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Methamphetamine (METH) addiction can damage the central nervous system, resulting in cognitive impairment and memory deficits. Low target effects have limited the utility of anti-addiction drugs because the presence of the blood-brain barrier hinders the effective delivery of drugs to the brain. Angiopep-2 can recognize and target low-density lipoprotein receptor-associated protein 1 (LRP-1) on the surface of cerebral capillary endothelial cells, causing cross-cell phagocytosis, and thus has high blood-brain barrier transport capacity. Resveratrol (RSV) has been found to be a neuroprotective agent in many nervous system diseases. In our study, we modified Angiopep-2 on the surface of the erythrocyte membrane to obtain a modified erythrocyte membrane (Ang-RBCm) and coated RSV-loaded poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG) nanoparticles with Ang-RBCm (Ang-RBCm@RSVNPs) to treat METH addiction. Our results showed that Ang-RBCm@RSVNPs can penetrate the blood-brain barrier and accumulate in the brain better than free RSV. Besides, mice treatetd with Ang-RBCm@RSVNPs showed less preference to METH-paired chamber and no noticeable tissue toxicity or abnormality was found in H&E staining images. Electrophysiological experiments demonstrated Ang-RBCm@RSVNPs could elevate synaptic plasticity impaired by METH. These indicated that Ang-RBCm@RSVNPs has better anti-addiction and neuroprotective effects. Therefore, Ang-RBCm@RSVNPs has great potential in the treatment of METH addiction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent research has emphasized the development of efficient drug delivery systems to facilitate the delivery of biological compounds such as polyphenols via skin absorption. Phytozomes have been employed as carriers of plant compounds in this context Hydrogen bonding between plant polyphenols and the phospholipid phosphate group enables efficient encapsulation of potent compounds for enhanced drug delivery systems. Additionally, the strong affinity of phytosomes for the skin's phospholipids enhances skin absorption. In this study, phytosomes were initially formulated using the thin-layer hydration method After optimizing the synthetic parameters, phytosomes were loaded with Resveratrol and Quercetin for enhanced delivery and skin absorption potential to assess the characteristics of the synthesized phytosomes, tests were conducted to determine particle distribution and size, zeta potential, and examine the microstructure morphology using a scanning electron microscope (SEM). Furthermore, a siloxane gel base was formulated in this study, and the stability of the physicochemical and biological properties of the final prepared nanoformulation was investigated. The results of this study indicated that the formulated phytosomes exhibit optimal characteristics for facilitating high skin penetration of resveratrol and quercetin. A high skin absorption was observed after 60 days of synthesis. Additionally, the base of the siloxane gel can play a significant role in preventing the formation of scars by reducing the passage of water vapor.

Objectives: To evaluate in vivo 1) the bioavailability of trans-resveratrol when administered through sublingual capsules; 2) the effect of resveratrol on the protein composition of the acquired enamel pellicle (AEP)., Design: Ten volunteers received a sublingual capsule containing 50 mg of trans-resveratrol. Unstimulated saliva was then collected after 0, 30, 60, and 120 min and AEP was collected after 120 min following administration of the capsule. In the next week, the volunteers received a placebo sublingual capsule, and saliva and AEP were collected again. Saliva samples were analyzed for free trans-resveratrol using high-performance liquid chromatopgraphy (HPLC), and AEP samples were subjected to proteomic analysis (nLC-ESI-MS/MS)., Results: Trans-resveratrol was detected in saliva at all the time points evaluated, with the peak at 30 min. A total of 242 proteins were identified in both groups. Ninety-six proteins were increased and 23 proteins were decreased in the Resveratrol group. Among the up-regulated proteins, isoforms of cystatins, PRPs, Mucin-7, Histatin-1, Lactotrasnferrin and Lysozyme-C were increased and the isoforms of Protein S100, Neutrophil defensins, Albumin, PRPs, and, Statherin were decreased in Resveratrol group., Conclusion: The sublingual capsule is effective at increasing the bioavailability of trans-resveratrol in saliva. Several proteins involved in important processes to maintain systemic and oral health homeostasis were identified. These proteins differently expressed due to the presence of trans-resveratrol deserve attention for future studies, since they have important functions, mainly related to antimicrobial action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Resveratrol is a non-flavonoid polyphenolic compound with numerous functional properties, such as anticancer, anti-inflammation, anti-oxidation, anti-obesity and more. However, resveratrol's poor solubility within aqueous media and low stability usually lead to compromised bioavailability, ultimately limiting its uptake and applications. Nanodelivery technologies have been studied intensively due to their potential in effectively improving resveratrol properties, thereby providing promising solutions for enhancing the bioavailability of resveratrol. Thus, this article aimed to review the recent advances of resveratrol nanodelivery systems, specifically on the types of nanodelivery systems, the corresponding preparation principles, advantages, as well as potential limitations associated. Meanwhile, studies have also found that coupled with nanodelivery systems, the functional properties of resveratrol could trigger apoptosis in cancer cells and inflammatory cells through various signaling pathways. Therefore, this article will also lead into discussions on the application aspects of resveratrol nanodelivery systems, emphasizing toward the fields of biomedical and food sciences. Potential pitfalls of resveratrol nanodelivery systems, such as issues with toxicity and target release, as well as outlooks regarding resveratrol nanodelivery systems are included in the Conclusion section, in the hope to provide insights for relevant future research.

