Bioavailability Of Resveratrol Research Articles

Does Resveratrol Improve Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)?

Metabolic dysfunction-associated steatotic liver disease (MASLD) is influenced by a variety of factors, including environmental and genetic factors. The most significant outcome is the alteration of free fatty acid and triglyceride metabolism. Lipotoxicity, impaired autophagy, chronic inflammation, and oxidative stress, as well as coexisting insulin resistance, obesity, and changes in the composition of gut microbiota, are also considered crucial factors in the pathogenesis of MASLD. Resveratrol is a polyphenolic compound that belongs to the stilbene subgroup. This review summarises the available information on the therapeutic effects of resveratrol against MASLD. Resveratrol has demonstrated promising antisteatotic, antioxidant, and anti-inflammatory activities in liver cells in in vitro and animal studies. Resveratrol has been associated with inhibiting the NF-κB pathway, activating the SIRT-1 and AMPK pathways, normalizing the intestinal microbiome, and alleviating intestinal inflammation. However, clinical studies have yielded inconclusive results regarding the efficacy of resveratrol in alleviating hepatic steatosis or reducing any of the parameters found in MASLD in human patients. The lack of homogeneity between studies, low bioavailability of resveratrol, and population variability when compared to animal models could be the reasons for this.

Third-Generation Solid Dispersion Through Lyophilization Enhanced Oral Bioavailability of Resveratrol.

Resveratrol (RES) is a biopharmaceutical classification system (BCS) class II compound with low solubility and high permeability. Several strategies have been explored to overcome the low bioavailability of RES, making the formation of solid dispersions (SDs) one of the most promising. This study aimed at the development of a RES third-generation SD prepared by lyophilization as a strategy to improve RES solubility, dissolution, and oral bioavailability. Eudragit E PO was selected as the hydrophilic carrier in a 1:2 (RES:carrier) ratio, and Gelucire 44/14 as the surfactant, at 16% (w/w) of RES. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), polarized light microscopy (PLM), X-ray powder diffraction (XRPD), and particle size distribution (Morphologi 4 Malvern) were used for solid-state characterization and to confirm the conversion of RES to the amorphous state in the SD. Third-generation SD presented an 8-, 12-, and 8-fold increase of RES solubilized compared to pure RES at pH 1.2, 4.5, and 6.8, respectively, and a 10-fold increase compared to the physical mixture (PM), at pH 6.8, after 24 h. In the gastric environment, the dissolution rate of third-generation SD and PM was similar, and 2-fold higher than pure RES after 30 min, while at pH 6.8, third-generation SD presented approximately a 5-fold increase in comparison to pure RES and PM. Third-generation SD presented higher in vitro intestinal permeability compared to its PM and second-generation SD (without Gelucire 44/14). A 2.4 and 1.7-fold increase of RES permeated, respectively in Caco-2 and Caco-2/HT2-MTX models, was obtained with third-generation SD compared to PM, after 3 h. Third-generation SD allowed a 3-fold increase of RES bioavailability compared to second-generation SD, after oral administration of 200 mg/kg of RES to Wistar rats. Enhanced RES oral bioavailability was obtained not only by solubility and dissolution improvement, but also by the interference of Gelucire 44/14, with RES metabolism, and inhibition of P-gp-mediated efflux. The presence of excipients like Gelucire 44/14 in the SD allows for greater bioavailability of orally administered RES, making it easier to obtain some of the physiological benefits demonstrated by this molecule.

Cardioprotective Potential of Resveratrol Alone and in Combination with Piperine on Isoproterenol-induced Myocardial Infarction in Rat: Investigation on Oral Bioavailability of Resveratrol

Cardioprotective Potential of Resveratrol Alone and in Combination with Piperine on Isoproterenol-induced Myocardial Infarction in Rat: Investigation on Oral Bioavailability of Resveratrol

Characteristics and in vitro digestion of resveratrol encapsulated in Pickering emulsions stabilized by tea water-insoluble protein nanoparticles.

