Formulation Of Resveratrol Research Articles

WITHDRAWN: Resveratrol-based Delivery Systems as Contemporary Nominees for Combating Pulmonary Diseases: A Comprehensive Review

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Copolymeric Micelles of Poly(ε-caprolactone) and Poly(methacrylic acid) as Carriers for the Oral Delivery of Resveratrol.

In this study, we report the development of a micellar system based on a poly(methacrylic acid)-b-poly(ε-caprolactone)-b-poly(methacrylic acid) triblock copolymer (PMAA16-b-PCL35-b-PMAA16) for the oral delivery of resveratrol. The micellar nanocarriers were designed to comprise a PCL core for solubilizing the poorly water-soluble drug and a hydrated PMAA corona with bioadhesive properties for providing better contact with the gastrointestinal mucosa. The micelles were first formed in an aqueous media via the solvent evaporation method and then loaded with resveratrol (72% encapsulation efficiency). Studies by transmission electron microscopy (TEM) and dynamic and electrophoretic light scattering (DLS and PALS) revealed a spherical shape, nanoscopic size (100 nm) and a negative surface charge (-30 mV) of the nanocarriers. Loading of the drug slightly decreased the hydrodynamic diameter (Dh) and increased the ƺ-potential of micelles. In vitro dissolution tests showed that 80% and 100% of resveratrol were released in 24 h in buffers with pH 1.2 and 6.8, respectively, whereas for the same time, not more than 10% of pure resveratrol was dissolved. A heat-induced albumin denaturation assay demonstrated the advantage of the aqueous micellar formulation of resveratrol, which possessed anti-inflammatory potential as high as that of the pure drug. Further, the micellar resveratrol (5 µM) exerted a strong protective effect and maintained viability of mucosa epithelial HT-29 cells in a co-cultural model, representing the production of inflammatory cytokines. For comparison, the pure resveratrol at the same concentration did not protect the damaged HT-29 cells at all. Thus, the present study revealed that the PMAA-b-PCL-b-PMAA copolymeric micelles might be considered appropriate nanocarriers for the oral delivery of resveratrol.

Nanoparticles Enhance Solubility and Neuroprotective Effects of Resveratrol in Demyelinating Disease.

Resveratrol is a natural polyphenol which may be useful for treating neurodegenerative diseases such as multiple sclerosis (MS). To date, current immunomodulatory treatments for MS aim to reduce inflammation with limited effects on the neurodegenerative component of this disease. The purpose of the current study is to develop a novel nanoparticle formulation of resveratrol to increase its solubility, and to assess its ability to prevent optic nerve and spinal cord degeneration in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Resveratrol nanoparticles (RNs) were made using a thin rehydration technique. EAE mice received a daily oral administration of vehicle, RNs or unconjugated resveratrol for one month. They were assessed daily for clinical signs of paralysis and weekly for their visual acuity with optokinetic responses (OKR). After one month, their spinal cords and optic nerves were stained for inflammation and demyelination and retinal ganglion cells immunostained for Brn3a. RNs were stable for three months. The administration of RNs did not have any effect on clinical manifestation of EAE and did not preserve OKR scores but reduced the intensity of the disease. It did not reduce inflammation and demyelination in the spinal cord and the optic nerve. However, RNs were able to decrease RGC loss compared to the vehicle. Results demonstrate that resveratrol is neuroprotective by reducing RGC loss. Interestingly, neuroprotective effects and decreased disease severity occurred without reduction of inflammation or demyelination, suggesting this therapy may fill an unmet need to limit the neurodegenerative component of MS.

