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TMEM16A regulator is an important tool to study the physiological functions and pathogenesis related to TMEM16A. In the present study, trans-ε-viniferin (TV) was identified as a TMEM16A inhibitor with inhibitory activity against TMEM16A mediated Cl− currents, which was reversible, without affecting intracytoplasmic Ca2+ concentration and TMEM16A protein expression. TV inhibited intestinal peristalsis and prolonged gastrointestinal transport time. TV could inhibit autonomic and Eact-stimulated intestinal contractility, and was equally effective in ACh- and HA-induced high contractile states. The results indicate that TV significantly inhibits the intestinal smooth muscle contraction, which may be applied in the treatment of TMEM16A-related intestinal dynamic abnormalities. [ABSTRACT FROM AUTHOR]

Trans-ε-viniferin (εVin) is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. The aim of this study was to measure the consequences of the encapsulation of εVin in multilamellar liposomes on its pharmacokinetic parameters, metabolism and tissue distribution in rats. After oral administration of εVin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS. The glucuronide metabolites (εVG) were also produced by hemisynthesis for their quantification in plasma and tissues. The encapsulation process did not significantly modify the pharmacokinetic parameters of εVin itself. However, a significant increase of the T1/2 was noticed for εVG after administration of the encapsulated form as compared to the free form. An accumulation of εVin and εVG in adipose tissues was noticed, and interestingly a significant increase of the latter in the mesenteric one after administration of the encapsulated form was highlighted. Since adipose tissues could represent storage depots, and encapsulation allows for prolonging the exposure time of glucuronide metabolites in the organism, this could be of interest to promote their potential biological activities.

• Grape canes are a natural source of compounds of interest. • Trans -resveratrol and trans -ε-viniferin can be extracted from them with high yields. • Emerging methods (UAE, MAE, PSE) are promising but require further investigations. • Other parameters independent of the extraction have to be seriously considered. Viticultural waste has been widely demonstrated to contain high-added value compounds named the stilbenes. Among them, trans -resveratrol (Rsv) and trans -ε-viniferin (Vf) are the most abundant in particular in grape canes. Various emerging methods such as ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) or pressurized solvent extraction (PSE) have been studied to recover Rsv and Vf from grape canes in order to enhance their extraction. This paper gives a critical overview of the techniques used to this end, integrating conventional and non-conventional methods investigated in the literature as well as those used in industrial processes. It finally highlights that the unconventional technics are usually less time-consuming than conventional extraction ones but further investigations for the discussed compounds and biomass are needed to optimize and understand the influence of the individual parameters of each extraction process. [ABSTRACT FROM AUTHOR]

The polyphenol trans-ε-viniferin (viniferin) is a dimer of resveratrol, reported to hold antioxidant and anti-inflammatory properties. The aims of our study were to evaluate the neuroprotective potential of viniferin in the nerve growth factor (NGF)-differentiated PC12 cells, a dopaminergic cellular model of Parkinson’s disease (PD) and assess its anti-inflammatory properties in a N9 microglia–neuronal PC12 cell co-culture system. The neuronal cells were pre-treated with viniferin, resveratrol or their mixture before the administration of 6-hydroxydopamine (6-OHDA), recognized to induce parkinsonism in rats. Furthermore, N9 microglia cells, in a co-culture system with neuronal PC12, were pre-treated with viniferin, resveratrol or their mixture to investigate whether these polyphenols could reduce lipopolysaccharide (LPS)-induced inflammation. Our results show that viniferin as well as a mixture of viniferin and resveratrol protects neuronal dopaminergic cells from 6-OHDA-induced cytotoxicity and apoptosis. Furthermore, when viniferin, resveratrol or their mixture was used to pre-treat microglia cells in our co-culture system, they reduced neuronal cytotoxicity induced by glial activation. Altogether, our data highlight a novel role for viniferin as a neuroprotective and anti-inflammatory molecule in a dopaminergic cellular model, paving the way for nutraceutical therapeutic avenues in the complementary treatments of PD.