This study focused on the characteristics and in vitro digestion of resveratrol encapsulated in Pickering emulsions stabilized by tea water-insoluble protein nanoparticles (TWINs). The absolute value of zeta potential of Pickering emulsions stabilized by TWIPNs (TWIPNPEs) encapsulating resveratrol was above 40mV. Resveratrol encapsulated in TWIPNPEs was located at a hydrophobic environment of emulsion droplets. Additionally, the encapsulation efficiency (EE) of TWIPNPEs at TWIPN concentrations of 3.0% and 4.0% was above 85%. The resveratrol encapsulated in TWIPNPEs at a TWIPN concentration of 4.0% was still greater than 80% after UV irradiation to reduce the susceptibility of resveratrol for photodegradation. Moreover, the bioavailability of resveratrol in TWIPNPEs was improved in the simulated in vitro digestion. The bioavailability of resveratrol in TWIPNPEs in the simulated system was two times higher than unencapsulated resveratrol. This research could be useful for the encapsulation and application of nutraceuticals like resveratrol based on TWIPNPEs.

Characterization and comparison of physical properties and in vitro simulated digestion of multi-component oleogels with different molecular weights prepared by the direct method

Due to the hazards of trans fatty acids and saturated fatty acids to human health, research on novel structured lipid-oleogels as lipid substitutes has attracted increasing attention. However, oleogelators of different molecular weights, oils of different properties, and adding lipophilic bioactive substances (LBAS) and/or surfactants to the system lead to differences in oleogel properties. This study characterized and compared the physical properties and in vitro simulated digestion of different multi-component oleogels of carnauba wax oleogels (CWOs), β-sitosterol/lecithin oleogels (S/LOs), and ethyl cellulose oleogels (ECOs) prepared by the direct method. Oleogel strength decreased in the order ECOs > CWOs > S/LOs and peanut oil oleogels > soybean oil oleogels. Regardless of oleogel type, resveratrol (RE) loading and surfactant addition altered the self-assembly or co-assembly behavior of oleogels, which improved their hardness, oil binding capacity (OBC), thermal stability, solid fat content (SFC), viscoelasticity, and RE loading capacity/encapsulation efficiency. The network structure of the different oleogels and the molecular properties of the oleogelators led to differences in the in vitro digestion of multi-component oleogels. Differences in oleogel processing conditions altered their degree of lipolysis and the bioavailability of RE within it. This research sets the direction toward the development of healthier fat substitutes in the future.

Phytoglycogen to Enhance the Solubility and in-vitro Permeation of Resveratrol.

This study investigated the capability of phytoglycogen (PG) to improve the water-soluble amount and bioavailability of resveratrol (RES). RES and PG were incorporated through co-solvent mixing and spray-drying to form PG-RES solid dispersions. The soluble amount of RES of PG-RES solid dispersions reached 289.6 μg/mL at PG:RES ratio of 50:1, compared with 45.6 μg/mL for RES alone. X-ray powder diffraction and Fourier-transform infrared spectroscopy tests suggested a significant reduction of RES crystallinity in PG-RES solid dispersions and the formation of hydrogen bonds between RES and PG. Caco-2 monolayer permeation tests showed that, at low RES loading concentrations (15 and 30 μg/mL), PG-RES solid dispersions achieved greater permeation of RES (0.60 and 1.32 μg/well, respectively) than RES alone (0.32 and 0.90 μg/well, respectively). At an RES loading of 150 μg/mL, PG-RES solid dispersion realized RES permeation of 5.89 μg/well, suggesting the potential of PG in enhancing the bioavailability of RES.

Encapsulation of resveratrol within size-controlled nanoliposomes: Impact on solubility, stability, cellular permeability, and oral bioavailability

This study examined the influence of the nanoliposomes (LPs) particle size on the solubility, antioxidant stability, in vitro release profile, Caco-2 cellular transport activity, cellular antioxidant activity, and in vivo oral bioavailability of resveratrol (RSV). LPs with sizes of 300, 150, and 75 nm were prepared using the thin-lipid film hydration method, followed by ultrasonication for 0, 2, and 10 min, respectively. Formulating small LPs (< 100 nm) was effective to enhance the solubility, in vitro release profile, cellular permeability, and cellular antioxidant activity of RSV. A similar pattern was observed for in vivo oral bioavailability. However, the size reduction of RSV-loaded LPs did not promote the antioxidant stability of RSV, owing to their large surface area used to interact with harsh environments. This study provides the better understanding of the appropriate particle size range of LPs to improve their in vitro and in vivo performances of RSV as an effective carrier for oral administration.