Resveratrol nanoparticles are neuroprotective in a model of Alzheimer's disease

AbstractPurpose: Alzheimer's disease (AD) is the major cause of dementia in the world with increasing evidences of the retina being affected. Since no cure exists, there is an urgent unmet need to find new treatments. Resveratrol, a natural polyphenol found in red wine, has been advocated as a potential neuroprotectant in this disease. However, resveratrol has a low solubility and bioavailability limiting its clinical translation. In this study, we assessed a novel formulation of resveratrol in vitro and in vivo in a triple transgenic Alzheimer's disease (3xTg‐AD) mouse model.Methods: Resveratrol nanoparticles (RNs) were formulated using a thin rehydration technique. They were assessed in vitro on R28 cells against glutamate excitotoxicity and cobalt chloride induced hypoxia. Next, 3xTg‐AD mice received intranasally either RNs (n = 7) or an equivalent vehicle (n = 6) 5 days a week for 3 months. After 3 months of treatment, animals were imaged using Detection of Apoptosing Retinal Cells (DARC). DARC count was defined as the number of fluorescent spots counted by a masked investigator. After sacrifice, their brains were harvested and immunostained for amyloid‐beta (Aβ) and phosphorylated tau (pTau). Retinas were immunostained with Brn3a, a retinal ganglion cell (RGC) marker.Results: RN formulation incorporating over 10 mg/ml resveratrol was stable over 90 days. RNs were able to protect R28 cells exposed to glutamate compared to the vehicle (IC50 25.1 ± 0.4 vs. 14.4 ± 1.0 mM, p < 0.0001) but did not show any neuroprotection against cobalt chloride compared to the vehicle (260.3 ± 16.5 vs. 200.7 ± 2 2.3 μM, p > 0.05). In vivo, DARC count was reduced with RN treatment compared to the vehicle (7.7 ± 2.1 vs. 49.1 ± 13.3, p < 0.01). However, these results did not correlate with a higher RGC density compared to the vehicle (1205 ± 203 vs. 1015 ± 100 cells/mm2, p > 0.05). Interestingly, Aβ and pTau depositions in the brain were reduced compared to the vehicle (3.6 ± 0.2 vs. 4.5 ± 0.2 Aβ score, p < 0.01 and 2.1 ± 0.5 vs. 6.6 ± 1.9 pTau score, p < 0.05). No adverse effects were seen in vivo either systemically or in the eye.Conclusions: These promising results show that RN is non‐toxic and neuroprotective in vitro and in vivo when administered intranasally. However, DARC imaging failed to show a correlation with RGC density. Further studies are needed to confirm these results.

Formulation of resveratrol into PGA-co-PDL nanoparticles increases its cytotoxic potency against lung cancer cells

Abstract Objectives Lung cancer is the commonest cause of cancer-related deaths, and current treatment involves the use of cytotoxic drugs that have many unwanted side effects. Resveratrol, a natural polyphenol, has promising anticancer efficacy, but its therapeutic application is hindered by low bioavailability, which the present study sought to improve through encapsulation into nanoparticles (NPs). Methods Resveratrol was loaded into poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL; MWt 16.5 KDa) NPs with sizes 220–230 nm, and tested against Calu-3 human lung cancer cells. Key findings About 5% and 10% resveratrol nanoparticles (RNPs) had a high encapsulation efficiency of 78 ± 0.24% and 70 ± 0.89% and a drug loading of 39 ± 0.12 µg and 70 ± 0.89 µg (w/w), respectively. The PGA-co-PDL blank NP (BNP) at 1 mg/ml had good cytocompatibility when Calu-3 cells were exposed to it for 24 h (cell viability of 87.5 ± 4.7%). Remarkably, the 5% RNP and 10% RNP lowered, up to 80%, the IC50 for 24 h cytotoxicity of resveratrol against the cells, from 158 ± 16 µM to 32 ± 10 µM and 70 ± 13 µM, respectively. Conclusions Loading of resveratrol into PGA-co-PDL NPs increases its anticancer potency, thus enhancing its prospect for treating lung cancer.

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.

Resveratrol nanoparticles reduce retinal ganglion cell loss in glaucoma

AbstractPurposeResveratrol is a natural polyphenol found in red wine and dark chocolate known for its antioxidant, anti‐inflammatory and anti‐apoptotic properties. All these properties can be used to treat neurodegenerative diseases such as glaucoma. To date, resveratrol low solubility in water and bioavailability limits its clinical use. The goal of this study was to develop a novel nanoparticle formulation of resveratrol and to assess it in an ocular hypertension (OHT) rat model of glaucoma.MethodsResveratrol nanoparticles (RNs) were formulated using a thin film rehydration technique. OHT rat model was induced with the injection of 1.85 M normal saline solution in two episcleral veins of the left eye of 10 Dark Agouti rats. The right eye was used as an internal control. RNs (n = 5) or vehicle (n = 5) were given topically as an eye drop daily for 3 weeks from induction. After 3 weeks, rats were imaged with the Detection of Apoptosing Retinal Cell (DARC) technology. DARC count was defined as the number of apoptosing retinal cells counted by a masked investigator. Next, all rats were sacrificed, and their retinas immunostained with Brn3a antibody. Retinal Ganglion Cell (RGC) density ratio was defined as the ratio between the left treated and the right untreated eye (control).ResultsRNs were formulated with an encapsulation efficiency >70% and a stability >90 days. They were well‐tolerated without any sign of ocular irritation and neuroprotective in the OHT glaucoma model as evidenced by the reduction of RGC apoptosis compared to the vehicle (1.02 ± 0.05 vs 0.70 ± 0.11 RGC density ratio, p < 0.05). RNs did not reduce the Intraocular Pressure (IOP) suggesting that their effect was independent from IOP modulation. However, RNs were not able to reduce significantly DARC count compared to the vehicle (493 ± 83 vs 612 ± 84 DARC count, p > 0.05).ConclusionsThese promising results show that topical administration of RNs is neuroprotective in an OHT glaucoma rat model by reducing significantly RGC apoptosis. DARC count reduction is not significant owing to the low number of animals used. Therefore, bigger studies are needed to confirm these encouraging results.

