Soy lipophilic protein self-assembled by pH-shift combined with heat treatment: Structure, hydrophobic resveratrol encapsulation, emulsification, and digestion.

This study evaluates the effect of pH (pH 3 and 11) and heat treatment (60 °C) in modifying the soybean lipophilic protein (LP) for the development of an encapsulation system to co-deliver resveratrol (Res) and vitamin D3. The structural and functional properties of LP after the modification will change to varying degrees. Meanwhile, Res was loaded into the hydrophobic core of LP, and the resulting Res-loaded structures have a uniform particle size distribution and a high encapsulation efficiency (78%). When the amount of Res encapsulation increases, the emulsification and oxidation resistance of the Pickering emulsion increased; the interfacial tension and interfacial protein adsorption increased to 11.21 mN/m and 97.34%, respectively. During simulated gastrointestinal digestion, the Pickering emulsion prepared with LP-Res nanoparticles at pH 11, 60 °C (pH 11, 60 °C-LP-Res) effectively protected Res and vitamin D3 from degradation or precipitation, indicating a significant increase in bioavailability.

Quantitative analysis of resveratrol derivatives in the seed coats of tree peonies and their hypoglycemic activities in vitro/vivo.

Tree peonies are well-known horticultural and medicinal plants. The tree peony seeds, as emerging woody oil crops, recently have attracted great attention for their metabolites and bioactivities. In this study, the phytochemicals isolated from tree peony seed coats were systematically investigated. Seven polyphenolics were separated and prepared, mainly belonging to resveratrol derivatives. There was a great variation in the seed coat polyphenolic content among eight Paeonia species, and the contents of the resveratrol trimers and dimers were significantly higher in the seed coats of Paeonia ostii than other species. Based on the HPLC fingerprint characteristics and chemometric analysis, a clear discrimination among Paeonia plants was found, including the composition patterns and contents of the constituents. Moreover, the characteristic phytochemicals (vateriferol and trans-ε-viniferin) could significantly reduce the starch-mediated levels of postprandial blood glucose in diabetic/normal mice. In addition, in vitro enzyme tests showed that the two compounds could effectively and competitively inhibit α-glucosidase, with the IC50 values of 3.01 and 7.75 µM, respectively, indicating that vateriferol and trans-ε-viniferin could be therapeutic potential agents for hyperglycemia and diabetes mellitus.

Anti-Proliferative and Anti-Telomerase Effects of Blackberry Juice and Berry- Derived Polyphenols on HepG2 Liver Cancer Cells and Normal Human Blood Mononuclear Cells.

BACKGROUND: Previous studies have provided strong evidence for the anticancer activity of berry fruits. OBJECTIVE: In this study, we investigated the effects of blackberry juice and three berry- polyphenolic compounds on cell proliferation and telomerase activity in human hepatoma HepG2 and normal peripheral blood mononuclear cells (PBMCs). METHODS: The cell viability and telomerase activity were measured by MTT and TRAP assay, respectively. Berry effects on the expression of genes were determined by quantitative RT-PCR assay. RESULTS: Blackberry, gallic acid, and resveratrol inhibited proliferation of both HepG2 and PBMC cells in a dosedependent manner. Resveratrol was more effective than gallic acid for reducing the viability of HepG2 cells, but both showed the same level of growth inhibition in PBMC cells. Berry, resveratrol, and gallic acid significantly inhibited telomerase activity in HepG2 cells. The antiproliferative effect of berry was associated with apoptotic DNA fragmentation. Gallic acid was more effective for reducing telomerase activity than resveratrol, but anthocyanin moderately increased telomerase activity in cancer cells. Telomerase activity was induced by all three polyphenols in PBMCs. Overall, Krumanin chloride was more effective to induce telomerase than gallic acid and resveratrol in PBMC cells. There was no significant difference in hTERT, hTR, and Dnmts expressions between berry treated and the control untreated HepG2 cells. But, a significant downregulation of HDAC1 and HDAC2 and upregulation of SIRT1 were observed in berry-treated cells. CONCLUSION: These data indicate that the berry anticancer effect is associated with antitelomerase activity and changes in HDACs expression. The data also suggest that berry antitelomerase activity is mainly related to its gallic acid and resveratrol, but not anthocyanin content.