Dietary Resveratrol Butyrate Monoester Supplement Improves Hypertension and Kidney Dysfunction in a Young Rat Chronic Kidney Disease Model.

Chronic kidney disease (CKD) remains a public health problem. Certain dietary supplements can assist in the prevention of CKD progression. In this regard, resveratrol is a polyphenol and has a potential therapeutic role in alleviating CKD. We previously utilized butyrate in order to improve the bioavailability of resveratrol via esterification and generated a resveratrol butyrate monoester (RBM). In this study, the hypothesis that RBM supplementation is able to protect against kidney dysfunction and hypertension was tested by using an adenine-induced CKD model. For this purpose, three-week-old male Sprague Dawley rats (n = 40) were equally categorized into: group 1-CN (sham control); group 2-CKD (adenine-fed rats); group 3-REV (CKD rats treated with 50 mg/L resveratrol); group 4-MEL (CKD rats treated with 25 mg/L RBM); and group 5-MEH (CKD rats treated with 50 mg/L RBM). At the end of a 12-week period, the rats were then euthanized. The adenine-fed rats displayed hypertension and kidney dysfunction, which were attenuated by dietary supplementation with RBM. The CKD-induced hypertension coincided with: decreased nitric oxide (NO) bioavailability; augmented renal protein expression of a (pro)renin receptor and angiotensin II type 1 receptor; and increased oxidative stress damage. Additionally, RBM and resveratrol supplementation shaped distinct gut microbiota profiles in the adenine-treated CKD rats. The positive effect of high-dose RBM was shown together with an increased abundance of the genera Duncaniella, Ligilactobacillus, and Monoglobus, as well as a decrease in Eubacterium and Schaedierella. Importantly, the mechanism of action of the RBM supplementation may be related to the restoration of NO, rebalancing of the RAS, a reduction in oxidative stress, and alterations to the gut microbiota. Moreover, RBM supplementation shows promise for the purposes of improving CKD outcomes and hypertension. As such, further translation to human studies is warranted.

Preparation of Solid Dispersion of Polygonum Cuspidatum Extract by Hot Melt Extrusion to Enhance Oral Bioavailability of Resveratrol.

The aim of this study was to improve the solubility, bioavailability, and stability of resveratrol (RES-SD) Solid Dispersion in Polygonum cuspidatum extract (PCE) by hot melt extrusion (HME). In addition, the role of the auxiliary substances in PCE was also studied. The solid dispersion of Polygonum cuspidatum extract was prepared by hot-melt extrusion. The optimum formula was selected by single factor design and orthogonal test. The optimum formula was barrel temperature 140 °C, screw rotation speed 40 rpm/min, and the ratio of Polygonum cuspidatum extract to HPMCAS was 1:2. The dissolution test showed that PCE-SD increased the dissolution of RES from 46.75 ± 0.47% to 130.06 ± 0.12%. The pharmacokinetics curve of rats showed that PCE-SD increased AUC0-t of RES from 111,471.22 ± 11.4% to 160,458.968 ± 15.7%, indicating an approximately 1.44-fold increase in absorption. In addition, the rotation speed of PCE-SD screw is less than that of RES-SD screw. The bioavailability of PCE-SD was slightly better than that of RES-SD. PCE-SD is more hygroscopic than RES-SD. PCE-SD increased the solubility and oral bioavailability of RES. The auxiliary substances in Polygonum cuspidatum extract have influence on its preparation technology, stability, and bioavailability.

