Resveratrol Isomers Research Articles

Exploring the molecular solvatochromism, stability, reactivity, and non-linear optical response of resveratrol.

This work analyzes the isomerization effects and solvent contributions to the stability, electronic excitations, reactivity, and non-linear optical properties (NLO) of resveratrol molecules within the formalism of the Density Functional Theory. The findings suggest that resveratrol solvatochromism is significantly influenced by solvent polarization. The electronic and free energies (E and G) indicate that trans is the most stable conformer. The system is classified as a strong nucleophile. However, the analysis of the Fukui functions and the Mulliken charges indicate that cis-trans isomerization jointly affects the reactive indices of the carbon and hydrogen atoms. The results also suggest that solvent is relevant to solvatochromism and the NLO response. Both cis and trans conformers present strong excitations that undergo a visible hypsochromic change when the polarity of the solvent increases. Once the absorption spectra are connected to the first hyperpolarization ( ) by the Oudar and Chemla relation, the hypsochromism of resveratrol is the reason for the drop in the generation of the second harmonic when the ambient polarity decreases. The CAM-B3LYP DFT results suggest that resveratrol is interesting for NLO applications. Depending on the choice of solvent, values 50 times those observed for urea ( esu), which is a standard NLO material. The optimized geometries of cis and trans isomers of resveratrol in vacuum were obtained using Density Functional Theory (DFT) with the hybrid exchange-correlation function (CAM-B3LYP) and Pople basis set functions, specifically 6-311++G(d,p). The solvent effect on the geometries of both isomers was included using the polarizable continuum model (PCM) with the same level of QM calculation. Vibrational analysis was conducted to confirm that all optimized geometries correspond to the minimum energy. Various electronic properties, including dipole moments, molecular orbitals, transition energy, dipole polarizabilities, and global reactivity parameters, were calculated using both continuum and discrete solvation models based on the sequential QM/MM methodology. All QM calculations were performed with the Gaussian 09 program and the MC simulations with the DICE program. All NLO analysis was carried out using the Multiwfn code.

Inhibition of ANO1 by Cis- and Trans-Resveratrol and Their Anticancer Activity in Human Prostate Cancer PC-3 Cells.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is involved in the proliferation, migration, and invasion of various cancer cells including head and neck squamous cell carcinoma, lung cancer, and prostate cancer. Inhibition of ANO1 activity or downregulation of ANO1 expression in these cancer cells is known to exhibit anticancer effects. Resveratrol, a natural polyphenol abundant in wines, grapes, berries, soybeans, and peanuts, shows a wide variety of biological effects including anti-inflammatory, antioxidant, and anticancer activities. In this study, we investigated the effects of two stereoisomers of resveratrol on ANO1 activity and found that cis- and trans-resveratrol inhibited ANO1 activity with different potencies. Cis- and trans-resveratrol inhibited ANO1 channel activity with IC50 values of 10.6 and 102 μM, respectively, and had no significant effect on intracellular calcium signaling at 10 and 100 μM, respectively. In addition, cis-resveratrol downregulated mRNA and protein expression levels of ANO1 more potently than trans-resveratrol in PC-3 prostate cancer cells. Cis- and trans-resveratrol significantly reduced cell proliferation and cell migration in an ANO1-dependent manner, and both resveratrol isomers strongly increased caspase-3 activity, PARP cleavage, and apoptotic sub-G1 phase ratio in PC-3 cells. These results revealed that cis-resveratrol is a potent inhibitor of ANO1 and exhibits ANO1-dependent anticancer activity against human metastatic prostate cancer PC-3 cells.

Greater habitual resveratrol intakes were associated with lower risk of hip fracture- a 1:1 matched case-control study in Chinese elderly.

The aim of the study was to testify the association of dietary resveratrol (RSV) intakes with hip fracture risk in Chinese elderly. This was a 1:1 age- and gender- matched case-control study. Eligible cases were newly diagnosed patients of hip fracture. Dietary assessment was made by a 79-item validated food frequency questionnaire. Habitual RSV intakes were estimated as the sum of trans- and cis- isomers of resveratrol and piceid according to the available database. Multivariable conditional logistic regression was applied to examine the relationship of dietary RSV and RSV-rich foods with hip fracture risk. A total of 1,070 pairs of hip fracture incident cases and controls were recruited and 1,065 were included for analysis. Compared with the lowest group, total RSV in the highest quartile group had significantly reduced hip fracture risk by 66.3% (OR: 0.337, 0.222 ~ 0.571, ptrend < 0.001). Similar findings were observed for cis- and trans-RSV, cis- and trans-Piceid, as well as RSV-rich foods (grapes, apples and nuts) respectively. Subgroup analysis suggested more evident findings among female and less obese participants. Our findings demonstrated that higher habitual RSV intakes and RSV-rich foods, even in a relatively low amount, were associated with reduced risk of hip fracture in Chinese elderly.