Enhancing bioaccessibility of resveratrol by loading in natural porous starch microparticles.

Resveratrol (RSV) is a lipophilic polyphenol susceptible to photo- and thermal degradation, and strategies are to be studied to enable its distribution in food matrices, prevent its degradation during storage, and increase its bioaccessibility during digestion. In this study, the porous matrix of natural starch, in the form of milled freeze-dried potato microparticles (FDPMs), was studied as an absorbent to load RSV. The binary solvent of ethanol and polyethylene glycol 400 (40:60 v/v) was used to dissolve 30% w/v RSV for diffusion into FDPMs. After ethanol was evaporated, the loading capacity was 112 mg RSV/g FDPMs and was maintained at 104 mg RSV/g FDPMs (92.9% retention) after 110-day ambient storage. The RSV stability under UV irradiation at 253 nm was improved by 32% due to shielding effect of FDPMs, and the ferric reducing power was 25% higher than the pristine RSV. The release of RSV in FDPMs was significantly higher than pristine RSV during simulated gastric and intestinal digestions (82.3% vs 51.4% bioaccessibility). The increased reducing power and bioaccessibility were supported by the amorphous state of RSV in FDPMs. The present study illustrates the potential of porous vegetable microparticles as natural matrices to load lipophilic bioactive compounds in functional foods.

Oral Administration of Resveratrol-Selenium-Peptide Nanocomposites Alleviates Alzheimer's Disease-like Pathogenesis by Inhibiting Aß Aggregation and Regulating Gut Microbiota.

Alzheimer's disease (AD) is a neurodegenerative disease associated with amyloid-ß (Aß) deposition, leading to neurotoxicity (oxidative stress and neuroinflammation) and gut microbiota imbalance. Resveratrol (Res) has neuroprotective properties, but its bioavailability in vivo is very low. Herein, we developed a small Res-selenium-peptide nanocomposite to enable the application of Res for eliminating Aß aggregate-induced neurotoxicity and mitigating gut microbiota disorder in aluminum chloride (AlCl3) and d-galactose(d-gal)-induced AD model mice. Res functional selenium nanoparticles (Res@SeNPs) (8 ± 0.34 nm) were prepared first, after which the surface of Res@SeNPs was decorated with a blood-brain barrier transport peptide (TGN peptide) to generate Res-selenium-peptide nanocomposites (TGN-Res@SeNPs) (14 ± 0.12 nm). Oral administration of TGN-Res@SeNPs improves cognitive disorder through (1) interacting with Aß and decreasing Aß aggregation, effectively inhibiting Aß deposition in the hippocampus; (2) decreasing Aß-induced reactive oxygen species (ROS) and increasing activity of antioxidation enzymes in PC12 cells and in vivo; (3) down-regulating Aß-induced neuroinflammation via the nuclear factor kappa B/mitogen-activated protein kinase/Akt signal pathway in BV-2 cells and in vivo; and (4) alleviating gut microbiota disorder, particularly with respect to oxidative stress and inflammatory-related bacteria such as Alistipes, Helicobacter, Rikenella, Desulfovibrio, and Faecalibaculum. Thus, we anticipate that Res-selenium-peptide nanocomposites will offer a new potential strategy for the treatment of AD.

Enhancing Bioavailability of Nutraceutically Used Resveratrol and Other Stilbenoids.

