Evaluation of natural resveratrol multimers as marine antifoulants.

In the current study we investigate the antifouling potential of three polyphenolic resveratrol multimers (-)-hopeaphenol, vaticanol B and vatalbinoside A, isolated from two species of Anisoptera found in the Papua New Guinean rainforest. The compounds were evaluated against the growth and settlement of eight marine microfoulers and against the settlement and metamorphosis of Amphibalanus improvisus barnacle cyprids. The two isomeric compounds (-)-hopeaphenol and vaticanol B displayed a high inhibitory potential against the cyprid larvae metamorphosis at 2.8 and 1.1 µM. (-)-Hopeaphenol was also shown to be a strong inhibitor of both microalgal and bacterial adhesion at submicromolar concentrations with low toxicity. Resveratrol displayed a lower antifouling activity compared to the multimers and had higher off target toxicity against MCR-5 fibroblasts. This study illustrates the potential of natural products as a valuable source for the discovery of novel antifouling leads with low toxicity.

Elucidation of the inhibitory effect of (+)-hopeaphenol on polyinosinic-polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells.

Drug development for regulating the innate immune system is important for the prevention and treatment of autoinflammatory and autoimmune diseases. In this context, we investigated the effect of resveratrol derivatives on the inflammatory reactions in the brain. Resveratrol, which can be found in Vitis plants in the form of oligomers, exhibits neuroprotective effects; however, its regulatory effects on innate immunity are still unclear. We examined the effects of (+)-hopeaphenol, a resveratrol tetramer, and its derivatives on the polyinosinic-polycytidylic acid (poly IC)-induced production of interferon (IFN)-ß and C-X-C motif chemokine 10 (CXCL10) in the cultured human cerebral microvascular endothelial cell line hCMEC/D3. (+)-Hopeaphenol (1-10 µM) inhibited the poly IC-induced production of not only CXCL10 but also retinoic acid-inducible gene-I in a dose-dependent manner and significantly reduced the poly IC-induced IFN-ß gene expression and protein release from hCMEC/D3 cells by inhibiting the phosphorylation of p65 but not that of the interferon regulatory transcription factor IRF3. A docking study indicated a high affinity of (+)-hopeaphenol for p65. These results suggest that (+)-hopeaphenol can regulate the innate immune system by inhibiting the poly IC/IFN-ß/CXCL10 signaling axis via suppression of the phosphorylation of the transcription factor NF-ĸB.

Vitisin B, a resveratrol tetramer from Vitis thunbergii var. taiwaniana, ameliorates impaired glucose regulations in nicotinamide/streptozotocin-induced type 2 diabetic mice.

Background and aim: In Taiwan, Vitis thunbergii var. taiwaniana (VTT) is used in traditional medicine and as a local tea. VTT rich in resveratrol and resveratrol oligomers have been reported to exhibit anti-obesity and anti-hypertensive activities in animal models; however, no studies have investigated type 2 diabetes mellitus (T2DM) treatments. This study aimed to investigate the anti-T2DM effects of resveratrol tetramers isolated from the VTT in nicotinamide/streptozotocin (STZ)-induced Institute of Cancer Research (ICR) mice. Experimental procedure: The oral glucose tolerance test (OGTT) was used to imitate postprandial blood glucose (BG) regulations in mice by pre-treatment with VTT extracts, resveratrol tetramers of vitisin A, vitisin B, and hopeaphenol 30 min before glucose loads. Vitisin B (50 mg/kg) was administered to treat T2DM-ICR mice once daily for 28 days to investigate its hypoglycemic activity. Results and conclusion: Mice pre-treated with VTT-S-95EE, or vitisin B (100 mg/kg) 30-min before glucose loading showed significant reductions (P < 0.001) in the area under the curve at 120-min (BG-AUC0-120) than those without pre-treatment with VTT-S-95 E E or vitisin B. Vitisin B-treated T2DM mice showed hypoglycemic activities via a reduction in plasma dipeptidyl peptidase (DPP)-IV activities to maintain insulin actions and differed significantly than those of untreated T2DM mice (P < 0.05), and also reduced BG-AUC0-120 and insulin-AUC0-120 in the OGTT.These in vivo results showed that VTT containing vitisin B would be beneficial for developing nutraceuticals and/or functional foods for glycemic control in patients with T2DM, which should be investigated further.

A resveratrol oligomer, hopeaphenol suppresses virulence activity of Pectobacterium atrosepticum via the modulation of the master regulator, FlhDC.