‘Poly phenolic phytoceutical loaded nano-bilosomes for enhanced caco-2 cell permeability and SARS-CoV 2 antiviral activity’: in-vitro and insilico studies

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predisposed to the emergence of worldwide catastrophe that impels the evolution of safe and effective therapeutic system. Polyphenols as resveratrol (RSV) exhibit a well evidenced antiviral activity. Unfortunately, like most phenolic nutraceuticals, RSV suffers from restrained solubility and massive degradation in GIT and liver which in turn prohibit its clinical use. Herein, PEGylated bilosomes (PBs) contain PEGylated edge activator along with the traditional components as (Span 60, cholesterol and bile salts) were proposed to boost both permeability and bioavailability of RSV. The investigation of the prominent effect of the diverse variables on the characteristics of the vesicles and picking of the optimum formula were conducted via construction of 23 factorial experiment. The appraisal of the formulae was conducted on the basis of entrapment efficiency percent (EE%), particle size (PS) and zeta potential (ZP). In addition, the spherical shaped optimal formula (F5) exhibited EE% of 86.1 ± 2.9%, PS of 228.9 ± 8.5 nm, and ZP of −39.8 ± 1.3 mV. The sorted optimum formula (F5) exhibited superior dissolution behaviors, and boosted Caco-2 cells cellular uptake by a round 4.7 folds relative to RSV dispersion. In addition, F5 demonstrated a complete in vitro suppression of SARS-CoV-2 at a concentration 0.48 μg/ml with 6.6 times enhancement in antiviral activity relative to RSV dispersion. The accomplished molecular modeling heavily provided proof for the possible interactions of resveratrol with the key residues of the SARS-CoV2 Mpro enzyme. Finally, F5 could be proposed as a promising oral panel of RSV for curation from SARS-CoV-2 infection.

Is It Possible to Improve the Bioavailability of Resveratrol and Polydatin Derived from Polygoni cuspidati Radix as a Result of Preparing Electrospun Nanofibers Based on Polyvinylpyrrolidone/Cyclodextrin?

The low bioavailability of resveratrol and polydatin obtained from Polygoni cuspidati extract limits the application of their pro-health properties. While nanofibers have attracted increasing attention in nutrition delivery due to their special properties, including an increase in the dissolution and permeability, which affects the bioavailability. Therefore, it is justified to obtain nanofibers from Polygoni cuspidati extract, which showed antioxidant and anti-inflammatory properties as a result of a presence of stilbene analogs in the Polygoni cuspidati extract (especially resveratrol and polydatin). In the first stage of the work, using the Design of Experiment (DoE) approach, the Polygoni cuspidati extract (70% of methanol, temperature 70 °C and 4 cycles) was obtained, which showed the best antioxidant and anti-inflammatory properties. Using the Polygoni cuspidati extract as a substrate, nanofibers were obtained by electrospinning. The identification of nanofibers was confirmed on the basis of the analysis of changes in XRPD diffractograms, SEM picture and FTIR-ATR spectra. Obtaining nanofibers from the Polygoni cuspidati extract significantly improved the solubility of resveratrol and polydatin (approx. 6-fold comparing to pure substance). As a consequence, the penetration coefficients of both tested resveratrol and polydatin also increased. The proposed strategy for the preparation of nanofibers from the Polygoni cuspidati extract is an innovative approach to better use the synergy of biological action of active compounds present in extracts. It is especially during the development of nutraceuticals based on the use of selected stilbenes.

Antioxidant and neuroprotective actions of resveratrol in cerebrovascular diseases.

Cerebralvascular diseases are the most common high-mortality diseases worldwide. Despite its global prevalence, effective treatments and therapies need to be explored. Given that oxidative stress is an important risk factor involved with cerebral vascular diseases, natural antioxidants and its derivatives can be served as a promising therapeutic strategy. Resveratrol (3, 5, 4′-trihydroxystilbene) is a natural polyphenolic antioxidant found in grape skins, red wine, and berries. As a phytoalexin to protect against oxidative stress, resveratrol has therapeutic value in cerebrovascular diseases mainly by inhibiting excessive reactive oxygen species production, elevating antioxidant enzyme activity, and other antioxidant molecular mechanisms. This review aims to collect novel kinds of literature regarding the protective activities of resveratrol on cerebrovascular diseases, addressing the potential mechanisms underlying the antioxidative activities and mitochondrial protection of resveratrol. We also provide new insights into the chemistry, sources, and bioavailability of resveratrol.

Lecithin-Polysaccharide Self-Assembled Microspheres for Resveratrol Delivery.