Stilbenoids are interesting natural compounds with pleiotropic in vitro and in vivo activity. Their well-documented biological properties include anti-inflammatory effects, anticancer effects, effects on longevity, and many others. Therefore, they are nowadays commonly found in foods and dietary supplements, and used as a part of treatment strategy in various types of diseases. Bioactivity of stilbenoids strongly depends on different types of factors such as dosage, food composition, and synergistic effects with other plant secondary metabolites such as polyphenols or vitamins. In this review, we summarize the existing in vitro, in vivo, and clinical data from published studies addressing the optimization of bioavailability of stilbenoids. Stilbenoids face low bioavailability due to their chemical structure. This can be improved by the use of novel drug delivery systems or enhancers, which are discussed in this review. Current in vitro and in vivo evidence suggests that both approaches are very promising and increase the absorption of the original substance by several times. However, data from more clinical trials are required.

Natural Product-Based Hybrids as Potential Candidates for the Treatment of Cancer: Focus on Curcumin and Resveratrol.

One of the main current strategies for cancer treatment is represented by combination chemotherapy. More recently, this strategy shifted to the "hybrid strategy", namely the designing of a new molecular entity containing two or more biologically active molecules and having superior features compared with the individual components. Moreover, the term "hybrid" has further extended to innovative drug delivery systems based on biocompatible nanomaterials and able to deliver one or more drugs to specific tissues or cells. At the same time, there is an increased interest in plant-derived polyphenols used as antitumoral drugs. The present review reports the most recent and intriguing research advances in the development of hybrids based on the polyphenols curcumin and resveratrol, which are known to act as multifunctional agents. We focused on two issues that are particularly interesting for the innovative chemical strategy involved in their development. On one hand, the pharmacophoric groups of these compounds have been used for the synthesis of new hybrid molecules. On the other hand, these polyphenols have been introduced into hybrid nanomaterials based on gold nanoparticles, which have many potential applications for both drug delivery and theranostics in chemotherapy.

Spray dried nanoemulsions loaded with curcumin, resveratrol, and borage seed oil: The role of two different modified starches as encapsulating materials.

Recently, food industries are directing on the promotion of innovative food matrices fortified with bioactive compounds in order to enhance the consumer's health. Octenyl succinic anhydride modified starches (OSA-MS) such as Hi-cap100 (HCP) and purity gum 2000 (PUG) were used to fabricate emulsions co-entrapped with borage seed oil (BSO), resveratrol (RES) and curcumin (CUR), which were further spray dried to obtain powders. The fabricated microcapsules loaded with BSO, RES, and CUR displayed excellent dissolution performance, high encapsulation efficiency (≈93.05%) as well as semi-spherical shape, revealed via scanning electron microscopy (SEM). We also evaluated the impact of storage time (4 weeks) and temperature (40 °C) on the physicochemical characterization of OSA-MS coated microcapsules. Microcapsules coated with HCP exhibited greater oxidative stability, lower water activity and moisture contents rather than PUG coated microcapsules during storage because of its good film-forming properties. Addition of CUR enhanced the oxidative stability and retention of bioactive compounds. HCP microcapsules loaded with BSO + RES + CUR presented supreme retention of RES (70.32%), CUR 81.6% and γ-linolenic acid (≈ 96%). Our findings showed that CUR acted as an antioxidant agent; also, lower molecular weight OSA-MS as wall material could be used for the entrapment of bioactive compounds and promotion of innovative food products.

Fabrication and performance evaluation of pectin-fish gelatin-resveratrol preservative films.

Resveratrol-loaded fish gelatin (FG)-low methoxyl pectin (LMP) composite films with different FG:LMP mass ratios were prepared and evaluated as food packaging materials. With increasing FG contents, the water solubility of the films decreased. Moreover, the UV (315-400 nm) blocking efficiency and opacity increased with increasing LMP contents. The elongation of the films at breaking and tensile strengths were adjusted using the ratio of FG and LMP. The lowest water vapour permeability was observed at an FG:LMP mass ratio of 2:1. All films exhibited good antioxidant properties and significantly delayed oil deterioration when used for beef tallow preservation. The release behaviour of resveratrol in 95% ethanol as a food simulant was determined by film composition. The fabricated films exhibit significant potential for beef tallow preservation applications. Furthermore, LMP can improve the stability of resveratrol-FG complexes and compete with resveratrol for binding FG to accelerate resveratrol release.

