Resveratrol Dimer Research Articles

Mechanistic exploration of bioactive constituents in Gnetum gnemon for GPCR-related cancer treatment through network pharmacology and molecular docking

G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that have gained considerable attention as drug targets, particularly in cancer treatment. In this study, we explored the capacity of bioactive compounds derived from Gnetum gnemon (GG) for the development of of pharmaceuticals targeting GPCRs within the context of cancer therapy. Integrated approach combined network pharmacology and molecular docking to identify and validate the underlying pharmacological mechanisms. We retrieved targets for GG-derived compounds and GPCRs-related cancer from databases. Subsequently, we established a protein-protein interaction (PPI) network by mapping the shared targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to predict the mechanism of action of these targets. Molecular docking was conducted to validate our findings. We identified a total of 265 targets associated with GG-derived bioactive compounds for the treatment of GPCRs-related cancer. Functional enrichment analysis revealed the promising therapeutic effects of these targets on GPCRs-related cancer pathways. The PPI network analysis identified hub targets, including MAPK3, SRC, EGFR, STAT3, ESR1, MTOR, CCND1, and PPARG, which demonstrate as treatment targets for GPCRs-related cancer using GG-derived compounds. Additionally, molecular docking experiments demonstrated the strong binding affinity of gnetin A, gnetin C, (-)-viniferin, and resveratrol dimer, thus inhibiting MAPK3, SRC, EGFR, and MTOR. Survival analysis established the clinical prognostic relevance of identified hub genes in cancer. This study presents a novel approach for comprehending the therapeutic mechanisms of GG-derived active compounds and thereby paving the way for their prospective clinical applications in the field of cancer treatment.

Identification of Grape Laccase Genes and Their Potential Role in Secondary Metabolite Synthesis.

Laccase, a copper-containing oxidoreductase, has close links with secondary metabolite biosynthesis in plants. Its activity can affect the synthesis and accumulation of secondary metabolites, thereby influencing plant growth, development, and stress resistance. This study aims to identify the grape laccases (VviLAC) gene family members in grape (Vitis vinifera L.) and explore the transcriptional regulatory network in berry development. Here, 115 VviLACs were identified and divided into seven (Type I-VII) classes. These were distributed on 17 chromosomes and out of 47 VviLACs on chromosome 18, 34 (72.34%) were involved in tandem duplication events. VviLAC1, VviLAC2, VviLAC3, and VviLAC62 were highly expressed before fruit color development, while VviLAC4, VviLAC12, VviLAC16, VviLAC18, VviLAC20, VviLAC53, VviLAC60 and VviLAC105 were highly expressed after fruit color transformation. Notably, VviLAC105 showed a significant positive correlation with important metabolites including resveratrol, resveratrol dimer, and peonidin-3-glucoside. Analysis of the transcriptional regulatory network predicted that the 12 different transcription factors target VviLACs genes. Specifically, WRKY and ERF were identified as potential transcriptional regulatory factors for VviLAC105, while Dof and MYB were identified as potential transcriptional regulatory factors for VviLAC51. This study identifies and provides basic information on the grape LAC gene family members and, in combination with transcriptome and metabolome data, predicts the upstream transcriptional regulatory network of VviLACs.

Cytotoxicity of Benzofuran-Containing Simplified Viniferin Analogues.

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids show wide structural diversity and mediate a great number of biological responses relevant for human health, including cancer prevention and cytotoxicity. Resveratrol is known to modulate several pathways directly linked to cancer progression, as well as its analogue pterostilbene, characterized by an increased metabolic stability and significant pharmacological activities. To study the potential anticancer activity of other stilbenoids, a home-made collection of resveratrol dimers and simplified analogues was tested on melanoma A375, non-small cell lung cancer H460 and PC3 prostate cancer cell lines. The structural determinants responsible for the antiproliferative activity have been highlighted. Moreover, to investigate the DNA damage ability of the selected molecules, the expression of the γ-H2AX after compound exposure was evaluated.