Resveratrol (RSV) has powerful antioxidant activities. However, the bioavailability is still limited due to low solubility and transport issues. Nanocrystal technology has been introduced to address these issues; however, the bulky formulation of the nanocrystal process through nanosuspension faces a big challenge in terms of stability and scale-up ability. This work aimed to enhance the bioavailability of RSV through nanocrystal formulation incorporated into soluble mesoporous carriers for superior solid-state stability and feasibility. This formulation was designed and developed rationally through scientific justification in the nanocrystal formulation along with quality by design paradigm. Box-Behnken design was applied to determine the optimized formulation based on the particle size and distribution, drug loading, zeta potential, and supersaturation parameters. The nanocrystal was formed through evaporation of drug, polymer, and surfactant in the solvent incorporated into mesoporous material. The nanocrystal was evaluated by vibrational spectroscopy, thermal analyses, and SEM and TEM photographs, followed by crystallinity evaluation. The results indicated that the factors only affected the particle size variation, zeta potential, drug loading, and the time to reach the supersaturation peak level. The optimized formulation was achieved by 68 % desirability value, producing 133.3 ± 1.2 nm particle size and -24.6 mV zeta potential. The physical and chemical evaluation characterization indicated no interaction between RSV and carrier. In addition, there was no difference in crystallinity between the RSV nanocrystal and native RSV. Moreover, the RSV nanocrystal improved the bioavailability nearly twice compared to the RSV suspension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hyaluronic acid (HA), an endogenous polysaccharide comprising alternating D-glucuronic acid and N-acetylglucosamine units, is renowned for its high hydrophilicity, biocompatibility, and biodegradability. These attributes have rendered HA invaluable across medical and drug delivery fields. HA can be altered through physical, chemical, or enzymatic methods to improve the properties of the modified substances. In this work, we synthesized a derivative via the esterification of HA with poly(glyceryl)10-stearate (PG10-C18), designated as HA-PG10-C18. This novel derivative was employed to fabricate a nano co-delivery system (HA-PG10-C18@Res-NE) for fish oil and resveratrol (Res), aiming to enhance their stability and bioaccessibility. An exhaustive investigation of HA-PG10-C18@Res-NE revealed that the HA-modified system displayed superior physicochemical stability, notably in withstanding oxidation and neutralizing free radicals. Moreover, in vitro simulated digestion underscored the system's enhanced bioaccessibility of Res and more efficient release of free fatty acids. These outcomes underscore the strategic advantage of HA in modifying PG10-C18 for nanoemulsion formulation. Consequently, HA-PG10-C18 stands as a promising emulsifier for encapsulating lipophilic bioactives in functional foods, nutraceuticals, and pharmaceuticals., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest with this research., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12-174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35-10.04 m 2 /sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In our previous studies, 3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-β-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, in vitro cellular uptake assay showed that Gal-Res NPs (37.5 μmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. Taken together, the in vitro/in vivo results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: To improve the bioavailability of trans- resveratrol ( trans -Res), it is commonly co-delivered with antioxidant bioactives using a complex synthetic intestinal targeted carrier, however, which makes practical application challenging., Methods: A nanogel (Ngel), as broad-spectrum autonomous ROS scavenger, was prepared using selenized thiolated sodium alginate (TSA-Se) and crosslinked with calcium lactate (CL) for loading trans- Res to obtain Ngel@Res, which maintained spherical morphology in the upper digestive tract but broke down in the lower digestive tract, resulting in trans -Res release., Results: Under protection of Ngel, trans- Res showed enhanced stability and broad-spectrum ROS scavenging activity. The synergistic mucoadhesion of Ngel prolonged the retention time of trans- Res in the intestine. Ngel and Ngel@Res increased the lifespan of Caenorhabditis elegans to 26.00 ± 2.17 and 26.00 ± 4.27 days by enhancing the activity of antioxidases, upregulating the expression of daf-16, sod-5 and skn-1 , while downregulating the expression of daf-2 and age-1 ., Conclusion: This readily available, intestinal targeted selenized alginate-based nanogel effectively improves the bioactivity of trans- Res., Competing Interests: The authors claim that there are no conflicts to declare., (© 2024 Xu et al.)

Background: The healing of burn wounds is a complicated physiological process that involves several stages, including haemostasis, inflammation, proliferation, and remodelling to rebuild the skin and subcutaneous tissue integrity. Recent advancements in nanomaterials, especially nanofibers, have opened a new way for efficient healing of wounds due to burning or other injuries., Methods: This study aims to develop and characterize collagen-decorated, bilayered electrospun nanofibrous mats composed of PVP and PVA loaded with Resveratrol (RSV) and Ampicillin (AMP) to accelerate burn wound healing and tissue repair., Results: Nanofibers with smooth surfaces and web-like structures with diameters ranging from 200 to 400 nm were successfully produced by electrospinning. These fibres exhibited excellent in vitro properties, including the ability to absorb wound exudates and undergo biodegradation over a two-week period. Additionally, these nanofibers demonstrated sustained and controlled release of encapsulated Resveratrol (RSV) and Ampicillin (AMP) through in vitro release studies. The zone of inhibition (ZOI) of PVP-PVA-RSV-AMP nanofibers against Staphylococcus aureus ( S. aureus) and Escherichia coli ( E. coli ) was found 31±0.09 mm and 12±0.03, respectively, which was significantly higher as compared to positive control. Similarly, the biofilm study confirmed the significant reduction in the formation of biofilms in nanofiber-treated group against both S. aureus and E. coli . X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis proved the encapsulation of RSV and AMP successfully into nanofibers and their compatibility. Haemolysis assay (%) showed no significant haemolysis (less than 5%) in nanofiber-treated groups, confirmed their cytocompatibility with red blood cells (RBCs). Cell viability assay and cell adhesion on HaCaT cells showed increased cell proliferation, indicating its biocompatibility as well as non-toxic properties. Results of the in-vivo experiments on a burn wound model demonstrated potential burn wound healing in rats confirmed by H&E-stained images and also improved the collagen synthesis in nanofibers-treated groups evidenced by Masson-trichrome staining. The ELISA assay clearly indicated the efficient downregulation of TNF-alpha and IL-6 inflammatory biomarkers after treatment with nanofibers on day 10., Conclusion: The RSV and AMP-loaded nanofiber mats, developed in this study, expedite burn wound healing through their multifaceted approach., Competing Interests: The authors declare no competing interests in this work., (© 2024 Kanaujiya et al.)