Poor water solubility and low chemical stability, seriously limit the efficient bioavailability of resveratrol. Here, we propose encapsulating resveratrol in lecithin-polysaccharide self-assembled microspheres (LPSM). An LPSM was designed with a lecithin core, and alginate-carboxymethyl chitosan biolayer shell. The LPSM had a spherical shape with 12.171 ± 0.960 μm of particle size and −30.86 ± 1.37 mV of zeta potential. The introduce of lecithin remarkably increased the encapsulation efficiency of resveratrol to 92.78 ± 0.82%. The LPSM elevated the antioxidant capacity and ultraviolet resistance of resveratrol. Moreover, LPSM inhibited release in a simulated gastric environment, promoted sustained release in simulated intestinal environment, and elevated the bioavailability of resveratrol during in vitro simulated digestion. Results indicate that LPSM is promising as a carrier for resveratrol delivery to enhance stability and bioaccessibility.

A QbD Approach to Design and to Optimize the Self-Emulsifying Resveratrol-Phospholipid Complex to Enhance Drug Bioavailability through Lymphatic Transport.

HighlightsThe FTIR, DSC, and the XRD characterization confirmed the successful complex formation between resveratrol and phospholipid.The optimal SEDDS formulation exhibited Grade-A self-emulsion properties.Implementation of a QbD approach to select appropriate excipients and their concentrations facilitated lymphatic resveratrol transport, which increased bioavailability 48-fold.The chylomicron flow blocking approach revealed that 91.3% of total systemically available resveratrol was transported through the intestinal lymphatic pathway.Objectives: Despite having profound therapeutic value, the clinical application of resveratrol is restrained due to its <1% bioavailability, arising from the extensive fast-pass effect along with enterohepatic recirculation. This study aimed to develop a self-emulsifying formulation capable of increasing the bioavailability of resveratrol via lymphatic transport. Methods: The resveratrol–phospholipid complex (RPC) was formed by the solvent evaporation method and characterized by FTIR, DSC, and XRD analyses. The RPC-loaded self-emulsifying drug delivery system (SEDDS) was designed, developed, and optimized using the QbD approach with an emphasis on resveratrol transport through the intestinal lymphatic pathway. The in vivo pharmacokinetic study was investigated in male Wister Albino rats. Results: The FTIR, DSC, and XRD analyses confirmed the RPC formation. The obtained design space provided robustness of prediction within the 95% prediction interval to meet the CQA specifications. An optimal formulation (desirability value of 7.24) provided Grade-A self-emulsion and exhibited a 48-fold bioavailability enhancement compared to the pure resveratrol. The cycloheximide-induced chylomicron flow blocking approach demonstrated that 91.14% of the systemically available resveratrol was transported through the intestinal lymphatic route. Conclusions: This study suggests that an optimal self-emulsifying formulation can significantly increase the bioavailability of resveratrol through lymphatic transport to achieve the desired pharmacological effects.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; “Jupiter”) is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich’s ataxia, and Alzheimer’s disease/mild cognitive impairment. This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer’s patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274).

Role of Drug Delivery System in Improving the Bioavailability of Resveratrol.

Resveratrol (RSV) is a natural polyphenolic compound known for its therapeutic activities but has limited bioavailability. The aim of our study was to explore various drug-delivering methods that are being employed to achieve target-oriented delivery and therapeutic performance of RSV. To improve the bioavailability and pharmacokinetic properties of RSV, efforts are being made to produce efficient formulations accompanying efficient drug delivery strategies. Several clinical trial studies have been conducted on RSV isomers, and the majority of studies indicated that trans-RSV had better clinical potential and therapeutic effectiveness in various types of complications such as colorectal cancer, metabolic syndrome, hypertension, obesity, neurodegenerative diseases, diabetes, hepatic disease, cardiac disorders, and breast cancer. However, multiple research studies enable us to understand various strategies that can enhance the systemic availability and efficacy of topical RSV formulations. In this article, we emphasize the hurdles of RSV delivery processes. We summarized that the micro- particulate system works efficiently for delivering liquid and solid microparticles of RSV. Another technique in which a coating encloses particles is called microencapsulation. This technique reduces the degradation of pharmaceutical compounds. Similarly, the cyclodextrin system is mainly used for poorly soluble drugs. On the other hand, the vesicular system is another micro-particulate system that can encapsulate hydrophilic and hydrophobic drugs. However, the RSV nanosponge formulations have advanced nano drug delivery systems, making it possible to use RSV for its antioxidant potential.

Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling

Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538–0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.

Resveratrol-Loaded Glutathione-Coated Collagen Nanoparticles Attenuate Acute Seizures by Inhibiting HMGB1 and TLR-4 in the Hippocampus of Mice.

Epilepsy is a relatively complicated neurological disorder that results in seizures. The use of resveratrol in treating seizures has been reported in recent studies. However, the low bioavailability of resveratrol and the difficulty of reaching the targeted location in the brain reduce its efficacy considerably. The side effects due to the higher concentration of drugs are another matter of concern. The purpose of the present study is to enhance the antiepileptic potential of resveratrol by delivering it to the brain's targeted location by encapsulating it in glutathione-coated collagen nanoparticles. The collagen nanoparticles increase the bioavailability of resveratrol, while the transport of resveratrol to its target location in the brain is facilitated by glutathione. By encapsulating resveratrol in glutathione-coated collagen nanoparticles, the concentration also substantially decreases. Resveratrol encapsulated in synthesized nanoparticles is referred to as nanoresveratrol. In the present study, nanoresveratrol effectiveness was studied through PTZ-induced seizures (PTZ-IS) and the increasing current electroshock (ICES) test. The efficacy of nanoresveratrol was further established using biochemical analysis, histopathological examinations, ELISA and real-time-PCR tests, and immunohistochemistry examination of the hippocampus of mice. Hence, this study is unique in the sense that it synthesized nanoresveratrol by using glutathione-coated collagen nanoparticles, followed by its application to treating seizures. On the basis of the study results, nanoresveratrol was found to be effective in preventing cognitive impairment in the mice and controlling epilepsy seizures to a greater extent than resveratrol. The proposed nanoformulation also reduces the concentration of resveratrol considerably. The present study results show that even 0.4 mg/kg of nanoresveratrol outperforms 40 mg/kg of resveratrol.

Micelle/Hydrogel Composite as a "Natural Self-Emulsifying Reversible Hybrid Hydrogel (N'SERH)" Enhances the Oral Bioavailability of Free (Unconjugated) Resveratrol.

The poor oral bioavailability, rapid biotransformation to less active metabolites, and fast elimination from systemic circulation have been identified as the major limitations responsible for the clinical insignificance of many drug candidates and phytonutrients. Despite the technological advancements in the nanoformulations of synthetic drugs, there exist many challenges for nutritional therapy, due to the regulatory issues, use of high levels of synthetic emulsifiers and polymers, low stability, low loading levels, mainly liquid state, etc. Herein, we report the characterization and human pharmacokinetics of a natural self-emulsifying hybrid-hydrogel formulation of trans-resveratrol prepared by uniformly impregnating resveratrol micelles into the fenugreek galactomannan hydrogel scaffold to form a water-soluble micelle/hydrogel composite in powder form (RF-20). Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), particle size analysis by dynamic light scattering (DLS), and transmission electron microscopy (TEM) demonstrated the uniform impregnation of resveratrol micelles within the galactomannan hydrogel matrix to form a soluble (average particle size of 172.0 ± 10.4 nm and −21.0 ± 2.5 mV zeta potential) and amorphous powder form with smooth and translucent surface morphology for RF-20, with no chemical alterations. Upon pharmacokinetic studies on healthy human subjects (n = 16) following a randomized, double-blinded, placebo-controlled, 2-arm, 4-sequence crossover design and tandem mass spectrometry (UPLC-ESI-MS/MS), 80 mg of trans-resveratrol from RF-20 provided enhanced free resveratrol bioavailability and pharmacokinetic properties compared to the unformulated resveratrol with 98% purity. The enhancement in bioavailability was more when supplemented in sachet (12.98-fold) form than the capsule (10.48-fold) with improved absorption (Cmax = 50.97 ± 15.82 ng/mL), circulation half-life (t1/2 = 7.01 ± 1.44 h), and sustained delivery (Tmax = 4.71 ± 0.73 h), as compared to the unformulated form (Cmax = 15.07 ± 5.10 ng/mL; t1/2 = 1.58 ± 0.65 h; Tmax = 1.21 ± 0.42 h).

JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model.

Alzheimer's disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROL™, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.