Free Resveratrol Research Articles

Sustained Anti-inflammatory Effect of Resveratrol-Phospholipid Complex Embedded Polymeric Patch.

Resveratrol-phospholipid complex (Phytosome®) (RSVP) was found better aqueous soluble and permeable than free resveratrol (RSV). RSVPs were incorporated in polymeric patch prepared by solvent casting method using Eudragit RL 100, PVP K30, and PEG 400 for application on dermal sites for sustained treating of inflammation. Prepared patches were evaluated for various physicochemical properties, surface morphology by SEM, TEM, and compatibility of patch components by FT-IR and DSC studies. Optimized formulation (F9) gave 95.79 ± 3.02% drug release and 51.36% (4.28 ± 0.48mg/cm2) skin permeation after 24h. Skin extract when examined for drug accumulation showed 38.31 ± 2.42% drug content. FE-SEM images of the patch taken after drug release and skin permeation studies showed that RSVPs in polymeric patch are stable and retain their structure after 24h long exposure to physiologic environment. Sustained anti-inflammatory effect was established in carrageenan-induced paw edema model in which test formulation gave 84.10% inhibition of inflammation at 24h as compared to 39.58% for standard diclofenac sodium gel. The CLSM study confirmed the localization of RSVPs for a longer period, thus enabling drug targeting to the dermis for sustained effect. Skin irritation test on rabbit revealed that the patches are safe for skin application. Histological observations suggested that after exposure to the permeants, the SC integrity had not altered and no evidence of presence of inflammatory cells found. RSVP (Phytosome®) containing patches abled to give sustained therapeutic effect that may be useful in treating acute and chronic inflammation.

Synergistic effects of resveratrol (free and inclusion complex) and sulfamethoxazole-trimetropim treatment on pathology, oxidant/antioxidant status and behavior of mice infected with Toxoplasma gondii

This study aimed to investigate the synergistic effects of resveratrol and sulfamethoxazole-trimethoprim (ST) on the treatment of mice experimentally infected by Toxoplasma gondii during the chronic phase of the disease considering infection, behavior, and oxidative/antioxidants profile aspects. For the study, 60 mice were initially divided into two groups: uninfected (n = 24) and infected by T. gondii (n = 36). These two groups were later subdivided into other groups and treated with resveratrol (free and inclusion complex containing resveratrol) alone and co-administered with ST: groups A to D were composed by healthy mice and groups E to J were consisted of animals infected by T. gondii (VEG strain). Treatments began 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg−1 of ST (groups B and F), 100 mg kg−1 of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), and lastly an co-administration of both drugs (groups I and J). Behavioral tests (memory, anxiety and locomotion) were performed after treatment. Liver and brain fragments were collected to evaluate pathological changes, brain cysts counts, as well as oxidant and antioxidant levels. A reduction on the number of cysts in the brain of animals treated with both drugs combined was observed; there was also reduced number of lesions on both organs. This drug combined effect was also able to reduce oxidative and increase antioxidant levels in infected mice, which might be interpreted as a resveratrol protective effect. In addition, the combination of ST and resveratrol was able to prevent behavioral changes in infected mice. Therefore, the use of co-administration drugs enhances the therapeutic effect acting on a synergic way, reducing the oxidizing effects of the chemical treatment for toxoplasmosis. In addition, resveratrol in inclusion complex when co-administered with ST showed an improved therapeutic effect of ST reducing oxidative damage, liver damage and the number of cysts in the brain of T. gondii infected mice.

Resveratrol-loaded nanocapsules inhibit murine melanoma tumor growth

In this study, resveratrol-loaded nanocapsules were developed and its antitumor activity tested on a melanoma mice model. These nanocapsules were spherically-shaped and presented suitable size, negative charge and high encapsulation efficiency for their use as a modified-release system of resveratrol. Nanoencapsulation leads to the drug amorphization. Resveratrol-loaded nanoparticles reduced cell viability of murine melanoma cells. There was a decrease in tumor volume, an increase in the necrotic area and inflammatory infiltrate of melanoma when resveratrol-loaded nanocapsules were compared to free resveratrol in treated mice. Nanoencapsulation of resveratrol also prevented metastasis and pulmonary hemorrhage. This modified-release technology containing resveratrol can be used as a feasible approach in order to inhibit murine melanoma tumor growth.