Role of Drug Delivery System in Improving the Bioavailability of Resveratrol.

Resveratrol (RSV) is a natural polyphenolic compound known for its therapeutic activities but has limited bioavailability. The aim of our study was to explore various drug-delivering methods that are being employed to achieve target-oriented delivery and therapeutic performance of RSV. To improve the bioavailability and pharmacokinetic properties of RSV, efforts are being made to produce efficient formulations accompanying efficient drug delivery strategies. Several clinical trial studies have been conducted on RSV isomers, and the majority of studies indicated that trans-RSV had better clinical potential and therapeutic effectiveness in various types of complications such as colorectal cancer, metabolic syndrome, hypertension, obesity, neurodegenerative diseases, diabetes, hepatic disease, cardiac disorders, and breast cancer. However, multiple research studies enable us to understand various strategies that can enhance the systemic availability and efficacy of topical RSV formulations. In this article, we emphasize the hurdles of RSV delivery processes. We summarized that the micro- particulate system works efficiently for delivering liquid and solid microparticles of RSV. Another technique in which a coating encloses particles is called microencapsulation. This technique reduces the degradation of pharmaceutical compounds. Similarly, the cyclodextrin system is mainly used for poorly soluble drugs. On the other hand, the vesicular system is another micro-particulate system that can encapsulate hydrophilic and hydrophobic drugs. However, the RSV nanosponge formulations have advanced nano drug delivery systems, making it possible to use RSV for its antioxidant potential.

Effect of Natural Deep Eutectic Solvents on trans-Resveratrol Photo-Chemical Induced Isomerization and 2,4,6-Trihydroxyphenanthrene Electro-Cyclic Formation.

trans-Resveratrol is a natural bioactive compound with well-recognized health promoting effects. When exposed to UV light, this compound can undergo a photochemically induced trans/cis isomerization and a 6π electrochemical cyclization with the subsequent formation of 2,4,6-trihydroxyphenanthrene (THP). THP is a potentially harmful compound which can exert genotoxic effects. In this work we improved the chromatographic separation and determination of the two resveratrol isomers and of THP by using a non-commercial pentafluorophenyl stationary phase. We assessed the effect of natural deep eutectic solvents (NaDES) as possible photo-protective agents by evaluating cis-resveratrol isomer and THP formation under different UV-light exposure conditions with the aim of enhancing resveratrol photostability and inhibiting THP production. Our results demonstrate a marked photoprotective effect exerted by glycerol-containing NaDES, and in particular by proline/glycerol NaDES, which exerts a strong inhibitory effect on the photochemical isomerization of resveratrol and significantly limits the formation of the toxic derivative THP. Considering the presence of resveratrol in various commercial products, these results are of note in view of the potential genotoxic risk associated with its photochemical degradation products and in view of the need for the development of green, eco-sustainable and biocompatible resveratrol photo-stable formulations.

Ethylchloroformate Derivatization for GC-MS Analysis of Resveratrol Isomers in Red Wine.

Resveratrol (3,5,4′-trihydroxystilbene) is a natural compound that can be found in high concentrations in red wine and in many typical foods found in human diet. Over the past decades, resveratrol has been widely investigated for its potential beneficial effects on human health. At the same time, numerous analytical methods have been developed for the quantitative determination of resveratrol isomers in oenological and food matrices. In the present work, we developed a very fast and sensitive GC–MS method for the determination of resveratrol in red wine based on ethylchloroformate derivatization. Since this reaction occurs directly in the water phase during the extraction process itself, it has the advantage of significantly reducing the overall processing time for the sample. This method presents low limits of quantification (LOQ) (25 ng/mL and 50 ng/mL for cis- and trans-resveratrol, respectively) and excellent accuracy and precision. Ethylchloroformate derivatization was successfully applied to the analysis of resveratrol isomers in a selection of 15 commercial Italian red wines, providing concentration values comparable to those reported in other studies. As this method can be easily extended to other classes of molecules present in red wine, it allows further development of new GC–MS methods for the molecular profiling of oenological matrices.

Resveratrol isoforms and conjugates: A review from biosynthesis in plants to elimination from the human body.

The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.