Cyclodextrin-based electrospun nanofibers are promising for encapsulating and preserving unstable compounds, but quick dissolution of certain nanofibers hinders their delivery application. In this study, hydroxypropyl-β-cyclodextrin (HPβCD) was used as an effective carrier of resveratrol (RSV) to obtain the RSV/HPβCD inclusion complex (HPIC), which was then incorporated into pullulan nanofibers. For enhancement of RSV release toward colon target, multilayer structure with a pullulan/HPIC film sandwiched between two layers of hydrophobic Eudragit S100 (ES100) nanofibers was employed. The relationship between the superiority of the ES100-pullulan/HPIC-ES100 film and its multilayer structure was verified. The intimate interactions of hydrogen bonds between two adjacent layers enhanced thermal stability, and the hydrophobic outer layers improved water contact resistance. According to release results, multilayer films also showed excellent colon-targeted delivery property and approximately 78.58 % of RSV was observed to release in colon stage. In terms of release mechanism, complex mechanism best described RSV colonic release. Additionally, ES100-pullulan/HPIC-ES100 multilayer films performed higher encapsulation efficiency when compared to the structures without HPIC, which further increased the antioxidant activity and total release amount of RSV. These results suggest a promising strategy for designing safe colonic delivery systems based on multilayer and HPIC structures with superior preservation for RSV., Competing Interests: Declaration of competing interest None of the authors have disclosed any conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Resveratrol (RSV) is a polyphenolic substance found in numerous natural products. Despite the wide range of therapeutic activities, including antioxidant and anti-inflammatory effects, the poor pharmacokinetic characteristics decrease the RSV bioavailability following oral administration. Milk-derived exosomes (MEXOs), as a class of natural nanocarriers, are promising candidates for oral drug delivery approaches., Main Methods: The current study developed RSV-loaded MEXOs to enhance the RSV oral bioavailability, introducing a suitable exosomal formulation for suppressing colon inflammation in acetic acid-induced rat models., Key Findings: The results showed a remarkable encapsulation efficiency of 83.33 %. The in vitro release profile demonstrated a good retaining capability in acidic conditions (pH 1.2) and a considerable release in a simulated duodenal environment (pH 6.8). According to the permeability study, encapsulation of RSV improved its transportation across the Caco-2 monolayer. Moreover, the in vivo and histological analysis results proved that the RSV-MEXOs formulation successfully alleviates the inflammation in colitis rat models and effectively relieves the colitis., Significance: Our findings suggest that MEXOs should be of great attention as promising oral drug delivery vehicles for further clinical evaluations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The study aimed to fabricate β-Lactoglobulin-catechin (β-La-Ca) conjugates as a natural designed antioxidant emulsifier to improve the physicochemical stability of resveratrol emulsion delivery system. Fourier transform infrared (FT-IR) and fluorescence spectroscopy analysis confirmed the formation of conjugates using free radical grafting. The antioxidant ability of emulsion was evaluated by DPPH scavenging activities and ORAC experiments. The emulsion stabilized by β-La-Ca conjugates exhibited strong antioxidant activity with ORAC value of 2541.39 ± 29.58 μmol TE/g, which was significantly higher than that by β-Lactoglobulin alone with 387.96 ± 23.45 μmol TE/g or their mixture with 948.23 ± 32.77 μmol TE/g. During the whole simulated gastrointestinal digestion, emulsion stabilized by β-La-Ca conjugates exhibited excellent oxidative stability that the lipid was mainly digested in the small intestine. This behavior attributed to the greater stability of resveratrol to chemical transformation leading to a higher overall bioavailability in vivo. These results suggested that the β-La-Ca conjugates could be used to fabricate the emulsion-based delivery system to improve the oxidative stability and bioavailability of chemically labile hydrophobic bioactive compounds., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to improve the mechanical properties of wheat starch gels (WSG) and the stability and bioaccessibility of resveratrol (Res) in prolamin nanoparticles. Res-loaded gliadin (Gli), zein, deamidated gliadin (DG) and deamidated zein (DZ) nanoparticles were filled in WSG. The hardness, G' and G'' of WSG were notably increased. It can be attributed to the more ordered and stable structure induced by the interaction of prolamin nanoparticles and starch. The Res retention of nanoparticles and nanoparticle-filled starch gels was at least 24.6 % and 36.0 % higher than free Res upon heating. When exposed to ultraviolet, the Res retention was enhanced by over 6.1 % and 37.5 %. The in-vitro digestion demonstrated that the Res releasing percentage for nanoparticle-filled starch gels was 25.8 %-38.7 % lower than nanoparticles in the simulated stomach, and more Res was released in the simulated intestine. This resulted in a higher bioaccessibility of 82.1 %-93.2 %. The bioaccessibility of Res in Gli/Res/WSG and DG/Res/WSG was greater than that of Zein/Res/WSG and DZ/Res/WSG. More hydrophobic interactions occurred between Res and Gli, DG. The interactions between Res and zein, DZ were mainly hydrogen bonding. The microstructure showed that nanoparticles exhibited dense spherical structures and were uniformly embedded in the pores of starch gels., Competing Interests: Declaration of competing interest No known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Development and evaluation of aqueous core nanocapsules (ACNs) of BCS-II-class drug like resveratrol (RSV) and pterostilbene (PTE) for prostate cancer. Materials & methods: Identify synergistic effects of molar ratios of RSV and PTE against PC-3 cell. Selected ratio of drugs was added to ACNs by double-emulsification-method using Box-Behnken design. Further, assessed for physicochemical characterization, release kinetics, compatibility, in vitro cytotoxicity, in vivo pharmacokinetic and biodistribution studies. Results: Selected 1:1 ratio of RSV and PTE had greatest synergy potential have smaller particle-size (128.1 ± 3.21 nm), zeta-potential (-22.12 ± 0.2 mV), 0.53 PDI, improved encapsulation (87% for RSV, 72% for PTE), stable, no systemic toxicity, high biodistributed/accumulated in prostate cells. Conclusion: ACNs exhibited high t 1/2 (12.42 ± 1.92 hs) and 8.20 ± 8.21 hs Mean Residence Time and lower clearance, proving the high effectiveness for prostate cancer.

Cancer poses a serious threat to human health and is the most common cause of human death. Polymer-based nanomedicines are presently used to enhance the treatment effectiveness and decrease the systemic toxicity of chemotherapeutic agents. However, the disadvantage of currently polymeric carriers is without therapy procedure. Herein, for the first time, glutathione (GSH)-responsive polymer (PRES) with anti-cancer effect was synthesized following the condensation-polymerization method using resveratrol (RES) and 3,3'-dithiodipropionic acid. PRES can not only suppress the tumor cells growth but can also self-assemble into nanoparticles (∼93 nm) for delivering antitumor drugs, such as paclitaxel (PTX@PRES NPs). The system could achieve high drug loading (∼7%) and overcome multidrug resistance (MDR). The results from the in vitro studies revealed that the NPs formed of PRES were stable in the systemic circulation, while could be efficiently degraded in tumor cells high GSH environment. Results from cytotoxicity tests confirmed that PTX@PRES NPs could effectively suppress the growth of cancer cells (A549) and drug-resistant cells (A549/PTX). The NPs could also be used to significantly increase the therapeutic efficacy of the drugs in A549/PTX tumor-bearing mice. In vivo investigations also demonstrated that the PRES-based NPs exhibited tumor inhibition effects. In summary, we report that the GSH-responsive polymer synthesized by us exhibited multiple interesting functions and could be used for effective drug delivery. The polymer exhibited good therapeutic effects and could be used to overcome MDR. Thus, the synthesized system can be used to develop a new strategy for treating cancer.

Chemopreventive properties of resveratrol has been studied for decades. Despite its potential for chemotherapeutic advancement, the compound has pharmaceutical limitations, such as, the drug has a poor pharmacokinetic profile and low bioavailability. Studies have comforting results that that the nano-formulations may aid the future resveratrol drug development. Resveratrol can also be encapsulated as co-drug with an anticipation of gaining improved targeting and pharmacokinetic parameters, as well as achieving desired therapeutic plasma levels. It has been envisaged that the nanoformulations can also address the issue of drug accumulation, which may lead to hepatotoxicity. Nanoformulations can bring a major improvement in the bioavailability of resveratrol but still the formulation still suffers with pharmacokinetics issues clinically. This review encompasses the pharmacokinetics barriers associated with resveratrol and a possible suggestion to overcome those barriers for improving absorbance, reducing toxicity andimproving the drug releaseand encapsulation efficiency. The article also suggest that co-administration of resveratrol with chemotherapeutic drugsmust be tested in vivo on a wide range of cancers to avoid accidental proliferation exacerbation. The review's focusses on the resveratrol formulation and make suggestions for improvements in order to overcome the pharmacokinetic and toxicity issues., (Copyright © 2022. Published by Elsevier B.V.)