Determination of in vivo virtue of dermal targeted combinatorial lipid nanocolloidal based formulation of 5-fluorouracil and resveratrol against skin cancer

The current study has been designed to appraise the efficacy of developed combinatorial lipid-nanosystem-based gel (linogel) of 5-fluorouracil and resveratrol for skin cancer treatment. Initially, linogel was prepared and characterized for different parameters, namely pH, texture, drug content uniformity, occlusiveness, etc. Then in vivo efficacy studies (tumor number, area, and volume, histopathology, ultrastructural and immunohistochemical analysis) of linogel were determined over-developed skin tumors. Developed linogel possessed significantly (p < 0.05) better texture and occlusiveness than conventional gel formulation. Decreased tumor number, area, and volume showed significant results (p < 0.05) in favor of linogel. Histopathological and ultrastructural analysis confirmed superior efficacy of linogel in terms of marked improvement in the nucleus and subcellular structures in photomicrographs. The antioxidants and anti-inflammatory analysis findings showed a significantly (p < 0.05) potent effectiveness of linogel. The apoptotic and anti-proliferation activity of linogel was confirmed by analysis of caspase-3 and ki-67, which showed significant (p < 0.05) elevation in the level of cleaved caspase-3 and reduction in the level of ki-67 than untreated and conventional gel formulation treated tumors, indicating antitumor effect due to cancerous cell death. Thus, developed linogel fulfilled all the criteria of dermal application and exhibited efficacious therapeutic results, which could be a beneficial therapeutic approach against skin cancer.

Formulation design, optimization and in vivo evaluation of oral co-encapsulated resveratrol-humic acid colloidal polymeric nanocarriers

The study aims at formulation and optimization of resveratrol and humic acid co-encapsulated colloidal polymeric nanocarriers to improve stability, oral bioavailability, and antiradical activity of water-insoluble, resveratrol. The eudragit E100 polymeric material was used to fabricate resveratrol and humic acid co-encapsulated oral colloidal polymeric nanocarriers (Res-HA-co-CPNs) using emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for oral bioavailability as well as for antiradical potential. Optimized Res-HA-co-CPNs demonstrated spherical and smooth surface including mean particle size, 120.56 ± 18.8 nm; polydispersity index, 0.122; zeta potential, +38.25 mV; and entrapment efficiency, 82.37 ± 1.49%. Solid-state characterization confirmed the amorphous characteristic of optimized Res-HA-co-CPNs. In vitro release profile of Res-HA-co-CPNs showed sustained release behavior up to 48 h and CPNs were found to remain stable at the refrigerated condition for 6 months. In vivo pharmacokinetic studies revealed significant (p < 0.05) improvement of ∼62.76-fold in oral bioavailability. The radical-scavenging activity was found to be increased with time and after 72 h, it was analogous to pure Res. IC50 values were reported to be decreased with time. Henceforth, developed Res-HA-co-CPNs was proven to be a proficient dosage form to increase stability, oral bioavailability, and antiradical activity of resveratrol. Highlights Resveratrol-humic acid co-encapsulated colloidal polymeric nanocarriers (Res-HA-co-CPNs) were fabricated by emulsification-diffusion-evaporation method and optimized by Taguchi orthogonal array design. The Res-HA-co-CPNs revealed favorable mean particle size and percent encapsulation efficiency with a spherical and smooth surface. The Res-HA-co-CPNs showed diffusion-controlled release of Res and were found to be stable at the refrigerated condition for 6 months. The optimized Res-HA-co-CPNs demonstrated significantly (p < 0.05) higher oral bioavailability with respect to pure Res and PM. The optimized Res-HA-co-CPNs demonstrated higher radical-scavenging activity with respect to time.