Glucuronide metabolites of trans-ε-viniferin decrease triglycerides accumulation in an in vitro model of hepatic steatosis.

Trans-ε-viniferin, a resveratrol dimer found mainly in grapevine wood, has shown protective capacities against hepatic steatosis in vivo. Nevertheless, this compound is very poorly bioavailable. Thus, the aim of the present study is to determine the potential anti-steatotic properties of 1 and 10µM of trans-ε-viniferin and its four glucuronide metabolites in AML-12 cells treated with palmitic acid as an in vitro model of hepatic steatosis. The effect of the molecules in cell viability and triglyceride accumulation, and the underlying mechanisms of action by Real-Time PCR and Western Blot were analysed, as well as the quantification of trans-ε-viniferin and the identified bioactive metabolite inside cells and their incubation media. Interestingly, we were able to determine the triglyceride-lowering property of one of the glucuronides (trans-ε-viniferin-2-glucuronide), which acts on de novo lipogenesis, fatty acid uptake and triglyceride assembly. The glucuronides of trans-ε-viniferin would therefore be partly responsible for the in vivo observed anti-steatotic properties of the parent compound.

Identification and Reduction of Bitter Taste Determinant Compounds in Chocolate Spread Formulated with Candlenut

Candlenuts can be used as a substitute in producing chocolate spread due to their high-fat content. However, the limitation of using candlenut in the spread formulation is the existence of a bitter taste. This study aimed to investigate the effect of sodium bisulfite and sodium bicarbonate soaking treatment (100, 300, and 500 ppm) on reducing the bitter taste of candlenut seed. In order to reach the goal, bitter compounds of candlenut and chocolate spread were identified using Liquid chromatography-mass spectrometry (LC-MS). The sensory characteristics of chocolate spread were profiled using the Rate All That Apply (RATA) descriptive method. It was shown that the panelists identified 14 sensory attributes in the samples, one of which was bitter taste. Treatment with sodium bisulfite, as well as sodium bicarbonate at the level of 300 ppm, reduced the intensity of the bitter taste. The treatment reduced flavonoid and tannin levels by 85.21% and 82.08% in candlenut seeds. It also reduced flavonoid and tannin levels by 88.47% and 72.71% in chocolate spread, respectively. LC-MS identified 13 compounds that cause the bitter taste, namely quercetin, oleuropein, kaemferol, resveratrol dimer, luteolin, epicatechin, theobromine, caffeine, iso-humolones, colaflavone, chlorogenic acid, feruloyl-caffeoylquinic acid, and coumaroylquinic acid. This study creates a new technique for producing chocolate spread formulated with candlenuts with lower bitterness levels.

An insight into the mechanistic role of (-)-Ampelopsin F from Vatica chinensis L. in inducing insulin secretion in pancreatic beta cells

Resveratrol oligomers, ranging from dimers to octamers, are formed through regioselective synthesis involving the phenoxy radical coupling of resveratrol building blocks, exhibiting remarkable therapeutic potential, including antidiabetic properties. In this study, we elucidate the mechanistic insights into the insulin secretion potential of a resveratrol dimer, (-)-Ampelopsin F (AmF), isolated from the acetone extract of Vatica chinensis L. stem bark in Pancreatic Beta-TC-6 cell lines. The AmF (50 µM) treated cells exhibited a 3.5-fold increase in insulin secretion potential as compared to unstimulated cells, which was achieved through the enhancement of mitochondrial membrane hyperpolarization, elevation of intracellular calcium concentration, and upregulation of GLUT2 and glucokinase expression in pancreatic Beta-TC-6 cell lines. Furthermore, AmF effectively inhibited the activity of DPP4, showcasing a 2.5-fold decrease compared to the control and a significant 6.5-fold reduction compared to the positive control. These findings emphasize AmF as a potential lead for the management of diabetes mellitus and point to its possible application in the next therapeutic initiatives.

Ganoderma tuberculosum Liquid Culture With Vineyard Pruning Extracts for Bioactive Composite Production With Antiproliferative Activity.