Both luteolin (LUT) and resveratrol (RES) are natural polyphenols that exert therapeutic effects on liver injuries. Extensive glucuronidation by uridine diphosphate-glucuronosyltransferases 1As (UGT1As) results in poor bioavailability of LUT, which limits its clinical application. As an inhibitor of UGT1A1 and UGT1A9, RES may affect the bioavailability of LUT. The purpose of this study was to develop and validate an HPLC-MS/MS method for the simultaneous determination of LUT, luteolin-3'-O-glucuronide (LUT-3'-G), RES and resveratrol-3-O-glucuronide (RES-3-G) in rat plasma to investigate the effects of RES on the bioavailability and metabolism of LUT after coadministration. The samples were extracted by protein precipitation with methanol using daidzein and naringenin as the internal standards. Separation was achieved on an XBridge TM C 18 column by isocratic elution using 88% methanol-12% water with 2 mM ammonium acetate and 0.01% formic acid. Multiple reaction monitoring mode with a negative electrospray ionization interface was used for quantification of the analytes. The calibration curves were linear over the concentration ranges of 1-1000 (r > 0.995), 2-2000 (r > 0.999), 5-5000 (r > 0.998) and 10-40000 ng/mL (r > 0.996) for LUT, LUT-3'-G, RES and RES-3-G, respectively. The method was fully validated in terms of accuracy, precision, matrix effect, recovery and stability. The validated data met the acceptance criteria in FDA guidelines. The method was successfully applied in a pharmacokinetic interaction study of LUT and RES. The results indicated that RES had a significant effect on the enhanced bioavailability of LUT by reducing the major glucuronidation metabolite in rats, which provides a reference for the combination of LUT and RES in liver diseases., (Copyright © 2022. Published by Elsevier B.V.)

Oxidized gellan gum (OGG) hydrogel beads as delivery systems for resveratrol were fabricated by ionic cross-linking with calcium chloride (CaCl 2 ). The degree of oxidation (DO) and CaCl 2 concentration had significant influences on the formation and functional properties of hydrogel beads. The resveratrol encapsulation efficiency (66.43%-79.84%) and loading capacity (4.15%-5.05%) of OGG hydrogel beads were enhanced as DO increased. The hydrogel beads exhibited a uniform spherical shape as observed by scanning electron microscope. Fourier transform infrared spectroscopy analysis confirmed that hydrogen bonds and ionic interaction participated in the formation of hydrogel beads. X-ray diffraction analysis revealed that the physical state of resveratrol was changed from crystalline to amorphous form after encapsulation. Furthermore, the physical stability and antioxidant capacity evaluation demonstrated that the hydrogel bead fabricated with DO80 OGG and CaCl 2 concentration of 1.0 M could provide high protection for resveratrol against degradation by environmental stresses and maintain its antioxidant capacity. The DO and CaCl 2 concentrations could modulate the in-vitro release behaviors of hydrogel beads and obtain a good small intestinal-targeted release of resveratrol at high DO and medium CaCl 2 concentration. These findings suggested that a promising delivery system for encapsulating bioactive ingredients can be fabricated by rational design., (Copyright © 2021. Published by Elsevier B.V.)

Balloon angioplasty and stent implantation are standard techniques to reopen stenotic vessels. Often, balloons or stents coated with cytostatic drugs are used to prevent re-occlusion of the arteries. Resveratrol, which is known for its numerous beneficial effects on cardiovascular health, is used as an antioxidant additive on paclitaxel-coated balloon catheters. What is still unclear is whether resveratrol-only balloon coating in combination with a bare metal stent (BMS) also has positive effects on vascular healing. Here, we analyzed neointimal thickening, fibrin deposition, inflammation, vasa vasorum density, and reendothelialization after implantation of BMS via a resveratrol coated balloon approach in a porcine model. In general, resveratrol treatment did not result in significantly altered responses compared to the control group in peripheral arteries. In coronary arteries, an increase in vasa vasorum density became evident three days after resveratrol treatment compared to the control group and abolished up to day 7. Significant effects of the resveratrol treatment on the fibrin score or intima-media area were transient and restricted to either peripheral or coronary arteries. In conclusion, local single-dose resveratrol treatment via a resveratrol-only coated balloon and BMS approach did not lead to adverse systemic or local effects, but also no significant beneficial effects on vascular healing were detected in the current study.

Resveratrol has a variety of physiological activities, but its bioavailability in the body is low. In this study, the interaction between the peptide SH, prepared from Scomberomorus niphonius , and resveratrol was judged by fluorescence spectroscopy. Then, SHa1 was obtained by the purification of SH, and its effect on the characteristics of resveratrol was studied. SHa1 interacted with resveratrol at 37 °C for 30 min to obtain the complex SHa1-R, which then showed an obviously stronger inhibition on B16 cells than resveratrol using the MTT assay after in vitro gastrointestinal digestion. The solubility and digestive stability of SHa1-R were higher than that of free resveratrol. The intestinal absorption rate of SHa1-R was also increased compared with resveratrol according to the non-inverted rat intestinal sac model. The structure of SHa1 was analyzed by UPLC, auto amino acid analysis, and UPLC-MS/MS. The molecular weight of SHa1 was mainly concentrated under 1000 Da, and it was rich in glutamic acid, aspartic acid, lysine, and leucine. Eighteen possible peptides were identified from SHa1. The results suggested that the peptide SHa-1 may help to increase the bioavailability of resveratrol by increasing the solubility, digestive stability and intestinal absorption of resveratrol, thereby promoting its inhibitory effect on B16 cells.

The purpose of this study is to develop a sensitive LC-MS-MS method to simultaneously quantify polydatin and its metabolite, resveratrol, for its application in a pharmacokinetic (PK) study and to determine polydatin hydrolysis by microflora. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Separation was achieved using an Acquity BEH C 18 column (2.1 × 50 mm) with acetonitrile and 0.1% formic acid as the mobile phases. Analysis was performed under negative ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 9.77-1250 nM for both resveratrol and polydatin with correlation coefficient values >0.99. Themethodhas been shown to be reproducible, with intra- and inter-day accuracy and precision ±10.4% of nominal values, for both analytes. The average extraction recovery rates were 81.78-98.3% for polydatin and 86.4-103.2% for resveratrol, respectively. Matrix effect was in the acceptable range (<15%). The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage (-4 °C) conditions. The metabolic studies showed that polydatin can be rapidly hydrolyzed by rat fecal S9 fractions and PK studies showed that both polydatin and resveratrol were exposed in the plasma and variable tissues. This novel UPLC-MS-MS method can quantify the levels of both polydatin and its major metabolite resveratrol in biological samples., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl- sn -glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl- sn -glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method ( K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (μg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.