Resveratrol nanoparticles are neuroprotective in a model of multiple sclerosis

AbstractPurposeOptic neuritis is the most common clinical manifestation of multiple sclerosis. Axonal damage and neuronal loss lead to permanent neurological disability in patients and its animal model, experimental autoimmune encephalomyelitis (EAE). Presently, treatments of this condition aim to reduce inflammation without showing any neuroprotection. Resveratrol is a natural polyphenol found in red wine with neuroprotective effects but poor solubility in water. Thus, a novel nanoparticle formulation of resveratrol was developed and assessed in a mouse model of EAE.MethodsResveratrol nanoparticles (RNs) were formulated using a thin rehydration technique and assessed for stability with spectrophotometric techniques. C57/BL6 mice were immunized with the myelin oligodendroglial glycoprotein peptide. From EAE induction, mice were treated daily for 30 days by oral gavage of RNs (n = 6), vehicle (n = 5) or unconjugated resveratrol (UnRSV); n = 6). Mice were assessed for EAE signs daily and for visual function weekly by optokinetic responses (OKR). Optic nerve and spinal cord inflammation were assessed by hematoxylin and eosin (H&amp;E). Retinal ganglion cells were immunostained with Brn3a.ResultsResveratrol nanoparticles (RNs) containing &gt;10 mg/ml resveratrol were stable over 3 months with an encapsulation efficiency &gt;70%. 16.9 mg/kg RNs reduced the EAE clinical score at day 30 compared to 16.9 mg/kg vehicle (1.4 ± 0.4 versus 3.0 ± 0.4, p &lt; 0.05) whereas up to 100 mg/kg UnRSV did not lead to reduction of EAE scores. OKR, optic nerve inflammation and spinal cord inflammation were not significantly modified by oral administration of RNs. 16.9 mg/kg RNs reduced RGC loss compared to 16.9 mg/kg vehicle (347 ± 12 versus 172 ± 12 cells/standardized field, p &lt; 0.0001). Importantly, to get a similar reduction, at least 100 mg/kg of UnRSV were needed suggesting that RNs increase resveratrol bioavailability.ConclusionsResveratrol nanoparticles (RNs) increase resveratrol solubility and bioavailability. They show neuroprotection by reducing RGC loss. However, as previously reported for resveratrol, these nanoparticles do not have any anti‐inflammatory effect.

Benefits of a novel highly bioavailable resveratrol formulation, JOTROL, for Alzheimer’s disease

AbstractBackgroundWith the recent Alzheimer’s disease (AD) clinical trial shortcomings, we and colleagues agree that an epigenetic approach is needed to address the polygenicity of AD. Recently, a randomized clinical trial with the SIRT1 activator resveratrol (3,5,4’‐trihydroxy‐trans‐stilbene) has shown positive effects in AD patients (Turner et al., 2015; Moussa et al., 2017). However, the high dose needed due to low bioavailability has been reported to cause a GI side effect. To increase bioavailability, JOTROL, a new oral formulation of resveratrol that shows significantly better pharmacokinetic properties than non‐formulated resveratrol, was manufactured by Jupiter Orphan Therapeutics. We hypothesize that equimolar concentrations of JOTROL, compared to non‐formulated resveratrol, will result in greater brain exposure to resveratrol and more efficacious responses on AD biomarkers, allowing for a reduction in dose regimen.MethodsFor acute studies, Sprague Dawley rats or C57B6 mice (n = 3/treatment) were administered a single oral dose of 50 mg/kg JOTROL 30 minutes prior to being euthanized. Blood, buffy coat and brains were harvested. For AD‐related studies, 15‐month‐old male triple‐transgenic (APPSW/PS1M146V/TauP301L; 3xTg‐AD) AD mice were treated by daily oral gavage with 50 mg/kg JOTROL (n = 5) or vehicle (n = 5) for 36 days. Animals were euthanized after behavior tests. The expression of AD‐related genes and proteins in brain, liver and spleen were analyzed using RT‐qPCR, Western blots and ELISAs. Effects on mitochondrial biogenesis were also investigated.ResultsJOTROL (50 mg/kg) increases brain and plasma resveratrol bioavailability in animals, significantly increases both SIRT1 (P&lt;0.0001) and α‐secretase ADAM10 (P&lt;0.0001) gene expression in rat brain, but significantly decreases Tau gene expression (P&lt;0.05). 36‐day treatment of 3xTg‐AD mice with 50 mg/kg JOTROL decreases expression of IL6 (P&lt;0.001 in liver, P&lt;0.05 in spleen) and TNFα (P&lt;0.001 in liver and P&lt;0.01 in spleen), concurrent with a marked decrease of splenomegaly. Increased mitochondrial biogenesis is also observed in the brain (P&lt;0.05) and in the liver (P&lt;0.05) of these mice.ConclusionsJOTROL has a strong anti‐inflammatory effect in the brain and peripheral organs, promotes non‐amyloidogenic processing of the amyloid precursor protein and increases mitochondrial biogenesis. Further investigation is underway to determine prophylactic effects of JOTROL for AD pathogenesis.