Gas Chromatographic–Mass Spectrometric Method for the Simultaneous Determination of Resveratrol Isomers and 2,4,6-Trihydroxyphenanthrene in Red Wines Exposed to UV-Light

Resveratrol (3,5,4'-trihydroxystilbene) is one of the most abundant polyphenols in red grapes, and red wine represents one of the most important dietary sources of this compound. Although its beneficial properties on human health have been widely investigated over the last 30 years, very little is known about its derivatives. Resveratrol can indeed undergo glycosylation, oligomerization and, upon UV-light exposure, it can isomerize from the trans-to the cis-isomer, which can further cyclize to 2,4,6-trihydroxyphenanthrene (THP). Although the effects of THP on human health are not yet known, being a polycyclic aromatic hydrocarbon, it can be potentially harmful. Because no data about THP occurrence in plant food and beverages are available, a simple procedure based on liquid-liquid extraction and gas chromatography-mass spectrometry has been developed and validated for the simultaneous qualitative and quantitative analysis of trans-resveratrol, cis-resveratrol, and THP in red wine, before and after UV-light exposure.

Adsorption of trans‐ and cis‐Resveratrol on Graphene

Resveratrol has a strong antioxidant activity which renders this compound very interesting for the biomedical field. However, the low aqueous solubility is a limiting factor for its bioavailability. For practical applications as a drug or nutraceutical, resveratrol needs to be transported by nanocarriers like, for instance, graphene materials. In this work, we explore the possibility of adsorbing the resveratrol isomers on graphene materials and the possible discrimination of enantiomers by such surfaces. The interaction between the resveratrol's (trans‐ and cis‐) isomers and graphene oxide are investigated by using UV‐Vis spectroscopy and zeta potential measurements. Quantum chemical calculations based on density functional theory are used to get insights into the geometries of adsorption and interaction energies between resveratrol and graphene.

Conformational Space and Electronic Absorption Properties of the Two Isomers of Resveratrol

Conformational Space and Electronic Absorption Properties of the Two Isomers of Resveratrol

Anti-proliferative and anti-metastasis effects of ten oligostilbenes from the seeds of Paeonia suffruticosa on human cancer cells.

Paeonia suffruticosa from the section Moutan of the genus Paeonia is an important Chinese medicinal herb. In our previous study, 10 oligostilbenes from the seeds of P. suffruticosa, including trans-resveratrol and its dimers and trimers, were isolated and identified. In the present study, the anti-proliferative effects of these 10 oligostilbenes were systemically evaluated in a panel of human lung, breast and bone cancer cell lines, and their apoptotic effects were analyzed using a high-content multiplex apoptosis assay and a fluorescent caspase-3/7 assay. Furthermore, their anti-metastasis effects were examined in an invasive breast cancer cell line. Among the ten compounds, two resveratrol dimers, trans- and cis-gnetin H, showed the most potent anti-proliferative and anti-metastasis effects. All trans-oligostilbenes were more effective than their cis-forms, and trimers of resveratrol were more effective than dimers and the resveratrol isomer. The structure-activity relationships revealed that the polymerization degree, the double bond in the stilbene skeleton, and the steric arrangement and conformation of oligostilbenes obviously affected their antitumor potential. The results from this study provide valuable information for future semi-synthesis of resveratrol derivatives to develop novel cancer chemopreventive agents.

Biorelevant physicochemical profiling of (E)- and (Z)-resveratrol determined from isomeric mixtures

Biorelevant, isomer-specific physicochemical parameters of resveratrol, a multifunctional component in red wines, with cardioprotective, anti-Alzheimer and several other pharmacologic activities were determined. The parameters include site-specific basicities, lipophilicities, solubilities and diffusion constants for the two geometric isomers. The protonation equilibria of (E)- and (Z)-resveratrol were monitored by 1H NMR-pH titrations. Five closely related auxiliary compounds ((E)-pinostilbene, (Z)-pinostilbene, (E)-pterostilbene, (Z)-pterostilbene and resorcinol) were also studied. Combining the datasets, the group-specific protonation constants of resveratrol isomers were determined. The results show that (Z)-resveratrol is more basic at every protonation site than the (E)-isomer. Lipophilicities are quantified in terms of logP values and were determined by octanol/water partition experiments and quantitative NMR spectroscopy: (E)-resveratrol was found to be more lipophilic. Since the molecular geometries of the isomers differ, diffusion ordered NMR spectroscopy (DOSY) experiments were also carried out to quantify the diffusion capabilities of the isomers: (Z)-resveratrol of bent shape has a slightly higher diffusion coefficient than its extended (E) counterpart. A striking 10-fold difference of water solubility was found in favor of the (Z) isomer, due obviously to the reduced water-repellent character in the more compact molecule. This is so far the greatest recorded solubility difference between geometric isomers of any compounds.