Resveratrol (RV) is a well-known polyphenolic compound in various plants, including grape, peanut, and berry fruits, which is quite famous for its association with several health benefits such as anti-obesity, cardioprotective neuroprotective, antitumor, antidiabetic, antioxidants, anti-age effects, and glucose metabolism. Significantly, promising therapeutic properties have been reported in various cancer, neurodegeneration, and atherosclerosis and are regulated by several synergistic pathways that control oxidative stress, cell death, and inflammation. Similarly, RV possesses a strong anti-adipogenic effect by inhibiting fat accumulation processes and activating oxidative and lipolytic pathways, exhibiting their cardioprotective effects by inhibiting platelet aggregation. The RV also shows significant antibacterial effects against various food-borne pathogens (Listeria, Campylobacter, Staphylococcus aureus, and E. coli) by inhibiting an electron transport chain (ETC) and F0F1-ATPase, which decreases the production of cellular energy that leads to the spread of pathogens. After collecting and analyzing scientific literature, it may be concluded that RV is well tolerated and favorably affects cardiovascular, neurological, and diabetic disorders. As such, it is possible that RV can be considered the best nutritional additive and a complementary drug, especially a therapeutic candidate. Therefore, this review would increase knowledge about the blend of RV as well as inspire researchers around the world to consider RV as a pharmaceutical drug to combat future health crises against various inhumane diseases. In the future, this article will be aware of discoveries about the potential of this promising natural compound as the best nutraceuticals and therapeutic drugs in medicine., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed., (Copyright © 2021. Published by Elsevier Inc.)

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.

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.

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human cytochrome P450 (CYP) 3A4 (CYP3A4) and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50 mg/kg resveratrol), and group C (150 mg/kg resveratrol). After 30 min administration of resveratrol, a single dose of ticagrelor (18 mg/kg) was administered orally. The in vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated ultra high-performance liquid chromatography - tandem mass spectrometer methods. For the in vivo study, the area under the concentration-time curve and mean peak plasma concentrations of ticagrelor in group B and C appeared to be significantly higher than the control group, while volume of distribution in terminal phase and apparent clearance of ticagrelor in group B and C were significantly decreased. For the in vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The half-maximal inhibitory concentration values of resveratrol were 56.75 μM, 69.07 μM, and 14.22 μM, respectively. Our results indicated that resveratrol had an inhibitory effect on the metabolism of ticagrelor in vitro and in vivo. Further research should focus on the clinical combination of resveratrol with ticagrelor, and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

Resveratrol (RES) has a low bioavailability. This limitation was addressed in an earlier review and several recommendations were offered. A literature search was conducted in order to determine the extent of the research that was conducted in line with these recommendations, along with new developments in this field. Most of the identified studies were pre-clinical and confirmed the heightened activity of RES analogues compared to their parent compound. Although this has provided additional scientific kudos for these compounds and has strengthened their potential to be developed into phytopharmaceutical products, clinical trials designed to confirm this increased activity remain lacking and are warranted.

Background: Resveratrol (3, 5, 4 ' -trihydroxystilbene), a natural polyphenol and phytoalexin, has drawn considerable attention in the past decade due to its wide variety of therapeutic activities such as anticancer, anti-inflammatory, and antioxidant properties. However, its poor water solubility, low chemical stability, and short biological half-life limit its clinical utility., Recent Findings: Nanoparticles overcome the limitations associated with conventional chemotherapeutic drugs, such as limited availability of drugs to the tumor tissues, high systemic exposures, and consequent toxicity to healthy tissues. This review focuses on the physicochemical properties of resveratrol, the therapeutic potential of resveratrol nano-formulations, and the anticancer activity of resveratrol encapsulated nanoparticles on various malignancies such as skin, breast, prostate, colon, liver, ovarian, and lung cancers (focusing on both in vitro and in vivo studies)., Conclusions: Nanotechnology approaches have been extensively utilized to achieve higher solubility, improved oral bioavailability, enhanced stability, and controlled release of resveratrol. The resveratrol nanoparticles have markedly enhanced its anticancer activity both in vitro and in vivo, thus considering it as a potential strategy to fight various cancers., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

In the present study, combinatorial nanostructured lipid carrier gel of 5-fluorouracil and resveratrol was formulated, optimized and characterized to enhance permeation in between epidermis and dermis layers of the skin to obtain a synergistic effect against skin cancer. After extensive trials, a newly modified emulsiosonication method was developed and additionally, for the first time, stability studies were done in the beginning to optimize formulation technique, which exhibited two major benefits simultaneously; first, it provided best-optimized technique for preparation of combinatorial lipid-nanosystem, and secondly, it also demonstrated a detailed report card of durability of formulations. In vitro release study showed a significantly improved, slow and prolonged release of drugs from the optimized lipid-nanosystem (***p < 0.05), which followed non-Fickian Higuchi kinetics. Besides, mechanism of skin permeation enhancement study, dermatokinetic assessment, and depth analysis of optimized formulation on skin exhibited improved permeation and well distribution of drugs up to the dermis layer of skin. Moreover, combinatorial linogel possessed significantly greater efficacy (**p < 0.01) on the A431 cell line, as compared to the conventional formulation. Thus, findings revealed that modified method of preparation for dual drug-loaded lipid-nanosystem lead to the production of a stable formulation that also improved the retention of both 5-fluorouracil and resveratrol in between the epidermis and dermis region of skin thereby helping in the management and treatment of skin cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to an extraordinary threat to the global healthcare system. This infection disease, named COVID-19, is characterized by a wide clinical spectrum, ranging from asymptomatic or mild upper respiratory tract illness to severe viral pneumonia with fulminant cytokine storm, which leads to respiratory failure. To improve patient outcomes, both the inhibition of viral replication and of the unwarranted excessive inflammatory response are crucial. Since no specific antiviral drug has been proven effective for the treatment of patients and the only upcoming promising agents are monoclonal antibodies, inexpensive, safe, and widely available treatments are urgently needed. A potential anti-inflammatory molecule to be evaluated, which possesses antiviral activities in several experimental models, is the polyphenol resveratrol. This compound has been shown to inhibit SARS-CoV-2 replication in human primary bronchial epithelial cell cultures and to downregulate several pathogenetic mechanisms involved in COVID-19 severity. The use of resveratrol in clinical practice is limited by the low bioavailability following oral administration, due to the pharmacokinetic and metabolic characteristics of the molecule. Therefore, topical administration through inhaled formulations could allow us to achieve sufficiently high concentrations of the compound in the airways, the entry route of SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rossi, Sacco, Capizzi and Mastromarino.)