Improved Antioxidant Capacity of Optimization of a Self-Microemulsifying Drug Delivery System for Resveratrol

The use of nano-encapsulated resveratrol (RSV) in self-micro-emulsified drug delivery systems (SMEDDS) formulations was investigated. Self-emulsifying grading tests were used to establish the optimal ratio of oil, surfactant, and co-surfactant. The optimized system was further investigated for the droplet size and zeta potential at the different medium pH values by a Malvern Zetasizer and transmission electron microscopy (TEM). The antioxidant capacity and cytotoxicity of the formulation were detected by DCFH-DA and a CCK-8 assays. The results showed that the nano-emulsion based on ethyl oleate, Tween-80, and PEG-400 (35:40:25, w/w/w) was the most stable formulation due to the small droplet size (approximately 50 nm) and high zeta potential in a neutral environment. Furthermore, this formulation also exhibited a greater antioxidant capacity with less toxicity than free RSV. Taken together, considering these results and the simple fabrication process, this formulation could be used to deliver nutritional food supplements in a stable, efficient, and safe manner.

Validated LC–MS/MS method for simultaneous quantification of resveratrol levels in mouse plasma and brain and its application to pharmacokinetic and brain distribution studies

A rapid, selective, and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated to simultaneously determine resveratrol levels in plasma and brain tissue in mice for supporting pharmacokinetic and brain distribution studies. Analytes were separated using a Sepax BR-C18 analytical column (5μm, 120Å, 1.0×100mm) and eluted using an isocratic elution mobile phase acetonitrile and 0.01% formic acid [60:40, v/v] at a flow rate of 0.1mL/min. Precursor and product ion transitions for analyte resveratrol m/z 226.9>184.8 and curcumin m/z 367.1>148.9 were monitored using triple quadrupole mass spectrometer with multiple reaction monitoring (MRM) in negative ionization mode. The method was validated with respect to accuracy, within- and between-day precision, linearity, limit of quantification, recovery, and matrix effects of analyte. The inter- and intra-day accuracy and precision were within the range of the US Food and Drug Administration (FDA) acceptance criteria, for both matrices. The method was also successfully applied to pharmacokinetic and brain distribution studies of resveratrol after intravenous administration of free resveratrol and resveratrol-loaded solid lipid nanoparticles to mice. The combined use of serial blood sampling, small sample volume, simple extraction, and capillary depletion method drastically improved resveratrol analysis from biological matrices.

Enhancing delivery and cytotoxicity of resveratrol through a dual nanoencapsulation approach

Despite the known anticancer potential of resveratrol, its clinical applications are often hindered by physicochemical limitations such as poor solubility and stability. The encapsulation of resveratrol in formulations such as polymeric nanoparticles and liposomes has shown limited success. This study aimed to develop and optimize a novel drug carrier by co-encapsulating pristine resveratrol alongside cyclodextrin–resveratrol inclusion complexes in the lipophilic and hydrophilic compartments of liposomes, respectively by using a novel dual carrier approach. The particle size, polydispersity index and zeta potential of the final formulation were 131±1.30nm, 0.089±0.005 and −2.64±0.51mV, respectively. Compared to free resveratrol and conventional liposomal formulations with drug release profile of 40–60%, our novel nanoformulations showed complete (100%) drug release in 24h. The formulation was stable for 14days at 4°C. We also studied the in vitro cytotoxicity of resveratrol encapsulated liposomes in HT-29 colon cancer cell lines. The cytotoxicity profile of our liposomes was observed to be dose dependent and enhanced in comparison to free resveratrol (in DMSO). Our study demonstrates that co-encapsulation of pristine resveratrol along with its cyclodextrin complex in liposomal formulations is a plausible option for the enhanced delivery of the hydrophobic chemotherapeutic agent.

Resveratrol loaded gelatin nanoparticles synergistically inhibits cell cycle progression and constitutive NF-kappaB activation, and induces apoptosis in non-small cell lung cancer cells

