stilbenes and delta-viniferin

The aim of the present work is the evaluation of biological effects of natural stilbenoids found in Vitis vinifera, with a focus on their activity as epigenetic modulators. In the present study, resveratrol, pterostilbene and for the first time their dimers (±)-trans-δ-viniferin, (±)-trans-pterostilbene dehydrodimer were evaluated in Caco-2 and HepG-2 cell lines as potential epigenetic modulators. Stilbenoids were added in a Caco-2 cell culture as a model of the intestinal epithelial barrier and in the HepG-2 as a model of hepatic environment, to verify their dose-dependent toxicity, ability to interact with DNA, and epigenomic action. Resveratrol, pterostilbene, and (±)-trans-pterostilbene dehydrodimer were found to have no toxic effects at tested concentration and were effective in reversing arsenic damage in Caco-2 cell lines. (±)-trans-δ-viniferin showed epigenomic activity, but further studies are needed to clarify its mode of action.

Topics: Caco-2 Cells; Epigenomics; Humans; Resveratrol; Stilbenes; Vitis

Stilbenoids are anti-inflammatory and antioxidant compounds, with resveratrol being the most investigated molecule in this class. However, the actions of most other stilbenoids are much less studied. This study compares five monomeric (resveratrol, piceatannol, pterostilbene, pinostilbene, and trimethoxy-resveratrol) and two dimeric (dehydro-δ-viniferin and

Topics: Animals; Antioxidants; Bone Marrow; Cytokines; Dendritic Cells; Escherichia coli; Interleukin-10; Interleukin-12; Lipopolysaccharides; Mice; Reactive Oxygen Species; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Over the last century, the number of epidemics caused by RNA viruses has increased and the current SARS-CoV-2 pandemic has taught us about the compelling need for ready-to-use broad-spectrum antivirals. In this scenario, natural products stand out as a major historical source of drugs. We analyzed the antiviral effect of 4 stilbene dimers [1 (trans-δ-viniferin); 2 (11',13'-di-O-methyl-trans-δ-viniferin), 3 (11,13-di-O-methyl-trans-δ-viniferin); and 4 (11,13,11',13'-tetra-O-methyl-trans-δ-viniferin)] obtained from plant substrates using chemoenzymatic synthesis against a panel of enveloped viruses. We report that compounds 2 and 3 display a broad-spectrum antiviral activity, being able to effectively inhibit several strains of Influenza Viruses (IV), SARS-CoV-2 Delta and, to some extent, Herpes Simplex Virus 2 (HSV-2). Interestingly, the mechanism of action differs for each virus. We observed both a direct virucidal and a cell-mediated effect against IV, with a high barrier to antiviral resistance; a restricted cell-mediated mechanism of action against SARS-CoV-2 Delta and a direct virustatic activity against HSV-2. Of note, while the effect was lost against IV in tissue culture models of human airway epithelia, the antiviral activity was confirmed in this relevant model for SARS-CoV-2 Delta. Our results suggest that stilbene dimer derivatives are good candidate models for the treatment of enveloped virus infections.

Topics: Antiviral Agents; COVID-19; Herpesvirus 2, Human; Humans; SARS-CoV-2; Stilbenes; Viruses

Topics: Benzofurans; Culture Media, Conditioned; Hydrogen Peroxide; Peroxidase; Resorcinols; Resveratrol; Stilbenes; Vitis

Topics: Anti-Bacterial Agents; Benzofurans; Microbial Sensitivity Tests; Resorcinols; Staphylococcus aureus; Stilbenes