Bioassay-Guided Identification of the Antiproliferative Compounds of Cissus trifoliata and the Transcriptomic Effect of Resveratrol in Prostate Cancer Pc3 Cells.

The bioassay-guided fractionation of a CHCl3-MeOH extract from the stems of Cissus trifoliata identified an active fraction against PC3 prostate cancer cells. The treatment for 24 h showed an 80% reduction in cell viability (p ≤ 0.05) by a WST-1 assay at a concentration of 100 µg/mL. The HPLC-QTOF-MS analysis of the fraction showed the presence of coumaric and isoferulic acids, apigenin, kaempferol, chrysoeriol, naringenin, ursolic and betulinic acids, hexadecadienoic and octadecadienoic fatty acids, and the stilbene resveratrol. The exposure of PC3 cells to resveratrol (IC25 = 23 µg/mL) for 24 h induced significant changes in 847 genes (Z-score ≥ ±2). The functional classification tool of the DAVID v6.8 platform indicates that the underlying molecular mechanisms against the proliferation of PC3 cells were associated (p ≤ 0.05) with the process of differentiation and metabolism. These findings provide experimental evidence suggesting the potential of C. trifoliata as a promising natural source of anticancer compounds.

Mammalian Arginase Inhibitory Activity of Methanolic Extracts and Isolated Compounds from Cyperus Species.

Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1-2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C.thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1-7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4-7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model.

Measurement of Saccharin and trans-Resveratrol Metabolites in Urine as Adherence Markers for Small Quantity Lipid-Based Nutrient Supplement Consumption.

Saccharin and trans-resveratrol were incorporated into small quantity lipid-based nutritional supplements (SQ-LNS) to be evaluated as the markers of consumption for nutritional intervention studies. Forty-seven healthy women consumed a single supplement with either 8.6 mg of saccharin or 5 mg of trans-resveratrol, and urine was collected for 4 h. A rapid 11 min method employing multiple reaction monitoring and ultrahigh performance liquid chromatography coupled to a triple quadrupole mass spectrometer was developed to measure saccharin and resveratrol metabolites in urine simultaneously. The linear dynamic range of the method was from 3 to 1000 ng mL-1, with the correlation coefficient of 0.999 and limits of quantification from 15.28 to 53.03 ng mL-1. Sample preparation was simple dilution with an average recovery of 97.8%. Ion suppression was observed with urine concentrations >10%. Mean levels of saccharin and resveratrol-3-O-sulfate in urine were 5.481 ± 4.359 and 3.440 ± 4.160 nmol L-1, respectively. We developed and validated a method to measure saccharin and trans-resveratrol metabolites in urine to objectively corroborate the consumption of SQ-LNS for the first time in nutrition intervention studies.

The isolation of secondary metabolites from Rheum ribes L. and the synthesis of new semi-synthetic anthraquinones: Isolation, synthesis and biological activity.

Rheum ribes L. (Rhubarb) is one of the most important edible medicinal plants in the Eastern Anatolia region and is called "Iskin" by local people. Resveratrol and 6-O-methylalaternin were isolated from the Rhubarb for the first time in addition to well-known secondary metabolites including emodin, aloe-emodin, ß-sitosterol and rutin. The new semi-synthetic anthraquinone derivatives with the NαFmoc-l-Lys and ethynyl group were synthesized from the isolated anthraquinones emodin and aloe-emodin of Rhubarb to increase the bioactivities. Aloe-emodin derivative with NαFmoc-l-Lys shows the highest inhibition values by 94.11 ± 0.12 and 82.38 ± 0.00% against HT-29 and HeLa cell lines, respectively, at 25 µg/mL. Further, modification of the aloe-emodin with both the ethynyl and the NαFmoc-l-Lys groups showed an antioxidant activity-enhancing effect. From molecular docking studies, the relative binding energies of the emodin and aloe-emodin derivatives to human serum albumin ranged from -7.30 and -10.62 kcal/mol.