PurposePreviously, we reported that the prepared resveratrol (RSV) loaded gelatin nanoparticles (GNPs) possessed enhanced anticancer effect than free RSV in non-small cell lung carcinoma cells and Swiss albino mice. The present study aims to explore the relevant mechanism of cell death induced by the combination of RSV-GNPs in NCI-H460 cells. Methods and resultsTo increase its bioavailability and anticancer efficacy, we have encapsulated RSV-GNPs by Coacervation method. The detailed methods of preparation and characterization of RSV-GNPs were reported in our earlier publication. RSV-GNPs treated cells showed a further increased level of lipid peroxidative markers, i.e. TBARS and LHP in NCI-H460 cells. Activities of antioxidant enzymes SOD, CAT, GPx and GSH levels were decreased upon the treatment with RSV-GNPs in NCI-H460 cells. The nuclear fragmentation was evaluated by DAPI staining and data showed condensed apoptotic bodies upon treatment with the combination of RSV-GNPs compared to RSV alone treatment group. In addition, cell death induced by RSV-GNPs was mainly due to apoptosis which was characterized by a nuclear DNA fragmentation in a ladder-pattern was obtained from the genomic DNA analysis. Moreover, Western blotting analysis showed that apoptosis induced by RSV-GNPs is associated with the increased Bax, p53, p21, caspase-3 protein levels, and decreased Bcl-2 and NF-κB proteins expression, which indicates the involvement of mitochondria-dependent apoptosis in the anticancer efficacy of RSV-GNPs in NCI-H460 cells. It was also found that this enhanced anticancer efficacy of RSV-GNPs induced cell arrest in the G0/G1 phase of cell cycle. ConclusionsTaken together, the results of our study clearly suggested that the cell death induced by the combination of RSV-GNPs would involve alteration in expression of p53, p21, caspase-3, Bax, Bcl-2 and NF-κB, indicating oxidative mechanism in NCI-H460 cells. Based on these results, it is concluded that GNPs is an ideal way to deliver RSV because of its high loading efficiency and superior efficacy in NCI-H460 cells.

Sulfamethoxazole-trimethoprim associated with resveratrol for the treatment of toxoplasmosis in mice: Influence on the activity of enzymes involved in brain neurotransmission

This study aimed to investigate the influence of sulfamethoxazole-trimethoprim (ST) associated with resveratrol on the enzymatic activities of acetylcholinesterase (AChE), adenylate kinase (AK), pyruvate kinase (PK), and creatine kinase (CK) in the brain of mice experimentally infected by Toxoplasma gondii. For that, 60 mice were divided into ten groups with 6 animals each: groups A to D composed by healthy mice and groups E to J consisting of animals infected by T. gondii (VEG strain). Animals started treatment 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg−1 of ST (groups B and F), 100 mg kg−1 of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), as well as with an association of both drugs (groups I and J). The results showed increased (P < 0.001) AChE activity on infected animals (groups E-J) when compared to not-infected (A) animals, and also uninfected animals treated with ST (group B) had increased AChE activity. AK activity decreased (P < 0.001) in the infected and untreated (group E), differently from the other groups that did not differ. PK activity did not differ between groups (P > 0.05). When comparing control groups (uninfected (A) and infected (E)), we verified a significant (P < 0.001) increase in CK activity in the brain, and it is noteworthy that the animals treated with resveratrol associated with ST (group I and J) had similar CK activity to those animals from the group A. Treatment with the combination of ST and resveratrol was able to reduce (P < 0.05) the number of parasitic cysts in the brain, thus reduced inflammatory infiltrates in the liver, and prevented the occurrence of hepatocytes lesions due to toxoplasmosis in mice. Based on these results, it is possible to conclude that increased AChE and CK activities after T. gondii infection did not change with the treatment of ST-resveratrol association. In addition, decreased AK activity caused by T. gondii infection was normalized by ST-resveratrol treatment. T. gondii infection and treatment does not affect PK activity in brain.

Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans.

Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol. Clarifying aspects like stability and pharmacokinetics of resveratrol metabolites would be fundamental to understand and apply the therapeutic properties of resveratrol.

Resveratrol-loaded polymeric nanoparticles suppress glucose metabolism and tumor growth in vitro and in vivo