Ganoderma species have been studied for their pharmacological approaches, such as anticancer, antitumor, antiproliferative, and antioxidant activity. Elicitors are used to increase Ganoderma bioactive composite production. This study aims to evaluate the antiproliferative activity of ethanolic extracts from mycelium of Ganoderma tuberculosum (G. tuberculosum) grown in a liquid medium with vineyard pruning waste (VPW) extracts as elicitors. Ethanolic and aqueous VPW extracts contain resveratrol dimer 4, resveratrol tetramer 1, and naringenin, while toluene and chloroform extracts contain tetradecanoic acid, hexadecanoic acid, and octadecanoic acid. Polar and nonpolar extracts could be promising elicitors for increasing bioactive molecules. Catechin gallate showed the highest correlation (r = 0.66) with biomass. Mycelial ethanolic extracts of G. tuberculosum (native strain from the Sonoran Desert) and Ganoderma lucidum (G. lucidum) (control) were analyzed by ESI-IT-MS, and 27 molecules were identified for the two species. They showed antiproliferative activity against the A549 and C-33 A cell lines but not for ARPE-19. G. tuberculosum culture with VPW had quinic acid, ganodermenonol, ganoderic acid I (GA-I), C2 (GA-C2), and 20-hydroxylucidenic acid P, among others. Molecular docking of ganodermenonol, GA-I, and GA-C2 demonstrates significant interaction with tumor necrotic factor (TNF-α). These ethanolic extracts of Ganoderma are promising sources of bioactive triterpenoids. Their antiproliferative activity did not change between species or treatment. Likewise, the G. tuberculosum and G. lucidum extracts only affected cancer cell lines. This property seems promising for pharmacological applications of these fungal extracts.

Radical scavenging activity of three Scirpusins: A kinetic and mechanistic study

The strong antioxidant activity of Scirpusin, a polyphenolic compound also known as resveratrol or piceatannol dimer, toward •OH/•OOH in gas phase and solvents was investigated through systematic thermodynamics and kinetics analyses using the density functional theory method. All mechanisms, including hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), sequential proton loss electron transfer (SPLET), and radical adduct formation (RAF), were investigated. The transition state theory was used to calculate potential energy surfaces and rate constants for HAT and RAF. The results revealed that Scirpusins exhibited considerable antioxidant activity, which followed the sequence: Scirpusin-B > Scirpusin-C ≈ Scirpusin-A, the amount of o-bisphenol is essential to enhance their antioxidant activity. Furthermore, Scirpusin-A, Scirpusin-B, and Scirpusin-C with structures of 13′-OH, 12′-OH, and 2-OH, respectively, shared the same parent nucleus but exhibited distinct strongest reactive sites. This result can provide a guidance for Scirpusin application in the future.

Combining Laccase-Mediated Dimerization of Resveratrol and Centrifugal Partition Chromatography: Optimization of E-Labruscol Production and Identification of New Resveratrol Dimers

Combining Laccase-Mediated Dimerization of Resveratrol and Centrifugal Partition Chromatography: Optimization of <i>E</i>-Labruscol Production and Identification of New Resveratrol Dimers

The mechanism of trans-δ-viniferin inhibiting the proliferation of lung cancer cells A549 by targeting the mitochondria.

Trans-δ-viniferin (TVN), as a natural extract, is a resveratrol dimer with attractive biological activities, particularly its anti-tumor character. However, the mechanism of TVN interfering with cancerous proliferation has not been fully understood. Herein in this study, we found that TVN could trigger cancerous mitochondrial membrane potential (ΔΨm) reduction, with intracellular reactive oxidative species (ROS) level increasing, leading to apoptosis, which makes TVN a promising candidate for lung cancer cells A549 treatment. Therefore, this study provides TVN as an option to meet the demand for higher antitumor availability with lower biotoxicity and other clinical applications.