A Molecular Electron Density Theory Study of the Chemical Reactivity of Cis- and Trans-Resveratrol.

The chemical reactivity of resveratrol isomers with the potential to play a role as inhibitors of the nonenzymatic glycation of amino acids and proteins, both acting as antioxidants and as chelating agents for metallic ions such as Cu, Al and Fe, have been studied by resorting to the latest family of Minnesota density functionals. The chemical reactivity descriptors have been calculated through Molecular Electron Density Theory encompassing Conceptual DFT. The active sites for nucleophilic and electrophilic attacks have been chosen by relating them to the Fukui function indices, the dual descriptor and the electrophilic and nucleophilic Parr functions. The validity of “Koopmans’ theorem in DFT” has been assessed by means of a comparison between the descriptors calculated through vertical energy values and those arising from the HOMO and LUMO values.

Vasorelaxing Effect of Resveratrol on Bovine Retinal Arteries.

Resveratrol is a red wine polyphenol that causes vasorelaxation, which could be of interest in the treatment or prevention of eye diseases with an impaired blood flow. In this study, the vasorelaxant capacity of resveratrol (cis and trans) on bovine retinal arteries, its vasorelaxing mechanism, and its influence on the relaxation induced by the retinal relaxing factor (RRF) were examined. Isolated bovine retinal arteries were mounted into wire myographs for isometric tension measurements. Concentration-response curves of cis- and trans-resveratrol and concentration-response curves of resveratrol in the absence or presence of the endothelium or different inhibitors were constructed. Relaxations elicited by the RRF with and without resveratrol incubation were also compared. Both resveratrol isomers caused a similar strong concentration-dependent relaxation. Removal of the endothelium or blocking endothelium-dependent pathways did not change the relaxation. Also, K+ channel blockers did not reduce the relaxation, except the 120 mM K+ Krebs Ringer bicarbonate solution. Phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate blocked the relaxation partially and so did the inhibition of heme oxygenase-1. Blocking adenylyl cyclase, AMP-activated protein kinase, estrogen receptors, sirtuin 1, or sarco/endoplasmic reticulum Ca2+ ATPase did not have an effect. The relaxation caused by the RRF was not altered by resveratrol incubation. Cis- and trans-resveratrol relax bovine retinal arteries similarly and concentration dependently. The main relaxation mechanism remains unclear, but K+ channels, carbon monoxide, and the myosin phosphatase pathway may be involved. Resveratrol does not have an influence on the RRF.

Anti-tumor properties of cis-resveratrol methylated analogs in metastatic mouse melanoma cells.

Resveratrol (E-3,5,4'-trihydroxystilbene) is a polyphenol found in red wine that has been shown to have multiple anti-cancer properties. Although cis-(Z)- and trans-(E)-isomers of resveratrol occur in nature, the cis form is not biologically active. However, methylation at key positions of the cis form results in more potent anti-cancer properties. This study determined that synthetic cis-polymethoxystilbenes (methylated analogs of cis-resveratrol) inhibited cancer-related phenotypes of metastatic B16 F10 and non-metastatic B16 F1 mouse melanoma cells. In contrast with cis- or trans-resveratrol and trans-polymethoxystilbene which were ineffective at 10μM, cis-polymethoxystilbenes inhibited motility and proliferation of melanoma cells with low micromolar specificity (IC50<10μM). Inhibitory effects by cis-polymethoxystilbenes were significantly stronger with B16 F10 cells and were accompanied by decreased expression of β-tubulin and pleckstrin homology domain-interacting protein, a marker of metastatic B16 cells. Thus, cis-polymethoxystilbenes have potential as chemotherapeutic agents for metastatic melanoma.

Stir bar sorptive extraction with gas chromatography–mass spectrometry for the determination of resveratrol, piceatannol and oxyresveratrol isomers in wines

A simple and highly sensitive procedure based on stir bar sorptive extraction coupled to gas chromatography–mass spectrometry by means of a thermal desorption unit (SBSE-TD-GC–MS) has been optimized for the determination of cis/trans isomers of resveratrol, piceatannol and oxyresveratrol in wine samples. Quantification of the cis-isomers was carried out by generating the standards from the corresponding trans-species once they had been preconcentrated on the SBSE extracting phase. The optimization of the acetylation derivatization, SBSE extraction and thermal desorption steps was investigated using Plackett–Burman designs, taking into account the high number of variables to be considered. The use of bisphenol F as internal standard allowed quantification of the samples against aqueous standards. Repeatability, expressed as relative standard deviation of 10 successive analyses was between 5% and 9%, confirming the high precision attained under the optimized conditions. Satisfactory recovery values of between 79% and 109% were obtained for spiked samples in the 0.2–1.0μgL−1 concentration range, depending on the compound. The main compound determined in the analyzed samples was trans-resveratrol, with concentrations in the range of 3–230μgL−1, depending on the type of wine.