As one of the most common complications of diabetes, nephropathy develops in approximately 40% of diabetic individuals. Although end stage kidney disease is known as one of the most consequences of diabetic nephropathy, the majority of diabetic individuals might die from cardiovascular diseases and infections before renal replacement treatment. Moreover, the routine medical treatments for diabetes hold undesirable side effects. The explosive prevalence of diabetes urges clinicians and scientists to investigate the complementary or alternative therapies. Phytochemicals are emerging as alternatives with a wide range of therapeutic effects on various pathologies, including diabetic kidney disease. Of those phytochemicals, resveratrol, a natural polyphenolic stilbene, has been found to exert a broad spectrum of health benefits via various signaling molecules. In particular, resveratrol has gained a great deal of attention because of its anti-oxidative, anti-inflammatory, anti-diabetic, anti-obesity, cardiovascular-protective, and anti-tumor properties. In the renal system, emerging evidence shows that resveratrol has already been used to ameliorate chronic or acute kidney injury. This review critically summarizes the current findings and molecular mechanisms of resveratrol in diabetic renal damage. In addition, we will discuss the adverse and inconsistent effects of resveratrol in diabetic nephropathy. Although there is increasing evidence that resveratrol affords great potential in diabetic nephropathy therapy, these results should be treated with caution before its clinical translation. In addition, the unfavorable pharmacokinetics and/or pharmacodynamics profiles, such as poor bioavailability, may limit its extensive clinical applications. It is clear that further research is needed to unravel these limitations and improve its efficacy against diabetic nephropathy. Increasing investigation of resveratrol in diabetic kidney disease will not only help us better understand its pharmacological actions, but also provide novel potential targets for therapeutic intervention., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Resveratrol is a phytoalexin produced by many plants as a defense mechanism against stress-inducing conditions. The richest dietary sources of resveratrol are berries and grapes, their juices and wines. Good bioavailability of resveratrol is not reflected in its high biological activity in vivo because of resveratrol isomerization and its poor solubility in aqueous solutions. Proteins, cyclodextrins and nanomaterials have been explored as innovative delivery vehicles for resveratrol to overcome this limitation. Numerous in vitro and in vivo studies demonstrated beneficial effects of resveratrol in cardiovascular diseases (CVD). Main beneficial effects of resveratrol intake are cardioprotective, anti-hypertensive, vasodilatory, anti-diabetic, and improvement of lipid status. As resveratrol can alleviate the numerous factors associated with CVD, it has potential as a functional supplement to reduce COVID-19 illness severity in patients displaying poor prognosis due to cardio-vascular complications. Resveratrol was shown to mitigate the major pathways involved in the pathogenesis of SARS-CoV-2 including regulation of the renin-angiotensin system and expression of angiotensin-converting enzyme 2, stimulation of immune system and downregulation of pro-inflammatory cytokine release. Therefore, several studies already have anticipated potential implementation of resveratrol in COVID-19 treatment. Regular intake of a resveratrol rich diet, or resveratrol-based complementary medicaments, may contribute to a healthier cardio-vascular system, prevention and control of CVD, including COVID-19 disease related complications of CVD.

Background: The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol., Objectives: This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines., Methods: A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7-14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively., Results: [14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake., Conclusions: Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate.This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Polyphenols such as curcumin (Cur) and resveratrol (Res) have been recently shown to have potential to inhibit proliferation of highly aggressive melanoma cells. This study was designed to investigate the feasibility of a topical delivery system, using a solid lipid nanoparticles (SLNs) loaded delivery systems, that can enhance the skin penetration and anti-cancer efficacy of combination of these polyphenols. Negatively charged Cur-Res SLNs with a mean diameter of 180.2 ± 7.7 nm were prepared using high shear homogenization method. Cur-Res SLNs were found to be stable up to 2 weeks under 4°C. The in vitro release study showed that Res was released five time more than curcumin. The permeability of resveratrol was about 1.67 times that of curcumin from the SLN-gel formulation which was significantly (p < 0.05) lower than from SLN suspension. More than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study suggesting potentially utility of Cur-Res SLNs in the treatment of localized melanoma. In fact, the electrical cell-substrate impedance sensing (ECIS) measurements suggested that Cur-Res combination has potential to stop cell migration of B16F10 melanoma cells. Furthermore, both, Cur-Res SLNs and Cur-Res solution at the ratio of 3:1 demonstrated a strong synergistic inhibition of SK-MEL-28 melanoma cell proliferation. Further evaluation of Cur-Res SLNs in vivo melanoma models are warranted to establish the clinical utility of Cur-Res formulations in melanoma therapy.

Lipophilic polyphenol compounds (LPCs) are claimed to exhibit a broad spectrum of biological activities that may improve human health and wellbeing, including antioxidant, anti-inflammatory, and anti-cancer properties. Nanoemulsion-based delivery systems have been developed to encapsulate LPCs so as to increase their food matrix compatibility, physicochemical stability, and bioavailability. LPCs vary in their structural features, including the number and position of phenolic hydroxyl, ketone, and aliphatic groups, which results in different molecular, physicochemical, and gastrointestinal properties. In this study, we examined the impact of plant-based carrier oils (coconut, sunflower, and flaxseed oils) and LPC type (curcumin, resveratrol, and quercetin) on the in vitro gastrointestinal fate of polyphenols loaded into quillaja saponin-stabilized nanoemulsions. Coconut oil contains high levels of medium-chain saturated fatty acids (MC-SFAs), sunflower oil contains high levels of long-chain monounsaturated fatty acids (LC-MUFAs), and flaxseed oil contains high levels of long-chain polyunsaturated fatty acids (LC-PUFAs). The encapsulation efficiency and gastrointestinal stability of the LPCs were slightly lower in the MC than the LC oils. Differences in the gastrointestinal stability of the three LPCs were linked to differences in their oil-water partition coefficients. Some of the LPCs inhibited lipid digestion for certain oil types. In particular, resveratrol retarded the digestion of all three oils, but it still had the highest GIT stability and bioaccessibility. This study provides valuable information about the gastrointestinal fate of LPC-loaded nanoemulsions and highlights important differences in the behavior of LPCs with different characteristics. This knowledge may facilitate the design of more effective plant-based delivery systems for bioactive lipophilic polyphenols.

Aim: The aim of this study was to develop a formulation that combines a phospholipid complex (PC) and self-microemulsifying drug delivery system (SMEDDS) to improve the bioavailability of poorly water-soluble resveratrol (RES), called RPC-SMEDDS. Methods: RES-PC (RPC) and RPC-SMEDDS were optimized by orthogonal experiment and central composite design, respectively. The characteristics and mechanism of intestinal absorption were studied by Ussing chamber model. The pharmacokinetics was evaluated in rats. Results: RES was the substrate of MRP2 and breast cancer resistance protein (BCRP) rather than P-gp. The prepared RPC-SMEDDS prevented the efflux mediated by MRP2 and BCRP and improved the bioavailability of RES. Conclusion: These results suggested that the combination system of PC and SMEDDS was a promising method to improve the oral bioavailability of RES.