Pectobacterium atrosepticum (P. atrosepticum: Pba) which causes potato soft rot and blackleg is a notorious plant pathogen worldwide. Discovery of new types of antimicrobial chemicals that target specifically to virulence factors such as bacterial motility and extracellular enzymes is required for protecting crops from pathogenic infection. A transcriptomic analysis of Pba upon hopeaphenol treatment revealed that bacterial motility-related gene expression, including a master regulator flhDC genes, was significantly influenced by hopeaphenol. We further generated a double knock-out mutant of flhDC genes by CRISPR/Cas9 system and confirmed phenotypic changes in bacterial motility, transcription of extracellular enzymes, and disease development consistent with the result of wild-type treated with hopeaphenol. The hopeaphenol-treated Pba strains, wild-type, double mutant, and complemented strain were unable to secrete the enzymes in vitro, while ΔflhDC double mutant strain reduced the secretion. Thus, our study supports that FlhDC is essential for the virulence of Pba, and proposes that hopeaphenol modulates FlhDC-dependent virulence pathways, suggesting a potential of hopeaphenol as an anti-virulence agent to manage potato soft rot and blackleg diseases.

Structural analysis of the inhibitory effects of polyphenols, (+)-hopeaphenol and (-)-isohopeaphenol, on human SIRT1.

Human sirtuin 1 (hSIRT1) is a NAD+ -dependent deacetylase that regulates several cellular processes. Unlike resveratrol, natural polymeric phenolic compounds isolated from Vitaceae are mostly hSIRT1 inhibitors. The resveratrol tetramer, (+)-hopeaphenol ((+)-HP), and its geometric isomer, (-)-isohopeaphenol ((-)-iHP), were tested for inhibitory effects on purified hSIRT1 using a fluorescent derivative of peptide substrate p53-AMC (Fluor de Lys) and a cofactor NAD+ . The Lineweaver-Burk plots indicated that both (+)-HP and (-)-iHP were competitive inhibitors against NAD+ . Computer-assisted modeling of the binding of these molecules with hSIRT1 protein provided the most feasible conformation of the enzyme-inhibitor complex. © 2018 BioFactors, 45(2):253-258, 2019.

Using the relative abundance of characteristic product ions in UHPLC-ESI-QTOF-MS2 methods to identify isomers of resveratrol oligomers in extracts of Xinjiang winegrape stems.

Stilbenoids, particularly resveratrol and its oligomer, are abundantly present in grapes, and their antioxidant activities have been widely reported. A quick and simple method based on UHPLC-ESI-QTOF-MS2 was established for the fragmentation pathways analysis of trans-ε-Viniferin, cis-ε-Viniferin, trans-δ-Viniferin and (-)-Hopeaphenol. MS/MS experiments on the [M-H]- ions provided abundant structural information, especially regarding the relative abundance of the key product ion at m/z 347. The product ion was used to further identify structures in isomers of resveratrol dimers and its analogues. Based on the fragmentation pathways, we tentatively determined two compounds from the crude extracts of Xinjiang winegrape stems as Gnetin C and cis-Scirpusin A. Results from these experiments contribute to a more complete understanding of the stilbene compounds found in grape stems. The UHPLC-QTOF-MS2 method can be used for the rapid analysis of stilbenes compounds in plant materials, foods and wine.

Mechanical stress rapidly induces E-resveratrol and E-piceatannol biosynthesis in grape canes stored as a freshly-pruned byproduct.

Grape canes represent a promising source of bioactive phytochemicals. However the stabilization of the raw material after pruning remains challenging. We recently reported the induction of stilbenoid metabolism after winter pruning including a strong accumulation of E-resveratrol and E-piceatannol during the first six weeks of storage. In the present study, the effect of mechanical wounding on freshly-pruned canes was tested to increase the induction of stilbenoid metabolism. Cutting the grape canes in short segments immediately after pruning triggered a transient expression of phenylalanine ammonia-lyase (PAL) and stilbene synthase (STS) genes, followed by a rapid accumulation of E-resveratrol and E-piceatannol. The degree of stilbenoid induction was related to the intensity of mechanical wounding. Data suggest that a global defense response is triggered involving jasmonate signaling, PR proteins and stilbenoid metabolism. Mechanical wounding of freshly-pruned canes drastically shortens the time required to reach maximal stilbenoid accumulation from 6 to 2weeks.

Investigation of the absorption of resveratrol oligomers in the Caco-2 cellular model of intestinal absorption.

Resveratrol oligomers are biologically active polyphenols found in wine. No information about the bioavailability of these polyphenols is available. In order to discover if the resveratrol oligomers can pass the intestinal barrier, transport of the dimer ε-viniferin and the tetramer hopeaphenol was studied in the Caco-2 transwell system. A flux through the cell monolayer could neither be observed for ε-viniferin nor for hopeaphenol (apparent permeability coefficient (Papp)<1×10(-6)cms(-1)). In contrast, resveratrol showed a Papp of 11.9×10(-6)cms(-1). Nevertheless, about 16-30% of the oligomers were found in the lysed cellular fraction. This leads to the conclusion that the intestinal absorption rate of the two resveratrol oligomers, ε-viniferin and hopeaphenol, is low and negligible when compared to resveratrol. Therefore, it is unlikely that the oligomers could elicit a systemic biological effect after dietary intake. However, the compounds may act locally on the intestinal epithelium.