Liquid Chromatographic Determination of Resveratrol and Piceid Isomers in Honey

In this work, a liquid chromatography method with diode array and fluorescence detection and electrospray ionization mass spectrometry (LC-DAD-FLD and LC-ESI-MS) has been developed for the determination of residues of resveratrol in all its forms (free isomers and glycosylates) in honey. This procedure involves a solid-phase extraction on polymeric cartridges for the isolation of trans/cis-isomers of resveratrol and piceid from diluted honey samples. Chromatographic separation of the analytes was performed in isocratic mode on a C18 column (150 mm × 4.6 mm i.d., 5 μm) operated at 30 °C. The mobile phase consisted of a mixture of water with 1% formic acid and acetonitrile (75/25, v/v), and the flow rate was set at 1.0 mL/min. Average analyte recoveries were from 71% to 113% in replica sets of fortified honey samples. The detection limits when using LC-DAD-FLD were between 40 and 120 μg/kg, meanwhile for LC-ESI-MS were between 1.4 and 14.6 μg/kg. The proposed method was applied to the analysis of honey samples collected from treated beehives in experimental apiaries after a preliminary field trial, and they were not found any residues over the detection limits of the studied compounds.

Authentication of Italian red wines on the basis of the polyphenols and biogenic amines

Seventy-three Southern Italian red wines were characterized according to their content in total polyphenols, trans- and cis-resveratrol and biogenic amines. These quality parameters were used in multivariate statistical analysis to discriminate the wines according to their specific geographical origin. The results indicated that total polyphenols, resveratrol isomers and biogenic amines provide a good prospect for discriminating wines by regions. The discrimination was also possible to a lesser extent by cultivar. In particular, canonical variate analysis suggested that the discrimination of wines according to their provenance is based on the following parameters: cis-resveratrol, total polyphenols, spermidine and tryptamine for Basilicata region; agmatine and trans-resveratrol for Calabria and Campania regions; cadaverine, ethanolamine, histamine, putrescine and tyramine for Puglia region.

Evolution of Resveratrol and Piceid Contents during the Industrial Winemaking Process of Sherry Wine

In the Jerez region, the sherry winemaking process involves a stage of aging carried out in a dynamic system known as "soleras" and "criaderas". In the case of fino sherry, this aging takes place in the presence of a yeast film growing on the surface of the wine, which gives it a very specific character. In this work, the influence of the sherry elaboration process on resveratrol and piceid levels has been studied. With this purpose, the contents of resveratrol isomers and piceid during the main stages of the sherry wine production system, from maturation until bottling, were monitored during two vintages. The results showed that resveratrol contents of both the skin and juice, for Palomino fino grape, are very similar to those described for other white grape varieties. Sherry wine fermentation, clarification, cold stabilization, and filtration processes considerably affect resveratrol and piceid contents. However, biological aging has the most important influence, diminishing their contents by 80%. These results were confirmed in several tests performed in the laboratory, in which various factors that could affect the resveratrol contents during aging were taken into account (oxidative phenomena and a combination with acetaldehyde and "flor" biofilm growth).

A Rapid Method for Determination of Resveratrol in Wines by HPLC-MS

A new, sensitive, high throughput liquid chromatography coupled with mass spectrometry (LC-MS/MS) method for quantification of trans- andcis-resveratrol in wine samples was elaborated. During method development the influence of multiple factors on the ionization efficiency of resveratrol was studied. These parameters included ion source (APCI and ESI, both being operated in positive and negative ionization mode), percentage of aqueous and organic phase, type of organic solvent, and concentration of additives. The optimum conditions were as follows: a mobile phase consisting of a mixture of 1 mM ammonium acetate/acetonitrile (73/27, v/v) with a flow rate of 1 mL/min, MS/MS detection with an APCI interface, operated in negative ionization mode. The monitored ion transition was m/z 227→184.7. Calibration curves were generated for both isomers of resveratrol in the range of 10.47–837.86 ng/mL (trans isomer) and 9.12 − 730.14 ng/mL (cis isomer), respectively. The developed method has been successfully applied to the analysis and comparison of trans- and cis-resveratrol content of 20 different Romanian wine samples.