Stilbenes, including resveratrol and viniferins, a small family of polyphenols, are considered the most important phytoalexin group in Vitis species. In a previous study, we found that co-treatment of methyl jasmonate (MJ) and stevioside (STE) resulted in enhanced extracellular production of viniferins in grapevine cell suspension cultures. Thus, to further understand the mechanisms of viniferin production in grapevine cell cultures, we performed transcriptome analysis and isolated seven candidates of grapevine peroxidase genes (VlAPX6, VlGPX5, VlPRX13, VlPRX21, VlPRX35, VlPRX40, and VlPRX50). Bioconversion of trans-resveratrol to δ-viniferin was examined using crude protein extracts isolated from agroinfiltration-based transient expression of VlPRXs in Nicotiana benthamiana. In addition, we found that crude protein extracts from VlPRX21-, VlPRX35-, and VlPRX40-overexpressing (OX) transgenic Arabidopsis plants led to the conversion of trans-resveratrol to δ-viniferin. We found that in vitro experiments with crude protein extracts from VlPRX21-OX and VlPRX35-OX Arabidopsis plants catalyzed the dimerization of trans-resveratrol to δ-viniferin. Our results suggest that VlPRX21 and VlPRX35 encode functional grapevine class III peroxidases and catalyze the oxidative dimerization of trans-resveratrol to form δ-viniferin in grapevine.

Topics: Arabidopsis; Benzofurans; Resorcinols; Resveratrol; Stilbenes; Vitis

Red wine compounds have been reported to reduce the rate of atherosclerosis by inducing nitric oxide (NO) production and antioxidant enzyme expression in vascular endothelial cells (VECs). The present study compared the effects of the three red wine compounds resveratrol and its dimers, ε-viniferin and δ-viniferin, on VECs function for the first time. Both 5 μM ε-viniferin and δ-viniferin, but not 5 μM resveratrol, significantly stimulated wound repair of VECs. Increased levels of wound repair induced by 10 and 20 μM ε-viniferin were significantly higher than those stimulated by 10 and 20 μM resveratrol, respectively. These stimulatory effects of the three compounds were suppressed by the NO synthase inhibitor L-NAME. When VECs were exposed to each compound, endothelial NO synthase was activated and the expression of sirtuin 1 (SIRT1) and HO-1 was induced. Addition of the SIRT1 and HO-1 inhibitors EX527 and ZnPPiX, respectively, suppressed wound repair stimulated by the three compounds, demonstrating that SIRT1 and HO-1 are involved in these wound repair processes. Furthermore, each compound induced the suppression of H

Topics: Animals; Antioxidants; Atherosclerosis; Benzofurans; Carbazoles; Catalase; Cell Line; Cell Survival; Dimerization; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation; Heme Oxygenase-1; Humans; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Protoporphyrins; Resorcinols; Resveratrol; Sirtuin 1; Stilbenes; Swine; Wine

A new approach for the total synthesis of the active stilbene dimer dehydro-

Topics: Benzofurans; Molecular Structure; Resorcinols; Resveratrol; Stilbenes

Stilbene derivatives, the principal constituent of Rheum undulatum L., are known to have a wide range of biological activities, such as anti-allergic, anti-diabetic, antioxidant, and anti-inflammatory activities. A phytochemical study on the methanol extract of Korean rhubarb (R. undulatum L.) led to the isolation of nine stilbene derivatives (1-9) and one flavonoid (10). All structures were elucidated based on a comprehensive analysis of spectroscopic data. Compound 1 (5-methoxy-cis-rhapontigenin) was elucidated as a new compound, while compound 2 (5-methoxy-trans-rhapontigenin) was isolated from a natural source for the first time. Among the isolated compounds, stilbene derivatives (7-9) showed a strong inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) with IC

Topics: Benzofurans; Catalytic Domain; Molecular Docking Simulation; Molecular Structure; Phytochemicals; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Republic of Korea; Resorcinols; Rheum; Rhizome; Stilbenes