Beneficial Effects of ε-Viniferin on Obesity and Related Health Alterations

Viniferin is a phenolic compound belonging to the group of stilbenoids. In particular, ε-viniferin is a dimer of resveratrol, found in many plant genders, among which grapes (Vitis vinifera) are a primary source. Due to the fact that ε-viniferin is mainly present in the woody parts of plants, their use as a source of this bioactive compound is a very interesting issue in a circular economy. Both, in vitro studies carried out in pre-adipocytes and mature adipocytes and in vivo studies addressed in mice show that ε-viniferin is able to reduce fat accumulation. Moreover, it prevents the development of some obesity co-morbidities, such as type 2 diabetes, dyslipidemias, hypertension and fatty liver. ε-viniferin can be absorbed orally, but it shows a very low bioavailability. In this scenario, further research on animal models is needed to confirm the effects reported in a great number of studies; to determine which metabolites are involved, including the main one responsible for the biological effects observed and the mechanisms that justify these effects. In a further phase, human studies should be addressed in order to use ε-viniferin as a new tool for obesity management, as a nutraceutical or to be included in functional foods.

Gnetin C Intercepts MTA1-Associated Neoplastic Progression in Prostate Cancer.

Nutritional chemoprevention is particularly suitable for prostate cancer. Gnetin C, a resveratrol dimer found abundantly in the melinjo plant (Gnetum gnemon), may possess more potent biological properties compared to other stilbenes. We examined the effects of gnetin C in a high-risk premalignant transgenic mouse model overexpressing tumor-promoting metastasis-associated protein 1 (MTA1) on the background of Pten heterozygosity (R26MTA1; Pten+/f; Pb-Cre+). Mice were fed diets supplemented with the following compounds: pterostilbene (70 mg/kg diet); gnetin C, high dose (70 mg/kg diet); and gnetin C, low dose (35 mg/kg diet). Prostate tissues were isolated after 17 weeks and examined for histopathology and molecular markers. Serum was analyzed for cytokine expression. Gnetin C-supplemented diets substantially delayed the progression of preneoplastic lesions compared to other groups. Prostate tissues from gnetin C-fed mice showed favorable histopathology, with decreased severity and number of prostatic intraepithelial neoplasia (PIN) foci, reduced proliferation, and angiogenesis. A decreased level of MTA1, concurrent with the trend of increasing phosphatase and tensin homolog expression and reduced interleukin 2 (IL-2) levels in sera, were also detected in gnetin C-fed mice. Importantly, gnetin C did not exert any visible toxicity in mice. Our findings demonstrate that a gnetin C-supplemented diet effectively blocks MTA1-promoted tumor progression activity in high-risk premalignant prostate cancer, which indicates its potential as a novel form of nutritional interception for prostate cancer chemoprevention.

Healing effects of monomer and dimer resveratrol in a mouse periodontitis model

BackgroundThe antioxidant and anti-inflammatory effects of resveratrol have been reported previously. Particularly, monomeric trans-resveratrol has been demonstrated to produce positive effects in various pathological processes. We reported previously that resveratrol dimer-rich melinjo extract, among others, caused bone healing, decreased local oxidative damage, and activated antioxidants nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a mouse model of experimentally induced periodontitis (EP). This study aimed to compare the bone-healing effects of the resveratrol monomer to the resveratrol dimer (gnetin C found in melinjo seed extract) in a model of EP and investigate the involvement of Nrf2 for effects of either form of resveratrol.MethodsEP was induced experimentally in mice by placement of a 9 − 0 silk ligature around the left second molar. Mice received 10 mg/kg of either resveratrol monomer or dimer intraperitoneally on day 15 after induction of EP. The bone level around the ligated teeth was measured over time, and levels of proinflammatory cytokines and oxidative stress were measured in the periodontal tissues around the ligated teeth.ResultsResveratrol dimer induced greater periodontal bone healing as compared to that related to use of the resveratrol monomer. It appears that healing of periodontal bone in either group was likely related to master regulation of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) significantly. Downregulation of IL-1β, a proinflammatory cytokine was also demonstrated in the resveratrol dimer group.ConclusionOur results showed that administration of resveratrol in either dimer form or the monomeric form reduced periodontal bone loss with greater inhibition of bone loss being demonstrated in the dimer group as compared to the monomer group and that these effects were related in all likelihood to decreased oxidative stress and hence reduction in local inflammation.