Resveratrol (RSV) is a natural phenol with promising anti-tumor activities, but its use for in vivo cancer treatment is limited by low aqueous solubility and poor stability. In this study, we prepared RSV-loaded polyethylene glycol–polylactic acid (PEG–PLA; M.W. 5000-5000) polymer nanoparticles (NPs) for improved stability and controlled delivery, and investigated its metabolic and anti-tumor effect in vitro and in vivo. CT26 colon cancer cells displayed significantly reduced cell number to 5.6% and colony forming capacity to 6.3% of controls by 72h treatment with 40 and 20μM of RSV-NP, respectively. Flow cytometry and western blots demonstrated increased apoptotic cell death, and 18F FDG uptake and reactive oxygen species was significantly reduced by RSV-NP. All of these effects were comparable to or greater in potency compared to free RSV. When RSV-NP was intravenously administered to CT26 tumor bearing mice, there was a reduction of 18F FDG uptake on PET/CT by day 4. Longer treatment led to retardation of tumor growth accompanied by an improvement in survival compared to empty NP-injected controls. These results demonstrate that the in vitro and in vivo metabolic and anti-tumor effects of RSV is preserved by PEG–PLA NP loading, and provide an encouraging outlook on the potential of polymeric NPs as an effective method to deliver RSV for cancer therapy.

In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery

Resveratrol is a potent anticancer. However, because of its low half-life (<0.25h) the molecule is difficult to achieve the therapeutic concentration at the site of action. The aim of this work was to check the brain targeting ability of glyceryl behenate-based solid lipid nanoparticles (SLN) for resveratrol. SLN were prepared by solvent evaporation technique employing high speed homogenization followed by ultrasonication. SLN were designed at varying drug–lipid ratios (1:5, 1:9, 1:10, 1:11, 1:12 and 1:15) using Tween 80 or a combination of Tween 80 and polyvinyl alcohol (PVA) as surfactants. The mean particle size and zeta potential of the optimized formulation (drug–lipid ratio of 1:10) were 248.30±3.80nm and −25.49±0.49mV, respectively. The particle size and the encapsulation efficiency (EE) increased when varying the drug–lipid ratio from 1:5 to 1:15. Scanning electron microscopic (SEM) analysis showed that SLN were spherical in shape and had a smooth surface. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses revealed that the matrix of drug-loaded SLN was in disordered crystalline phase. The in vitro release study in phosphate buffer pH 7.4 followed a sustained release pattern. The drug release data was found to fit best into Higuchi kinetic model suggesting the diffusion controlled mechanism of drug release. The cytotoxicity assay (MAT) showed that SLN were equally effective (P<0.5) as free resveratrol, as an anti-tumor agent. The in vivo biodistribution study using Wistar rats demonstrated that SLN could significantly (P<0.001) increase the brain concentration of resveratrol (17.28±0.6344μg/g) as compared to free resveratrol (3.45±0.3961μg/g). The results showed that our resveratrol-loaded SLN serve as promising therapeutic systems to treat neoplastic diseases located in the brain tissue.

Resveratrol Metabolism in a Non-Human Primate, the Grey Mouse Lemur (Microcebus murinus), Using Ultra-High-Performance Liquid Chromatography–Quadrupole Time of Flight

The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 mg.kg−1 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MSE mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo- and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo- and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism.

PTEN mediates the antioxidant effect of resveratrol at nutritionally relevant concentrations.

Introduction. Antioxidant properties of resveratrol have been intensively studied for the last years, both in vivo and in vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant. Aims. In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect. Methods. We used mammary gland tumor cells (MCF-7), which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibitor (bpV: bipy). Hydrogen peroxide levels were determined by fluorimetry, PTEN levels and Akt phosphorylation by Western Blotting, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Results. Resveratrol treatment for 48 h lowered peroxide levels in MCF-7, even at low nutritional concentrations (1 nM). This effect was mediated by the activation of PTEN/Akt pathway, which resulted in an upregulation of catalase and MnSOD mRNA levels. Conclusion. Resveratrol acts as an antioxidant at nutritionally relevant concentrations by inducing the expression of antioxidant enzymes, through a mechanism involving PTEN/Akt signaling pathway.

Lipid-Core Nanocapsules Improve the Effects of Resveratrol Against A&lt;I&gt;β&lt;/I&gt;-Induced Neuroinflammation

