit the inhibitory activity. Successive solvent partition followed by an inhibition activity assay revealed that the ethyl acetate fraction showed the main inhibition activity. However, due to the coexistence of polydatin and compounds with inhibitory activity, the concentration of RJE can only be used at limited concentration as substrate.

Synthesis and Characterization of Novel Resveratrol Butyrate Esters That Have the Ability to Prevent Fat Accumulation in a Liver Cell Culture Model.

To facilitate broad applications and enhance bioactivity, resveratrol was esterified to resveratrol butyrate esters (RBE). Esterification with butyric acid was conducted by the Steglich esterification method at room temperature with N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) and 4-dimethyl aminopyridine (DMAP). Our experiments demonstrated the synthesis of RBE through EDC- and DMAP-facilitated esterification was successful and that the FTIR spectra of RBE revealed absorption (1751 cm-1) in the ester region. 13C-NMR spectrum of RBE showed a peak at 171 ppm corresponding to the ester group and peaks between 1700 and 1600 cm-1 in the FTIR spectra. RBE treatment (25 or 50 µM) decreased oleic acid-induced lipid accumulation in HepG2 cells. This effect was stronger than that of resveratrol and mediated through the downregulation of p-ACC and SREBP-2 expression. This is the first study demonstrating RBE could be synthesized by the Steglich method and that resulting RBE could inhibit lipid accumulation in HepG2 cells. These results suggest that RBE could potentially serve as functional food ingredients and supplements for health promotion.

Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition.

BACKGROUND: Currently approved Alzheimer's disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. OBJECTIVE: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. METHODS: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. RESULTS: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 µM) and 12a (IC50 = 0.31 µM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced ß-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. CONCLUSION: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer's disease agents.

Resveratrol - A comprehensive review of recent advances in anticancer drug design and development.

Resveratrol is a natural polyphenolic stilbene isolated from various plants, foods and beverages with a broad spectrum of biological and pharmacological properties through modulating diverse targets and signaling pathways. Particularly, it has attracted a great deal of attention as a promising and multitarget anticancer agent due to its potential use in chemoprevention and chemotherapy of various tumors. However, unfavorable pharmacokinetics/pharmacodynamics profile such as poor bioavailability restricted its applications. Therefore, medicinal chemists have synthesized a lot of novel derivatives and analogues of resveratrol using different modification strategies to overcome these limitations and improve anticancer efficacy. Herein, we reviewed the design, synthesis, structure-activity relationship and mechanism of the most potent and privileged resveratrol-based compounds that showed promising anticancer activities in the last five years. We classified these compounds into the ten different categories based on their chemical structure similarities.

Synthesis and biological evaluation of resveratrol derivatives with anti-breast cancer activity.

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17ß-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the "A" or "B" ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment.

Finding a resveratrol analogue as potential anticancer agent with apoptosis and cycle arrest.

Resveratrol has been extensively studied as the anti-cancer agent. A variety of resveratrol analogues have been developed with structural modification to improve its bioactivity. In this work, resveratrol analogues, compound 1-4, were designed and synthesized with the Stille-Heck reaction. These results showed compound 1-4 had better anticancer effect than that of parent resveratrol. Especially compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3-methylphenol)) displayed the excellent cytotoxicity and high selectivity. The mechanism research indicated compound 1 inhibited cell proliferation by binary paths of cell cycle arrest in S phase regulated by cyclin A1/A2 and apoptosis induction mediated by Bax/Bcl2 in a prooxidant manner.

Resveratrol Counteracts Hypoxia-Induced Gastric Cancer Invasion and EMT through Hedgehog Pathway Suppression.

BACKGROUND: Gastric Cancer (GC) is one of the most malignant and lethal tumors worldwide. The hypoxic microenvironment is correlated with GC cell invasion, metastasis and Epithelial-Mesenchymal Transition (EMT). Resveratrol is a compound extracted from various plants, including grapes, berries, and some traditional Chinese medicines. Recently, the anticancer properties of resveratrol against many cancers have been reported in a range of studies. However, the exact mechanism through which resveratrol prevents GC invasion and metastasis under hypoxic conditions remains unclear. OBJECTIVE: The objective of this study is to show to what extent resveratrol could inhibit the hypoxia-induced malignant biological behavior of GC. METHODS: SGC-7901 cells were cultured in a consistent 3% O2 hypoxic condition or 21% O2 normal condition for 48 hours to establish an in vitro hypoxia model. Western blot and qRT-PCR were used to detect EMT markers of SGC- 7901 cells, including E-cadherin, HIF-1a, Vimentin, etc. Transwell Matrigel Invasion Assays were used to test the invasive ability of SGC-7901 cells. The siRNA targeting Gli-1 showed its role in hypoxia-induced EMT and invasion of SGC-7901 cells. RESULTS: Resveratrol was found to significantly decrease HIF-1α protein levels induced by hypoxia in SGC-7901 cells. HIF-1α accumulation was found to promote cell proliferation, migration, and invasive capacities in addition to EMT changes through the activation of the Hedgehog pathway. These effects were found to be reversed by resveratrol. CONCLUSION: Therefore, these data indicate that resveratrol may serve as a potential anticancer agent for the treatment of GC, even in a hypoxic tumor microenvironment.

Etiology of atherosclerosis informs choice of animal models and tissues for initial functional genomic studies of resveratrol.

Resveratrol, a phytoalexin, is a natural polyphenol synthesized exclusively by plants in response to environmental stresses. However, the molecule has also many exogenous bioactivities in animal cells. These bioactivities may lead to anti-cancer and cardio-protective health benefits. Because cellular responses to the treatment with resveratrol include the changes of expression patterns, functional genomics is an attractive tool to study them. In recent and today's experimental practice, this mostly means microarray profiling of gene expression (using RNAs isolated from bulk tissues). Herein, we review such published studies undertaken in the context of cardiovascular diseases (CVDs). CVDs are a number one public health problem in developed countries, outweighing in magnitude even cancer. In particular, we review the studies of resveratrol in several animal models relevant to CVDs. These models included: normal and pre-mature aging in mice, as well as atherogenic diet in mice / pigs / non-human primates. Additionally, there were few clinical studies published in the context of the comorbidities of atherosclerosis in humans (e.g. obesity, diabetes, hypertension). For the purposes of these studies, three types of samples were most commonly profiled with microarrays: the liver, the skeletal muscle, and peripheral blood mononuclear cells. Resveratrol-induced changes of gene expression typically mimicked those associated with calorie restriction and lifespan extension. They also opposed changes induced by the atherogenic diet. We conclude by discussing few experimental factors that were relatively neglected thus far, but which could be interesting to investigate in the future. These factors include sex and the exact formulation of resveratrol (plant extract, or synthetic chemical).