A novel delivery system using micron-scale grape skin powder (GSP) was developed that enhanced loading, stability and bioaccessibility of trans-resveratrol (trans-Res). Vacuum assisted infusion of GSP results in a high yield (~1 mg/g) of trans-Res and improved photostability of infused trans-Res in GSP exposed to UV-A light. The release of trans-Res from GSP was ~ 45% during gastric digestion and the total release in the intestinal phase during sequential digestion processes using low and high bile salts was ~ 70% and ~ 90%, respectively. Moreover, the release of endogenous polyphenols in GSP during simulated gastrointestinal digestion was similar to the release profile of infused resveratrol, suggesting strong interactions of infused resveratrol with the GSP matrix. In summary, this research illustrates a novel approach to utilize food by-products to enhance stability and bioaccessibility of bioactive compounds., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hydrogel wound dressings are highly effective in the therapy of wounds. Yet, most of them do not contain any active ingredient that could accelerate healing. The aim of this study was to prepare hydrophilic active dressings loaded with an anti-inflammatory compound - trans-resveratrol (RSV) of hydrophobic properties. A special attention was paid to select such a technological strategy that could both reduce the risk of irritation at the application site and ensure the homogeneity of the final hydrogel. RSV dissolved in Labrasol was combined with an aqueous sol of poly(vinyl) alcohol (PVA), containing propylene glycol (PG) as a plasticizer. This sol was transformed into a gel under six consecutive cycles of freezing (-80 °C) and thawing (RT). White, uniform and elastic membranes were successfully produced. Their critical features, namely microstructure, mechanical properties, water uptake and RSV release were studied using SEM, DSC, MRI, texture analyser and Franz-diffusion cells. The cryogels made of 8 % of PVA showed optimal tensile strength (0.22 MPa) and elasticity (0.082 MPa). The application of MRI enabled to elucidate mass transport related phenomena in this complex system at the molecular (detection of PG, confinement effects related to pore size) as well as at the macro level (swelling). The controlled release of RSV from membranes was observed for 48 h with mean dissolution time of 18 h and dissolution efficiency of 35 %. All in all, these cryogels could be considered as a promising new active wound dressings.

Resveratrol is a very promising anti-oxidant drug candidate with low oral bioavailability due to its intrinsic poor water solubility, intestinal efflux and metabolization mechanisms. Resveratrol solubility high-throughput screening with different carriers was performed showing an enhancement above 2000-fold with Soluplus® and Tween® 80. The former was selected as a carrier at the ratio of resveratrol: Soluplus® (1:2). Then, third-generation solid dispersions were developed with Gelucire® and poloxamer 407 at 5 and 15% to resveratrol: Soluplus® (1:2). All formulations enhanced solubility around 2-fold when compared to resveratrol: Soluplus® (1:2) solid dispersion. Caco-2 cells permeability studies showed that both surfactants increased drug permeability and the fraction recovered (2-fold) suggesting that these could reduce efflux mechanism and metabolism. Formulation with 15% poloxamer 407 demonstrated most promising results and was selected for further studies. In in vivo studies, resveratrol:Soluplus®: poloxamer 407 (1:2-15%) third generation solid dispersion presented an AUCo-t of 279 ± 54 ng.h/mL and a Cmax of 134 ± 78 ng/mL, 2.5 fold higher than solid dispersion without poloxamer 407. This work reports the development of third-generation solid dispersion that significantly improved resveratrol bioavailability. This was accomplished by an increased solubility and most probably by reducing intestinal efflux and metabolism mechanisms., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Resveratrol (RES) is a nutraceutical with promising anti-inflammatory properties for the treatment of inflammatory bowel diseases (IBD). However, the clinical effectiveness of resveratrol as an oral anti-inflammatory agent is hindered by its extremely poor solubility and poor stability. In this study, we encapsulated resveratrol in β-lactoglobulin (BLG) nanospheres and systematically analyzed their formulation parameters in vitro followed by a thorough in vivo anti-inflammatory testing in a highly specialized spontaneous murine UC model (Winnie mice model). Complexation of resveratrol with BLG increased the aqueous solubility of resveratrol by ≈1.7 times with 10% w/w loading. Additionally, the in vitro dissolution of resveratrol from the particles was found to be higher compared to resveratrol alone, resulting in >90% resveratrol dissolution in ∼8 h. The anti-inflammatory activity of resveratrol was examined for the first time in Winnie mice, a mouse model that closely represents the clinical signs of IBD. At a 50 mg/kg oral dose for 2 weeks, BLG-RES significantly improved both % body weight and disease activity index (DAI), compared to free resveratrol in Winnie mice. Importantly, histological evaluations revealed a similar trend with striking improvement in the pathology of the colon via an increase in goblet cell numbers and recovery of colonic epithelium. BLG-RES significantly increased the expression level of cytokine interleukin-10 ( Il10 ), which confirms the reduction in inflammation potentially because of the increased dissolution and stability of resveratrol by complexation with BLG. This comprehensive study demonstrates the effectiveness of biocompatible nanomaterials such as BLG in oral delivery of poorly soluble anti-inflammatory molecules such as resveratrol in the treatment of IBD.

Amphiphilic polymers represent one of the main class of stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles, being essential for their formation and stability. In the present study, poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymers were incorporated as stabilizers in liquid crystalline nanoparticles prepared from glyceryl monooleate. The polymers were chosen according to their high biocompatibility and promising stealth properties, in order to develop safe and efficient drug delivery nanosystems. The physicochemical characteristics and fractal dimension of the resultant nanosystems were obtained from light scattering techniques, while their micropolarity and microfluidity from fluorescence spectroscopy. The effect of temperature, serum proteins and ionic strength on the physicochemical behavior was monitored. Their morphology was assessed by cryo-TEM, while their thermal behavior by microcalorimetry and high-resolution ultrasound spectroscopy. Their properties were dependent on the stabilizer chemistry and topology (block/gradient copolymer) and its concentration. Subsequently, resveratrol, as model hydrophobic drug, was loaded into the nanosystems, the entrapment efficiency was calculated and in vitro release studies were carried out, highlighting how the different stabilizer can differentiate the drug release profile. In conclusion, the proposed copolymers broaden the toolbox of polymeric stabilizers for the development of liquid crystalline nanoparticles intended for drug delivery applications., (Copyright © 2020. Published by Elsevier B.V.)