Combinatorial analysis of quercetin and resveratrol by HPTLC in Sesbania grandiflora/phyto-based nanoformulations.

A sensitive HPTLC method was developed for the simultaneous estimation of quercetin (QUR) and resveratrol (RES). The chromatographic separation was achieved using mobile phase toluene:chloroform:ethyl acetate:formic acid (3:2:4.9:0.1% v/v) and densitometric scan performed at 280 nm. The developed method was linear at 2-10 µg/mL with correlation coefficient of 0.9907 (QUR) and 0.9917 (RES). The method was validated for its precision, specificity, detection and quantification limits and % RSD was found to be less than 4.0%. The developed HPTLC method was evaluated in QUR and RES-loaded nanoformulation and Sesbania grandiflora leaf extract. The amount of QUR and RES present in the SG leaf extract was found to be 26.13 ± 0.7 µg/mg and 4.31 ± 0.8 µg/mg, respectively. The pH-dependent stability of RES has checked using the developed method. The above-developed method can be used to check the QUR/RES content in herbal/pharmaceutical formulation with scope towards industries.

Development and in vitro evaluation of novel nutraceutical formulations composed of Limosilactobacillus fermentum, quercetin and/or resveratrol.

This study developed and carried out an in vitro evaluation of nutraceutical formulations composed of potentially probiotic Limosilactobacillus fermentum (L. fermentum 139, L. fermentum 263 or L. fermentum 296), quercetin and/or resveratrol. L. fermentum strains had counts of >9 log CFU/g and contents of QUE and RES of >200 µg/mg in formulations after freeze-drying. Formulations with QUE and RES protected L. fermentum during exposure to in vitro acidic stomach conditions. L. fermentum strains had counts of >6 log CFU/g on day 60 and/or 90 of refrigeration storage. Contents of QUE (>29%) and RES (>50%) in formulations were potentially bioaccessible. Higher counts of L. fermentum and higher contents of QUE and RES were found in formulations stored under refrigerated rather than under room temperature. All nutraceutical formulations had antioxidant properties. Combinations of probiotic L. fermentum and QUE and/or RES should be an innovative strategy to develop added-value nutraceutical formulations.

Protective Effect of Resveratrol against Glioblastoma: A Review.

BACKGROUND: One of the most common tumors of the central nervous system is Glioblastoma (GBM). OBJECTIVE: There is not still an appropriate cure for this malignant tumor. Plant-derived natural products have demonstrated great potential in cancer therapy, and Resveratrol (Res) is among them. Therefore, the current study focused on the protective effect of resveratrol against glioblastoma and its underlying mechanism. METHODS: PubMed, Medline, Scopus, Web of Science, and Google Scholar were searched by using the following keywords: Resveratrol, Glioblastoma, Brain tumor, Cancer therapy, Medicinal herbs to July 2020. RESULTS: Res is a non-flavonoid polyphenol responsible for the protection of plants against pathogen attacks. Res has multiple pharmacological effects, including antioxidant, anti-inflammatory, anti-diabetic, and anti-tumor. Res is capable of penetration into the blood-brain barrier, making it suitable for brain tumor therapy. Besides, Res targets various molecular signaling pathways in cancer therapy. CONCLUSION: In the present review, it was found that Res administration is beneficial in GBM therapy by inhibition of proliferation, viability, and migration via modulation of molecular pathways.

Lactobacillus casei YRL577 combined with plant extracts reduce markers of non-alcoholic fatty liver disease in mice.