Oxidative stress plays a critical role in the pathogenesis of diabetic vascular complications. Trans-δ-viniferin (TVN), a polyphenolic compound, has recently attracted much attention as an antioxidant exhibiting a hypoglycemic potential. In the present study, we aimed at investigating the protective effect of TVN against high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and the potential mechanism involved. We found that TVN attenuated reactive oxygen species (ROS) production, increased catalase (CAT) activity and decreased malondialdehyde (MDA) levels to ameliorate cell survival induced by 35 mM glucose. Meanwhile, it inhibited high glucose-induced apoptosis by maintaining Ca(2+) and preserving mitochondrial membrane potential (MMP) levels. The immunoblot analysis indicated that TVN efficiently regulated the cleavage of caspase family, p53, Bax and Bcl-2, all mediated by SIRT1. Furthermore, the increased level of SIRT1 induced by TVN was inhibited by nicotinamide and siRNA-medicated SIRT1 silencing (si-SIRT1), thereby confirming the significant role of SIRT1 in these events. In conclusion, our results indicated that TVN efficiently reduced oxidative stress and maintained mitochondrial function related with activating SIRT1 in high glucose-treated HUVECs. It suggested that TVN is pharmacologically promising for treating diabetic cardiovascular complications.

Topics: Apoptosis; Benzofurans; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Mitochondria; Oxidative Stress; Protective Agents; Resorcinols; Signal Transduction; Sirtuin 1; Stilbenes

Resveratrol is widely known as an antioxidant and anti-inflammatory molecule. The present study first reports the effects of trans-δ-viniferin (TVN), a dimer of resveratrol, on human erythrocytes. The antioxidant activity of TVN was tested using in vitro model systems such as hydroxy radical scavenging, DPPH and lipid peroxidation. In addition we have examined the influence of the 15R,22R- and 15S,22S-enantiomers (abbreviated R,R-TVN, and S,S-TVN, respectively) on anion transport, ATP release, caspase 3 activation. Given that hemoglobin (Hb) redox reactions are the major source of RBC oxidative stress, we also explored the effects of TVN on hemoglobin function. TVN showed moderate antioxidant properties and good protective activity from hemoglobin oxidation. Potential binding sites of R,R-TVN and S,S-TVN with oxy- and deoxy-Hb were also investigated through an extensive in silico docking approach and molecular dynamics calculations. The whole molecular modeling studies indicate that binding of R,R-TVN and S,S-TVN to Hb lacks of specific ligand-target interactions. This is the first report on the biological activity of the individual enantiomers of a resveratrol-related dimer.

Topics: Antioxidants; Benzofurans; Erythrocyte Membrane; Erythrocytes; Free Radical Scavengers; Hemoglobins; Humans; Hydrogen Bonding; Methemoglobin; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Nitrites; Oxidation-Reduction; Oxidative Stress; Protein Binding; Resorcinols; Resveratrol; Stilbenes

Grapevine (Vitis spp) is susceptible to serious fungal diseases usually controlled by chemical treatments. Arbuscular mycorrhizal fungi (AMF) are obligate plant symbionts which can stimulate plant defences. We investigated the effect of mycorrhization on grapevine stilbenoid defences. Vitis vinifera cvs Chasselas, Pinot noir and the interspecific hybrid Divico, on the rootstock 41B, were mycorrhized with Rhizophagus irregularis before leaf infection by Plasmopara viticola or Botrytis cinerea. Gene expression analysis showed an up-regulation of PAL, STS, and ROMT, involved in the stilbenoid biosynthesis pathway, in plant leaves, 48 h after pathogen inoculation. This defense response could be potentiated under AMF colonization, with an intensity level depending on the gene, the plant cultivar and/or the pathogen. We also showed that higher amounts of active forms of stilbenoids (i.e trans-form of resveratrol, ε- and δ-viniferins and pterostilbene) were produced in mycorrhized plants of the three genotypes in comparison with non-mycorrhized ones, 10 days post-inoculation with either pathogen. These results support the hypothesis that AMF root colonization enhances defence reactions against a biotrophic and a necrotrophic pathogen, in the aerial parts of grapevine.