Resveratrol, a natural polyphenolic compound, has attracted considerable interest for its anti-inflammatory and neuroprotective properties. However, the biological effects of resveratrol appear strongly limited because it is photosensitive, easily oxidized, and has unfavorable pharmacokinetics. The present study aimed to elucidate the effect of resveratrol on Abeta-triggered neuroinflammation by comparing the effects of free resveratrol (RSV) treatment with those of treatment with resveratrol-loaded lipid-core nanocapsules (RSV-LNC). Organotypic hippocampal cultures were stimulated by Abeta1-42 with or without different concentrations of RSV or RSV-LNC. We found that Abeta triggered a harmful neuroinflammation process in organotypic hippocampal cultures. Pre- and co-treatments with RSV-LNC were able to protect cultures against ROS formation and cell death induced by Abeta, possibly through sustained blocking of TNF-alpha, IL-1beta, and IL-6 release. Furthermore, RSV-LNC was able to increase IL-10 release even in the presence of Abeta and prevent or decrease both glial and JNK activation. On the other hand, both pre- and co-treatment with RSV exhibited a lower ability to prevent or decrease neuroinflammation, ROS formation, and cell death, and failed to increase IL-10 release. Our findings suggest that modulation of neuroinflammation through a combination of resveratrol and a lipid-core nanocapsule-based delivery system might represent a promising approach for preventing or delaying the neurodegenerative process triggered by Abeta. The results open new vistas to the interplay between inflammation and amyloid pathology.

Abstract 4516: Targeted delivery of resveratrol to improve therapeutic outcome in prostate cancer.

Abstract Conventional chemotherapeutics offered to treat prostate cancer (PCa) are not selectively targeted and due to this fact they are toxic to the normal cells. Thus, it is imperative to identify new anti-cancer agents and/or methods to selectively target PCa cells without affecting normal cells. In this regard, resveratrol (trans-3, 5, 4’-trihydroxystilbene), a plant polyphenol, has shown very promising results. Despite the proven anti-tumor effects of resveratrol, clinical use of this compound is restricted due to its poor bioavailability. To surmount these problems, we developed nanoparticles, loaded with resveratrol, using a planetary-balled milling (PBM) technique and tagged them with folate for targeted delivery to PCa cells, which express high affinity folate receptors. Image Stream multispectral imaging was used to measure the response of resveratrol-loaded PBM nanoparticles, and free resveratrol on various PCa cell lines. Resveratrol-loaded folic acid-coated PBM nanoparticles selectively targeted PCa cells and induced apoptosis. Furthermore, our results indicate that targeted delivery of resveratrol using PBM nanoparticles was 70-85% more effective in killing PCa cells at concentrations lower than the IC50 of free resveratrol. Citation Format: Rajesh Singh, Pranav Gupta, Shailesh Singh, James W. Lillard. Targeted delivery of resveratrol to improve therapeutic outcome in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2013-4516

Antibacterial Activity of Oligostilbenoid Derivatives from the Stem Bark of Dryobalanops Lanceolata

Oligostilbenoid (oligomers of 3,5,4’-trihydroxystilbene) have drawn much attention due to its structure complexity, diversity and biological activities. The differences in the structures of oligostilbenoids in each family or genera has attracted interests from scientists of various disciplines to investigate its properties such as phytochemical, biogenetic pathway and chemotaxonomic. The oligostilbenoids in Dryobalanops species (Dipterocarpaceae) is unique due to the unusual condensation type displayed in Dipterocarpaceae family as compared to other oligostilbenoids from other families. In this study, eight oligostilbenoid tetramers derivatives, including malaysianol B (1) [1], hopeaphenol (2) [2], stenophyllol A (3) [3], nepalensinol B (4) [4], vaticanol B (5) and C (6) [5], upunaphenol D (7) [6], and flexuosol A (8) [7] have been isolated from D. lanceolata by using combination of vacuum and radial chromatography techniques. Their structures were established on the basis of their spectroscopic evidences and comparison with published data. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay against Gram-positive and Gram-negative bacterial strains. Compounds 7 and 8 exhibited promising antibacterial property as they inhibited the cell growth of three Gram-positive strains, Staphylococcus epidermidis, S. aureus and S. xylosus with MIC 25/75, 50/100 and 25/75 μM, respectively. If compared with compounds 1-6, the presence of free resveratrol in the skeleton of 7 and 8 showed significance effect to their activity. In addition, the position of isolated free resveratrol unit in 8 gave less activity than terminal in 7 due to a disruption of the double bond resonance in the free resveratrol.