Computation-Guided Total Synthesis of Vitisinol G.

Computational chemistry is useful in synthetic organic chemistry, as it can be used not only to analyze reaction mechanisms, but also to calculate biosynthetic pathways and to plan and evaluate strategies for total syntheses. Here we report the computation-guided total synthesis of vitisinol G, a resveratrol dimer.

Exploring the mechanism of stilbenes to quench singlet oxygen based on the key structures of resveratrol and its analogues

Stilbenes, especially resveratrol and resveratrol dimers, can quench singlet oxygen (1O2) effectively. Studies found resorcinol, catechol, carbon–carbon double bonds in resveratrol dimers and resveratrol monomers all contributed to quenching 1O2. However, which structures play a key role in quenching of 1O2 by stilbenes had not yet been determined. To explore it, UHPLC-QQQ-MS2 and UHPLC-QTOF-MS2 were used to analyze and compare the 1O2 quenching activities of piceatannol, resveratrol, dihydroresveratrol, pterostilbene, trimethoxystilbene and oxyresveratrol in vitro. The results showed that all six compounds exhibited some capacity to quench 1O2. Catechol [i.e., C6H4(OH)2] had the strongest capacity to quench of 1O2 amongst the stilbenes tested followed by the presence of carbon–carbon double bonds. This offers insight a route for screening for stilbenes with higher activities that might have a role in development of novel food-related antioxidants and functional foods with potential health benefits.

Highly Efficient Bioconversion of trans-Resveratrol to δ-Viniferin Using Conditioned Medium of Grapevine Callus Suspension Cultures.

δ-Viniferin is a resveratrol dimer that possesses potent antioxidant properties and has attracted attention as an ingredient for cosmetic and nutraceutical products. Enzymatic bioconversion and plant callus and cell suspension cultures can be used to produce stilbenes such as resveratrol and viniferin. Here, δ-viniferin was produced by bioconversion from trans-resveratrol using conditioned medium (CM) of grapevine (Vitis labruscana) callus suspension cultures. The CM converted trans-resveratrol to δ-viniferin immediately after addition of hydrogen peroxide (H2O2). Peroxidase activity and bioconversion efficiency in CM increased with increasing culture time. Optimized δ-viniferin production conditions were determined regarding H2O2 concentration, incubation time, temperature, and pH. Maximum bioconversion efficiency reached 64% under the optimized conditions (pH 6.0, 60 °C, 30 min incubation time, 6.8 mM H2O2). In addition, in vitro bioconversion of trans-resveratrol was investigated using CM of different callus suspension cultures, showing that addition of trans-resveratrol and H2O2 to the CM led to production of δ-viniferin via extracellular peroxidase-mediated oxidative coupling of two molecules of trans-resveratrol. We thus propose a simple and low-cost method of δ-viniferin production from trans-resveratrol using CM of plant callus suspension cultures, which may constitute an alternative approach for in vitro bioconversion of valuable molecules.

Practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin

A practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin (2) with benzyl as protecting group for phenols was achieved with high overall yield. The synthetic approach involved a palladium-catalyzed direct arylation, triethylsilane-mediated reduction of benzofuran, and selective debenzylation reaction. Selective debenzylation in the presence of reducible and acid-sensitive groups catalyzed using Pd/C and 1,4-cyclohexadiene was implemented to complete the total synthesis.

In the shadow of resveratrol: biological activities of epsilon-viniferin.