By-products from the winemaking companies, specifically woody vine material, can be an interesting source of bioproducts, specifically stilbenes and related compounds, however the extraction conditions can dramatically modify the final recoveries of these beneficial compounds. The effects of microwave-assisted extraction on the recovery of stilbenes have been evaluated in this manuscript. The stability under the extraction conditions was assessed in order to define the working range. A fractional factorial experimental design was developed to analyse the influence on the extraction process of seven different extraction variables: solvent, stirring, extraction temperature, extraction time, microwave power, sample weight and extraction volume. This new method enables stilbenes to be extracted from grape stems and canes in only 5 min, with an extraction temperature of 125 °C and 80% ethanol in water as the extraction solvent. Repeatability and reproducibility were also evaluated and the resulting RSD values (n = 5) were lower than 10% for all analysed stilbenes. Additionally, stilbenes in 20 different grape stem and cane samples were determined. [ABSTRACT FROM AUTHOR]

The article investigates the impact of trans-E-viniferin on in vitro maturation (IVM) and developmental competence after in vitro fertilization (IVF or parthenogenesis (PA). Topics discussed include the methodology used by the authors in testing the effect of trans-E-viniferin, the results of the trans-E-viniferin treatment during IVM, and the effect of trans-E-viniferin treatment on blastocyst formation. Also mentioned is issues associated with in vitro and in vivo systems.

Cytotoxic and antimutagenic effects of a novel cis-ε-viniferin and five known stilbenes, trans-resveratrol, frans-ε-viniferin, gnetin H, suffruticosols A and B, isolated from the seeds of Paeonia lactiflora Pall. (Paeoniaceae) were determined against five different cancer cell lines, and mutagenicity of N-methyl- N'-nitro- N-nitrosoguanidine (MNNG) in Salmonella typhimurium TA100, respectively. Six stilbenes showed cytotoxic activity in a dose-dependent manner, and especially did potent cytotoxic activity against C6 (mouse glioma) cancer cell with IC50 values ranging from 8.2 to 20.5 ug/ml. trans-Resveratrol showed significant cytotoxic activity against HepG2 (liver hepatoma) and HT-29 (colon) human cancer cell lines with IC50 values of 11.8 and 25.2 g/ml, respectively. In contrast, trans-ε-viniferin and cis--viniferin, and gnetin H exhibited marked cytotoxic activity against Hela (cervicse) and MCF-7 (breast) human cancer cell lines with IC50 values of 20.4, 21.5, and 12.9 μg/ml, respectively. However, suffruticosol A and B had less cytotoxic effect against all cancer cells except C6. Meanwhile, six stilbenes exerted antimutagenic activity in a dose-dependent fashion. Of them, trans-resveratrol exhibited the strongest antimutagenic effect against MNNG with IC50 value of 27.0 μg/plate, while other five resveratrol oligomers also did moderate antimutagenic activity with IC50 values ranging from 31.7 to 35.2 μg/plate. [ABSTRACT FROM AUTHOR]

Scirpusin A is generally present in plants in trans configuration, which has strong biological activities, but the synthetic pathway of trans-scirpusin A still unclear. We previously identified three candidate sequences in the transcriptome of Vitis vinifera treated by UV-B, which may be involved in the synthesis of trans-scirpusin A. Here, we characterized a trans-scirpusin A hydroxylases (SAH) gene in Vitis vinifera. The SAH ORF is predicted to encode 278 amino acids belonging to Cytochrome P450 proteins (CYP) super family. In addition, molecular simulation was performed that the binding site between trans-ε-viniferin and SAH is Ser 276 in SAH, and it was speculated that trans-ε-viniferin and SAH may be combined by hydrogen interaction. Further, the function of the candidate gene was tested using heterologous expression in Pichia pastoris. UHPLC-ESI-MS2 analysis revealed that SAH can catalyze trans-ε-viniferin to trans-scirpusin A in vitro. And subcellular analysis showed that the SAH gene was expressed in the nucleus and membrane. Overall, our research demonstrates that SAH is trans-scirpusin A enzyme in trans-scirpusin A biosynthesis and provides a new sight for exploring the biosynthesis mechanism of trans-scirpusin A. • An P450 enzyme that catalyzes the conversion of trans-ε-viniferin to trans-scirpusin A was discovered for the first time. • Characterization, subcellular localization of the trans-scirpusin A hydroxylases in Vitis vinifera. • SAH has the ability to transform trans-ε-viniferin into trans-scirpusin A in vitro. • 4.The findings established the foundation for further clarifying the biosynthesis mechanism of trans-scirpusin A. [ABSTRACT FROM AUTHOR]

Trans -ε-viniferin (εVin) is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. The aim of this study was to measure the consequences of the encapsulation of εVin in multilamellar liposomes on its pharmacokinetic parameters, metabolism and tissue distribution in rats. After oral administration of εVin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS. The glucuronide metabolites (εVG) were also produced by hemisynthesis for their quantification in plasma and tissues. The encapsulation process did not significantly modify the pharmacokinetic parameters of εVin itself. However, a significant increase of the T 1/2 was noticed for εVG after administration of the encapsulated form as compared to the free form. An accumulation of εVin and εVG in adipose tissues was noticed, and interestingly a significant increase of the latter in the mesenteric one after administration of the encapsulated form was highlighted. Since adipose tissues could represent storage depots, and encapsulation allows for prolonging the exposure time of glucuronide metabolites in the organism, this could be of interest to promote their potential biological activities.