Probiotics and plant extracts are considered to prevent the development of non-alcoholic fatty liver disease (NAFLD). The present study explores the effects of using both probiotics and plant extracts on NAFLD. The present study evaluated the effects of plant extracts on lipid droplet accumulation and the growth of probiotics in vitro. A C57BL/6 mouse model was used to examine the effects of probiotics and plant extracts on NAFLD. Body weight and food intake were measured. The levels of serum lipids, oxidative stress and the liver injury index were determined using commercial kits. Haematoxylin and eosin staining, GC and real-time PCR were also used for analysis. The results revealed that administration of Lactobacillus casei YRL577 and L. paracasei X11 with resveratrol (RES) or tea polyphenols (TP) significantly reduced the levels of total cholesterol, TAG and LDL-cholesterol and increased the level of the HDL-cholesterol. The groups of L. casei YRL577 with RES and TP also regulated the liver structure, oxidative stress and injury. Furthermore, L. casei YRL577 with TP exhibited a more positive effect towards improving the NAFLD and increased the concentrations of the butyric acid than other three combined groups. L. casei YRL577 with TP up-regulated the mRNA levels of the farnesoid X receptor and fibroblast growth factor 15 and decreased the mRNA levels of the apical Na-dependent bile acid transporter. These findings showed that L. casei YRL577 + TP-modified genes in the intestinal bile acid pathway improved markers of NAFLD.

Spiral-Dextrin Complex Crystals: Efficient Approach for Colon-Targeted Resveratrol Delivery.

In this work, spiral dextrin/resveratrol (SD/Res) crystal, a new colon-specific drug-delivery system, was established by a novel method of encapsulation and cocrystallization to improve the antidigestion ability compared with the SD/Res inclusion complex (SD/Res IC) prepared by encapsulation and coprecipitation. X-ray diffraction (XRD) and scanning electron microscopy (SEM) revealed that the SD/Res crystal formed a more regular and perfect crystallite than SD/Res IC. Moreover, the encapsulation ability and thermostability of the SD/Res crystal were enhanced as the chain length of SD was increased. In vitro digestion indicated that SD/Res IC merely achieved small intestine-targeted release of resveratrol, while the SD/Res crystal could act as a colon-specific delivery system to protect resveratrol from degradation by gastric acid and pancreatic enzymes. The SD-1/Res crystal presented much higher thermal stability and stronger gastrointestinal stability than other SD/Res crystals and SD/Res ICs, which facilitated its application as a novel colon-target delivery system for resveratrol.

Cancer Stem Cell (CSC) Inhibitors in Oncology-A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives.

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

In Vivo Effect of Resveratrol-Loaded Solid Lipid Nanoparticles to Relieve Physical Fatigue for Sports Nutrition Supplements.

Resveratrol (RSV) is a natural flavonoid polyphenol compound extracted from the plants which shows various biological activities. However, the clinical application of RSV is limited by its poor aqueous solubility, rapid metabolism and poor bioavailability. In this study, resveratrol-loaded solid lipid nanoparticles (RSV- SLNs) was design as a nano-antioxidant against the physical fatigue. The resultant RSV-SLNs were characterized by photon correlation spectroscopy (PCS), transmission electron micrographs (TEM), zeta potential, differential scanning calorimetry (DSC) and Raman spectroscopy pattern. Furthermore, the in vivo anti-fatigue effect assays showed that RSV-SLNs prolonged the mice exhausted time and running distance. The biochemical parameters of blood related to fatigue suggested that RSV-SLNs have potential applications to improve the antioxidant defense of the mice after extensive exercise and confer anti-fatigue capability. Furthermore, the molecular mechanisms of antioxidant by RSV-SLNs supplementation was investigated through the analysis of silent information regulator 2 homolog 1 (SIRT1) protein expression, which demonstrated that it could downregulate the expression of SIRT1 and increase autophagy markers, microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome-1 (SQSTM1/p62). These results reveal that the RSV-SLNs may have great potential used as a novel anti-fatigue sports nutritional supplement.