Topics: Benzofurans; Botrytis; Oomycetes; Phenylpropionates; Plant Components, Aerial; Plant Diseases; Plant Leaves; Resorcinols; Resveratrol; Stilbenes; Symbiosis; Vitis

Topics: Acetates; Benzofurans; beta-Cyclodextrins; Cyclopentanes; Glucosides; Oxylipins; Plant Roots; Resorcinols; Resveratrol; Stilbenes; Vitis

The first aerobic oxidative coupling of resveratrol and its analogues by mesoporous graphitic carbon nitride as a bioinspired catalyst with visible light has been developed. With this method, δ-viniferin and its analogues were synthesized in moderate to high yield. The metal-free conditions, visible-light irradiation, and the ideal oxidant, molecular oxygen, make this coupling reaction environmental friendly and practical.

Topics: Benzofurans; Catalysis; Dimerization; Light; Nitriles; Oxidative Coupling; Porosity; Resorcinols; Resveratrol; Stilbenes

A preparative chiral high speed counter-current chromatography (HSCCC) method based on induced circular dichroism (ICD) spectrum was developed to separate trans-δ-viniferin (TVN) enantiomers successfully. The important parameters for the chiral HSCCC separation process, including the type of chiral selector (CS), the concentration of chiral selector and the equilibrium temperature, were optimized using induced circular dichroism spectrum. The final separation procedure was established with a biphasic solvent system composed of n-hexane-ethyl acetate-25 mmol L(-1) hydroxypropyl-β-cyclodextrin aqueous solution (5:5:10, v/v/v) in the head-to-tail elution mode at 5 °C. Under optimum chiral HSCCC separation conditions, 8.2mg of (7S, 8S)-TVN (1) and 9.4 mg of (7R, 8R)-TVN (2) were successfully separated from 20mg TVN enantiomers with the purity of 99.51% and 99.36%, respectively.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Benzofurans; beta-Cyclodextrins; Chromatography, Liquid; Circular Dichroism; Countercurrent Distribution; Resorcinols; Stereoisomerism; Stilbenes

In this study, an accurate and reliable LC-MS/MS assay was firstly developed and validated for the quantitative determination of trans δ-veniferin (TVN) in rat plasma. Chlorzoxazone was used as the internal standard (IS). After one-step protein precipitation with methanol, the analyte and IS were separated on an ODS column by gradient elution with mobile phase of acetonitrile-0.2% formic acid at a flow rate of 0.3mL/min. Negative electrospray ionization was performed using multiple reactions monitoring (MRM) mode with transitions of m/z 453.0>410.9 for TVN, and m/z 168.0>132.0 for IS. Good linearity (R≥0.996) was observed over the concentration range of 5-5000ng/mL for TVN with a lower limit of quantification (LLOQ) of 5ng/mL. The mean recoveries for TVN and IS were 91.05% and 96.68%, respectively. The intra- and inter-day precisions (RSD) were no more than 10.5% and accuracies (RE) were within the range of -6.3% to 2.1%. The validated method was suitable for quantification of TVN and successfully applied to the pharmacokinetic study of TVN after oral and intravenous administration to rats. The oral absolute bioavailability of TVN was 14.2% in rat.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Benzofurans; Chromatography, High Pressure Liquid; Limit of Detection; Male; Rats; Rats, Sprague-Dawley; Resorcinols; Stilbenes; Tandem Mass Spectrometry

Leaves, shoots and flowers from two different economy-relevant grape cultivars, Merlot and Cabernet Sauvignon, were examined to assess the distribution of phytoalexins upon inoculation with Botrytis cinerea at pre-bloom, bloom, and post-bloom stages. Mass spectrometric analysis evidenced considerable levels of trans-resveratrol (3,5,4'-trihydroxystilbene), albeit higher in Cabernet Sauvignon, in leaves from both grape cultivars following fungal infection at all the examined stages of development. Although both these cultivars are reported to be sensitive against fungal infections, in Cabernet Sauvignon leaves and flowers, we were also able to measure relevant quantities of the resveratrol dehydrodimer delta-viniferin. While infection by B. cinerea occurs at bloom stage, high-sensitivity of the HPLC-mass spectrometric analytic method allowed detecting measurable levels of viniferins even in early pre-bloom stages in Cabernet Sauvignon flowers and to evidence even slight resveratrol differences between the cultivars. Concordingly, Cabernet Sauvignon better responded to fungal infection. This analysis allowed us to conclude that, even when analyzing fungal infection-sensitive cultivars, the HPLC-MS method holds the sensitivity to highlight the slightest differences in the concentrations of the two phytoalexins and correlate them to different anti-fungal response potential.