The polyphenol trans-ε-viniferin (viniferin) is a dimer of resveratrol, reported to hold antioxidant and anti-inflammatory properties. The aims of our study were to evaluate the neuroprotective potential of viniferin in the nerve growth factor (NGF)-differentiated PC12 cells, a dopaminergic cellular model of Parkinson's disease (PD) and assess its anti-inflammatory properties in a N9 microglia–neuronal PC12 cell co-culture system. The neuronal cells were pre-treated with viniferin, resveratrol or their mixture before the administration of 6-hydroxydopamine (6-OHDA), recognized to induce parkinsonism in rats. Furthermore, N9 microglia cells, in a co-culture system with neuronal PC12, were pre-treated with viniferin, resveratrol or their mixture to investigate whether these polyphenols could reduce lipopolysaccharide (LPS)-induced inflammation. Our results show that viniferin as well as a mixture of viniferin and resveratrol protects neuronal dopaminergic cells from 6-OHDA-induced cytotoxicity and apoptosis. Furthermore, when viniferin, resveratrol or their mixture was used to pre-treat microglia cells in our co-culture system, they reduced neuronal cytotoxicity induced by glial activation. Altogether, our data highlight a novel role for viniferin as a neuroprotective and anti-inflammatory molecule in a dopaminergic cellular model, paving the way for nutraceutical therapeutic avenues in the complementary treatments of PD. [ABSTRACT FROM AUTHOR]

• Stilbenes (ST-99, the mixture and trans- ε -viniferin) induced cytotoxic effects in both cells. • Trans -resveratrol underwent the lowest toxic effects. • Inhibiting cell proliferation and induction of apoptosis were observed in HepG2. • The mixture of major stilbenes showed antagonistic effects by isobologram analysis. The use of stilbenes has been proposed as an alternative to sulfur dioxide in wine. Provided the feasibility from a technological approach, the cytotoxicity of an extract from grapevine shoots containing a stilbene richness of 99% (ST-99 extract) was assessed in the human cell lines HepG2 and Caco-2. In addition, the effects of the main stilbenes found in ST-99, trans -resveratrol and trans -ε-viniferin were studied, as well as its mixture. Similar cytotoxic effects were obtained in the exposures to trans -ε-viniferin, ST-99 and the mixture; however, trans -resveratrol alone exerted less toxicity. When HepG2 cells were exposed to trans -ε-viniferin, ST-99 and the mixture, the mean effective concentration (EC 50) were 28.28 ± 2.15, 31.91 ± 1.55 and 29.47 ± 3.54 µg/mL, respectively. However, in the exposure to trans -resveratrol, the EC 50 was higher 50 µg/mL. The morphological study evidenced damage at ultrastructural level in HepG2 cells, highlighting the inhibition of cell proliferation and the induction of apoptosis. The type of interaction produced by trans -ε-viniferin and trans- resveratrol mixtures was assessed by an isobologram analysis using the CalcuSyn software, evidencing an antagonist effect. These data comprise a starting point in the toxicological assessment; further studies are needed in this field to assure the safety of the extract ST-99. [ABSTRACT FROM AUTHOR]

We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC 50 ∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca 2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of trans-ε-viniferin in small volumes (10μl) of mouse plasma using chlorpropamide as an internal standard was developed and validated. Plasma samples were precipitated with acetonitrile and separated using an Eclipse Plus C 18 column (100×4.6mm, 1.8-μm) with a mobile phase consisting of 0.1% formic acid in acetonitrile and 0.1% formic acid in water (60:40v/v) at a flow rate of 0.5ml/min. A triple quadrupole mass spectrometer operating in positive ion mode with selected reaction-monitoring mode was used to determine trans-ε-viniferin and chlorpropamide transitions of 455.10→215.05 and 277.00→111.00, respectively. The lower limit of quantification was 5ng/ml with a linear range of 5-2500ng/ml (r≥0.9949). All validation data, including the selectivity, precision, accuracy, recovery, dilution integrity, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of trans-ε-viniferin following intravenous (2.5mg/kg), intraperitoneal (2.5, 5 and 10mg/kg), and oral (40mg/kg) administration in mice. This is the first report on the pharmacokinetic properties of trans-ε-viniferin. The results provide a meaningful basis for evaluating the pre-clinical or clinical applications of trans-ε-viniferin., (Copyright © 2016 Elsevier B.V. All rights reserved.)