Stilbenes are secondary metabolites belonging to the polyphenol family. Those compounds are derived from the glycosylation, prenylation, methoxylation, hydroxylation, or also oligomerization of the well-known trans-resveratrol. One of them, trans-epsilon-viniferin (ε-viniferin), is a trans-resveratrol dimer that arouses the interest of researchers in the field of human health. The biosynthesis of this molecule in various plant species, particularly high in the Vitaceae family, explains its presence in some red wines, which represent the main source of ε-viniferin in the human diet. Although bioavailability studies have shown poor absorption and high metabolism of this stilbene, multiple studies demonstrated its biological properties. The ε-viniferin exhibits strong activities against inflammatory and oxidative stress. Moreover, various studies have reported great activity of this compound not only in a wide range of disorders and diseases, such as cancer, obesity, and its associated disorders, but also in vascular diseases and neurodegeneration, for which the pathophysiology is closely related to the state of oxidation and inflammation. This review provides a state of art of the main activities of ε-viniferin demonstrated in vitro and in vivo, highlighting that this resveratrol dimer could be a promising candidate for future functional foods or supplement foods used for the management of many chronic diseases of concern in terms of public health.

UPLC MS/MS Profile and Antioxidant Activities from Nonpolar Fraction of Patiwala (Lantana camara) Leaves Extract

One of the plants used in Indonesian traditional medicine, namely, Patiwala (Lantana camara), is traditionally used to treat some diseases, including itching, wounds, ulcers, swelling, eczema, tetanus, malaria, tumors, rheumatism, and headaches. This study aimed to characterize the compound nonpolar fraction of Patiwala leaf capable of scavenging free radicals. The characterization of compound was carried out using the Ultra-Performance Liquid Chromatography–tandem Mass Spectrometry (UPLC-MS/MS) with positive ion method, while the antioxidant testing was carried out using the radical DPPH (2,2-diphenyl-1-picrylhidrazyl) and FRAP (ferric reducing antioxidant power) methods. The results showed that the nonpolar fraction of the methanol extract of L. camara leaves was very strong toward DPPH radicals (IC50 34.65 ± 1.26 μg/mL and 40.23 ± 0.18 μg/mL), and FRAP radical (IC50 4.93 ± 0.22 μg/mL and 12.79 ± 0.09 μg/mL). Nineteen compounds identified by UPLC-MS/MS method were Resveratrol dimer, iso-humolones, oleuropein glucoside, quercetin-3-O-glycoside, myricetin, oleuropein, 12-deoxy-16-hydroxy-phorbol, aloeresin A, humulones, ursolic acid, viniferin, Epicatechin, oleanolic acid, 5-hydroxy-3′,4′,7-trimerthoxy-flavanone, Apigenin-6,8-di-C-β-D-glucoside, procyanidin A2, caffeoyl-O-hexoside, tansihnone IIA, and phillyrin. The methanolic extract of L. camara leaves can be developed as a source of antioxidants from natural ingredients.

Mechanistic study on the radical scavenging activity of viniferins

As an important chemical component of grapes, viniferins are essential dimers of natural product resveratrol with good antioxidant activity. In this study, we have examined the antioxidant activity of two viniferin molecules (δ-viniferin and ε-viniferin) with ·OH/·OOH radicals. Density functional theory (DFT) calculations at the M062X/6–311++G(d,p)-SMD//M062X/6–311G(d,p) level of theory in the gas phase, water, and benzene used to examine two crucial radical scavenging pathways: hydrogen atom transfer (HAT) and the radical adduct formation (RAF). Then, the radical scavenging activities of the two molecules are compared kinetically and thermodynamically. The Gibbs free energy of activation (ΔG≠) and rate constant (kTST) are calculated using the conventional transition state theory (TST), and the results reveal that HAT and RAF processes compete in different solvents. Furthermore, molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) of both the compounds are computed to elucidate their antioxidant activity. The results show that the RAF site appears at the >C7C8< double bond position of δ- and ε-viniferins, and the most favorable HAT positions of δ-viniferin and ε-viniferin are 12′-OH and 12-OH, respectively; in addition, ε-viniferin is a more potent radical scavenging agent than δ-viniferin. These findings provide useful insights on the antioxidant activity of viniferins and different radical scavenging mechanisms of antioxidants, which can be beneficial for improving the practical utilization of resveratrol dimer and other analogs.