Topics: Benzofurans; Botrytis; Chromatography, High Pressure Liquid; Mass Spectrometry; Phenols; Phytoalexins; Resorcinols; Resveratrol; Sesquiterpenes; Species Specificity; Stilbenes; Vitis; Wine

This study examined for the first time the effect of low-energy ultrasound (US), used alone or in combination with methyl jasmonate (MeJA), on viniferin production in cell cultures of Vitis vinifera L. cv Alphonse Lavallée. Cell suspensions were exposed for 2 min to US (power 30, 60, and 90 mW cm(-3)). The highest viniferin production was obtained at 30 mW cm(-3). When sonication was performed twice, the effect on viniferin production was negligible, whereas triple sonication slightly increased production. US treatment at 30 mW cm(-3) for 5 min decreased viniferin production and induced cellular death. The combined use of MeJA and US (2 min) increased the production of δ-viniferin, the dominant stilbene, more than each elicitor used alone. These results suggest that low-energy US, alone and in combination with MeJA, can act as a physical elicitor to stimulate viniferin production in V. vinifera cell cultures.

Topics: Acetates; Benzofurans; Chromatography, High Pressure Liquid; Cyclopentanes; Mass Spectrometry; Molecular Dynamics Simulation; Oxylipins; Quantum Theory; Resorcinols; Stilbenes; Ultrasonics; Vitis

Methyl jasmonate, jasmonic acid and chitosan were tested as elicitors on cell suspension cultures obtained from Vitis vinifera cv Italia to investigate their effect on stilbene production. Stilbene accumulation in the callus, grown under nonelicited conditions, was also investigated. Calli and cell suspensions were obtained in a B5 culture medium supplemented with 0.2 mg L(-1) NAA and 1 mg L(-1) KIN. Stilbene determination was achieved by HPLC/DAD/MS. Whereas callus biosynthesized only piceid, cell suspensions elicited with jasmonates produced several stilbenes, mainly viniferins. In suspended cells, methyl jasmonate and jasmonic acid were the most effective in stimulating stilbene biosynthesis, whereas chitosan was less effective; in fact, the amount of stilbenes obtained with this elicitor was not significantly different from that obtained for the control cells. The maximum production of total stilbenes was at day 20 of culture with 0.970 and 1.023 mg g(-1) DW for MeJA and JA, respectively.

Topics: Acetates; Benzofurans; Cells, Cultured; Chitosan; Cyclopentanes; Oxylipins; Plant Growth Regulators; Plant Stems; Resorcinols; Resveratrol; Stilbenes; Vitis

Two stilbenes, trans-resveratrol and (-)-epsilon-viniferin, as well as a mixture of both, were biotransformed using horseradish peroxidase and hydrogen peroxide. Under the applied conditions trans-resveratrol afforded one major product, which was identified as trans-delta-viniferin, a resveratrol-trans-dehydrodimer. Large-scale biotransformation of a mixture of trans-resveratrol and (-)-epsilon-viniferin yielded two novel resveratrol trimers, resviniferin A and resviniferin B, which were obtained in a pure form after fractionation by high-speed countercurrent chromatography and final purification by preparative HPLC. Their structures were established by means of mass spectrometry and 2D NMR spectroscopic analyses, including HSQC, HMBC, COSY, and ROESY.