In this study, the resveratrol was nano-encapsulated in three different sources of starch like Water chestnut Horse chestnut and Lotus stem to safeguard it from gastric conditions and to improve its bioavailability and bioactivity upon digestion. The nano-capsules were prepared using safe and eco-friendly ultra-sonication method and studied for encapsulation-efficiency, particle-size and zeta-potential measurement. These were also characterized by ATR-FTIR, SEM, XRD and DSC. The release behaviour of resveratrol and its activity against anti-diabetic and anti-obesity were also studied. The particle size of HSR, LSR and WSR was found to be 419, 797 and 691 nm with a zeta potential of -16.09, -24.28 and -14.77 and encapsulation efficiency of 81.46, 75.83 and 79.37 %, respectively. The nanoparticles showed porous or film-like structures with decreased crystallinity and higher transition temperatures. The maximum percentage of resveratrol was released in intestinal juice and exhibited higher anti-obesity and anti-diabetic activities than free resveratrol after digestion., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Phytochemicals are the most valuable and comprehensive structures, which may have a broad range of protective benefits, from reducing inflammation and speeding healing to preventing infection and fighting cancer. Resveratrol (RSV) is a natural phenolic compound from the oligomeric stilbenoids group, which is usually found in daily human diet, such as grape, peanut, berries and grains. It exhibits anti-inflammatory, neuroprotective, antioxidant, and cancer prevention and treatment effects. RSV is thought to have an impressive outcome in colorectal cancer (CRC) treatment through the vital molecules and cancer signaling pathways, including SIRT1, P53, P21, AMPK, ROS, BMP7, COX-2, NO, caspases, Wnt, TNFs, NF-κB, EMT, and pentose phosphate pathway. Therefore, this paper reviews the current researches on the pharmacological effects and pharmacokinetics of resveratrol and its drug delivery system, as well as clinical studies involving CRC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oxidative stress and inflammation play a pivotal role in ocular diseases. Resveratrol (RSV) is a natural bioactive that has recently attracted attention due to it potent antioxidant and anti-inflammatory properties. However, RSV presents poor aqueous solubility and chemical instability. Besides, effective drug delivery to the posterior segment of the eye is challenge. Nanotechnology emerges as a possible solution to improve both limitations. Here, we developed and characterized nanogels (NG) based on high molecular weight chitosan (HCS) crosslinked with sodium tripolyphosphate. The distribution size of NG presented a major population around 140 nm with a ζ-potential value of 32 ± 2 mV. TEM and AFM images showed that NG exhibited a rounded morphology. RSV encapsulation efficiency was 59 ± 1%. Photodegradation experiments showed that HCS by its own protects RSV from UV light-induced degradation. Biocompatibility assays revealed that NG were not cytotoxic neither inflammatory in human retinal pigment epithelial cells (ARPE-19), which constitutes the outer blood-retinal barrier. After cellular internalization, we report an endo-lysosomal escape of NG, which is crucial for efficient nanocarriers delivery systems. In conclusion, we envision that HCS based NG could constitute novel carriers for RSV, opening the possibility of its application in ocular diseases., Competing Interests: Declaration of competing interest Authors have no competing interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There are many kinds of biological activities of resveratrol itself, but its clinical application is limited by its poor solubility in water and low bioavailability. Therefore, we have prepared glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles (GL-HSA-RESNPs). The purpose of this study was to investigate the bioavailability, pharmacokinetics and tissue distribution of resveratrol in rats after single-dose tail vein injection administration of GL-HSA-RESNPs. A sensitive and reliable high performance liquid chromatography (HPLC) method was established to verify the content of resveratrol in rat plasma and organs. The C max value after GL-HSA-RESNPs administration was significantly higher than that of resveratrol suspension (933 ± 76.64 ng/mL vs . 618 ± 42.54 ng/mL, p  < .01). The T max value obtained after GL-HSA-RESNPs administration was significantly shorter than that after resveratrol suspension administration (0.17 ± 0.01 h vs . 0.25 ± 0.01 h, p  < .001). The bioavailability of GL-HSA-RESNPs was 4.25 times higher than that of the pure resveratrol. The concentration of resveratrol in the main organs of rats treated with the GL-HSA-RESNPs was higher than that in rats treated with the pure resveratrol. Rats treated with GL-HSA-RESNPs had the highest concentration of resveratrol in their liver. It is indicated that GL-HSA-RESNPs is a promising liver-targeted delivery system that improves the in vivo bioavailability of resveratrol.

Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factor in sporadic Alzheimer's disease (AD). Neuronal mitochondria have been proposed to be a promising therapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloid-β (Aβ) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological environment. Recently, biomaterials-based nanomedicine has been widely investigated for the treatment of AD. Herein, we devised a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules attached to the RBC membrane surface (RVG/TPP NPs@RBCm). With the advantage of suitable physicochemical properties of NLC and unique biological functions of the RBC membrane, RVG/TPP NPs@RBCm are stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of RVG29 and TPP, RVG/TPP NPs@RBCm can not only penetrate the blood-brain barrier (BBB) but also target neuron cells and further localize in the mitochondria. After encapsulating Resveratrol (RSV) as the model antioxidant, the data demonstrated that RVG/TPP-RSV NPs@RBCm can relieve AD symptoms by mitigating Aβ-related mitochondrial oxidative stress both in vitro and in vivo . The memory impairment in APP/PS1 mice is significantly improved following the systemic administration of RVG/TPP-RSV NPs@RBCm. In conclusion, intravenous neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems are a promising therapeutic candidate for ROS-induced mitochondrial dysfunction in AD.

Resveratrol is a polyphenolic compound which is found in many nutrients including grapes, peanuts, raspberries, and apples. Anti-proliferative, anti-angiogenic and apoptotic effects of resveratrol have been shown on various cancer cells. Doxorubicin is considered as one of the most effective anticancer agents and reveals its antitumor activity by induction of apoptosis and inhibition of angiogenesis. Our study reports for the first time the potent ability of resveratrol in combination with doxorubicin to inhibit angiogenesis in vitro and in vivo. The cytotoxic effect of resveratrol (1.56-100 μM), doxorubicin (0.01-0.92 µM) and their combination were analyzed in the human umbilical vein endothelial cells (HUVECs) by ATP assay. In vitro angiogenesis was evaluated using tube formation assay in HUVECs. In vivo anti-angiogenic activity was assessed in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs. All test groups were compared to thalidomide as a positive control, three concentrations of resveratrol (10-5-2.5 µg/pellet) and a 2 µg/pellet concentration of doxorubicin was examined. All data were evaluated statistically. Resveratrol and doxorubicin alone displayed inhibitory effects on angiogenesis and cell viability at higher doses. However, the combination of resveratrol and doxorubicin exhibited a significant dose-dependent inhibition of CAM angiogenesis in vivo as well as proliferation and tube formation in HUVECs compared to the positive control (±)-thalidomide. Our results suggest that resveratrol in combination with doxorubicin is a novel strategy in the prevention and treatment of angiogenesis., (Copyright© by the Polish Academy of Sciences.)