Resveratrol: distribución, propiedades y perspectivas

Resveratrol is a natural polyphenol which can be found in many plants and fruits, such as peanuts, mulberries, blueberries and, above all, in grapes and red wine. Its synthesis is regulated by the presence of stressful factors, such as fungal contamination and ultra-violet radiation. In plants, it plays a role as a phytoalexin, showing a capacity to inhibit the development of certain infections. Plant extracts which contain resveratrol have been employed by traditional medicine for more than 2000 years. Resveratrol was first isolated, and its properties were initially studied with scientific methods, thirty years ago. Its in vitro properties have been extensively studied and demonstrated. It is worth highlighting its activity as an anti-cancer agent, platelet anti-aggregation agent, anti-inflammatory, antiallergenic, etc. The activity of its in vivo properties are not so clear. There are many studies that report benefits on the cardiovascular system, illnesses such as diabetes, and in longevity. However, other authors did not find any agreement between in vitro and in vivo studies. This discrepancy is due to the bioavailability of resveratrol. After an oral dose, it has been demonstrated that the absorption is very high, but the metabolic pathways leave just a little free resveratrol in blood, therefore the bioavailability in the target tissues is very low and the concentrations used in in vitro studies are not found in these tissues. Thus, resveratrol is a very active molecule for maintaining health, but due to the low bioavailability not all the in vitro effects can be translated to in vivo. This opens a new potential approach, seeking derivatives of resveratrol that can be measured in the desired tissues

Neuroprotective Effects of Resveratrol Against Aβ Administration in Rats are Improved by Lipid-Core Nanocapsules

Alzheimer's disease (AD), a neurodegenerative disorder exhibiting a gradual decline in cognitive function, is characterized by the presence of neuritic plaques composed of neurofibrillary tangles and amyloid-β (Aβ) peptide. Available drugs for AD therapy have small effect sizes and do not alter disease progression. Several studies have been shown that resveratrol is associated with anti-amyloidogenic properties, but therapeutic application of its beneficial effects is limited. Here we compared the neuroprotective effects of free resveratrol treatment with those of resveratrol-loaded lipid-core nanocapsule treatment against intracerebroventricular injection of Aβ1-42 in rats. Animals received a single intracerebroventricular injection of Aβ1-42 (2 nmol), and 1 day after Aβ infusion, they were administered either free resveratrol (RSV) or resveratrol-loaded lipid-core nanocapsules (5 mg/kg, each 12 h, intraperitoneally), for 14 days. Aβ1-42-infused animals showed a significant impairment on learning memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels. Furthermore, animals exhibited activated astrocytes and microglial cells, as well as disturbance in c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3β (GSK-3β) activation, beyond destabilization of β-catenin levels. Our results clearly show that by using lipid-core nanocapsules, resveratrol was able to rescue the deleterious effects of Aβ1-42 while treatment with RSV presented only partial beneficial effects. These findings might be explained by the robust increase of resveratrol concentration in the brain tissue achieved by lipid-core nanocapsules. Our data not only confirm the potential of resveratrol in treating AD but also offer an effective way to improve the efficiency of resveratrol through the use of nanodrug delivery systems.

Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy

Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy.

Anticancer activity of resveratrol-loaded gelatin nanoparticles on NCI-H460 non-small cell lung cancer cells

Resveratrol (RSV), a grape phytochemical, has drawn greater attention because of its beneficial effects against cancer. However, RSV has some drawbacks such as unstabilization, poor water solubility and short biological half time, which limit the utilization of RSV in medicine, food and pharmaceutical industries. In this study, we have encapsulated RSV in gelatin nanoparticles (GNPs) and studied its anticancer efficacy in NCI-H460 lung cancer cells. SEM and DLS studies have revealed that the prepared RSV-GNPs possess spherical shape with a mean diameter of 294nm. The successful encapsulation of RSV in GNPs has been achieved by the cross-linker glutaraldehyde probably through Schiff base reaction and hydrogen bond interaction. Spectrophotometric analysis revealed that the maximum of 93.6% of RSV has been entrapped in GNPs. In vitro drug release kinetics indicated that there was an initial burst release followed by a slow and sustained release of RSV from GNPs. The prepared RSV-GNPs exhibited very rapid and more efficient cellular uptake than free RSV. Further, RSV-GNPs treatment showed greater antiproliferative efficacy than free RSV treatment in NCI-H460 cells. It has been found that greater ROS generation, DNA damage and apoptotic incidence in RSV-GNPs treated cells than free RSV treatment. Erythrocyte aggregation assay showed that the prepared RSV-GNPs formulation elicit no toxic response. HPLC analysis revealed that RSV-GNPs was more bioavailable and had a longer half-life than free RSV. Hence, GNPs carrier system might be a promising mode for controlled delivery and for improved therapeutic index of poorly water soluble RSV.