Topics: Benzofurans; Catalysis; Horseradish Peroxidase; Molecular Structure; Resorcinols; Resveratrol; Stilbenes

Resveratrol (1) is a polyphenolic natural product, which functions as both a mechanism-based inactivator and a co-reductant of the COX-1 peroxidase. These functions are mediated through different moieties on the molecule, namely, the m-hydroquinone moiety (mechanism-based inactivator) and the phenol moiety (co-reductant). Implicit in this bifunctionality is the notion that resveratrol is oxidized at the peroxidase active site of COX-1, resulting in the formation of two hypothetical radical species. Oxidation of the m-hydroquinone moiety can generate a hypothetical m-semiquinone radical, which is unstabilized and leads to irreversible enzyme inactivation. Oxidation of the phenol moiety can generate a hypothetical phenoxy radical, which is stabilized and leads to co-reduction during peroxidase catalysis. These two radicals have been trapped as the resveratrol dimers, cis-epsilon-viniferin (4, trapped m-semiquinone radical) and trans-delta-viniferin (5, trapped phenoxy radical), and identified by liquid chromatography (LC), absorbance spectroscopy, and LC/tandem mass spectrometry (MS(n)) methods. Methoxy-resveratrol analogues, in which either the m-hydroquinone or the phenol moiety were protected as methyl ethers, were used to confirm the proposed mechanism of viniferin production by COX-1.

Topics: Benzofurans; Catalysis; Chromatography, High Pressure Liquid; Cyclooxygenase 1; Mass Spectrometry; Models, Chemical; Molecular Structure; Oxidation-Reduction; Prostaglandin-Endoperoxide Synthases; Resorcinols; Resveratrol; Stilbenes; Structure-Activity Relationship

Phenolics from grapes and wines can play a role against oxidation and development of atherosclerosis. Stilbenes have been shown to protect lipoproteins from oxidative damage and to have cancer chemopreventive activity. We describe a method for the direct determination of stilbenes in several red wines using high-performance liquid chromatography with UV detection. In a survey of 12 commercial wines from the south of Brazil (Rio Grande del Sul), levels of delta-viniferin are reported for the first time in different varieties of red wines. Brazilian red wine contains trans-astringin, trans-piceid, trans-resveratrol, cis-resveratrol (in high quantity: 5 times more than the trans form), epsilon-viniferin, and a compound isolated for the first time in wine, trans-delta-viniferin. Isolation and identification of delta-viniferin was achieved by NMR after extraction and fractionation of red wine phenolics. delta-Viniferin contributes, as well as cis-resveratrol and trans-piceid, to a significant proportion of stilbenes in wine dietary intake, particularly with Merlot varieties containing an average level of 10 mg/L for delta-viniferin, 15 mg/L for cis-resveratrol, and 13 mg/L for trans-piceid. The total stilbene intake from wine origin was estimated for the Brazilian population as 5.3 mg/day per person (on the basis of a regular wine consumption of 160 mL/day). delta-Viniferin can contribute to around 20% of total stilbenes in wine (average of 6.4 mg/L in red Brazilian wines). It would be important in the future to investigate the origins of the differences in wine stilbene levels in relation to the vine varieties, and the bioavailability of the newly extracted stilbene delta-viniferin in plasma after consumption of different types of wines.

Topics: Benzofurans; Brazil; Chromatography, High Pressure Liquid; Glucosides; Magnetic Resonance Spectroscopy; Resorcinols; Resveratrol; Stilbenes; Wine

Delta-viniferin is a resveratrol dehydrodimer, an isomer of epsilon-viniferin. This compound has been reported as a molecule produced in vitro by the oxidative dimerization of resveratrol by plant peroxidases or fungal laccases. It was also recently identified in wines and in grape cell cultures. We have now identified this dimer by NMR, high-performance liquid chromatography-diode array detection (HPLC-DAD), and HPLC-mass spectrometry (MS) in grapevine leaves infected by Plasmopara viticola (downy mildew) or UV-C irradiated. Its concentration was higher than that of epsilon-viniferin and constitutes one of the most important phytoalexins derived from resveratrol.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Dimerization; Magnetic Resonance Spectroscopy; Oomycetes; Oxidation-Reduction; Plant Diseases; Plant Leaves; Resorcinols; Stilbenes; Ultraviolet Rays; Vitis