Resveratrol Supported on Magnesium DiHydroxide (Resv@MDH) Represents an Oral Formulation of Resveratrol With Better Gastric Absorption and Bioavailability Respect to Pure Resveratrol.

Resveratrol attracts great interest because of the plethora of in vitro effects at the micromolar concentration range. Unfortunately, these effects are difficult to establish in vivo, due to the low concentration of resveratrol reached. This discrepancy is due to the molecules low solubility in water that favors the propensity for an intestinal absorption rather than in the gastric compartment. To address these challenges, we developed a Solid Dispersion of Resveratrol Supported by Magnesium Di Hydroxide formulation (Resv@MDH). This formulation displays increased water solubility and better bioavailability relative to pure resveratrol in the rabbit animal model. In our study, we evaluated the pharmacokinetics profile of resveratrol in six healthy human subjects following 180 mg of oral resveratrol administration, derived from Resv@MDH or pure resveratrol. Free resveratrol was evaluated in the whole blood sample by using HPLC - MS/MS. In comparison with pure resveratrol that displays an increase of the maximum plasma concentration, Cmax at about 90 min and 2 μM, Resv@MDH displays an earlier peak of resveratrol concentration with an increase of Cmax at about 30 min and 6 μM. The different kinetics suggest a main gastric route for resveratrol absorption from Resv@MDH, where, because of its improved dissolution rate, there seems to be a higher propensity for an acidic environment, as opposed to that with pure resveratrol. This conclusion is also supported by the numerical simulation analysis, which considers the principal steps during the oral route administration. Moreover, there is a 2-fold increase in the amount of free resveratrol with respect to pure resveratrol confirming a better bioavailability observed in the animal model. The characteristic feature of the pharmacokinetic profile of Resv@MDH implies that the beneficial properties of resveratrol in human health should be capitalized on it.

Statistical development and in vivo evaluation of resveratrol-loaded topical gel containing deformable vesicles for a significant reduction in photo-induced skin aging and oxidative stress

Objective The present study aims to formulate and evaluate a novel vesicular formulation of resveratrol to achieve its dermatological benefits in terms of antiphotoaging and antioxidant. Method In this study, resveratrol-loaded deformable vesicular gel was prepared and optimized using Box–Behnken design. Selected critical material attributes were amount of phospholipid (X1), concentration of ethanol (X2), and amount of sodium cholate (X3). The prepared transethosomal vesicles were incorporated into carbopol gel base and evaluated. Ultraviolet radiation-induced skin aging and oxidative stress model in Swiss Albino mice was used to evaluate the clinical potential of the developed formulation and compared with conventional gel. Levels of Super Oxide Dismutase (SOD), catalase, glutathione peroxidase, protein content, and malondialdehyde were measured to assess the extent of lipid peroxidation and reactive oxygen species inhibition in different groups. Result DoE was successfully employed to optimize the vesicular formulation. Vesicle size was found to be 158.9 ± 7.65 nm, while values of entrapment efficiency and skin deposition were found to be 77.83 ± 2.87% and 371.84 ± 5.12 µg cm−2, respectively. Visual skin grading and histopathological studies confirmed the higher efficacy of transethosomal resveratrol against oxidative stress. Significant enhancement in the levels of antioxidant enzymes and protein content confirmed the ameliorated potential of flexible transethosomal resveratrol as compared to the plain gel of resveratrol. Conclusion Restoration of first-line defense mechanism in chronic UV-exposed animal model has proved that transethosomal resveratrol can be developed as an innovative cosmetic product for significant improvement and repair of photo-aged skin.

Focus on the Use of Resveratrol as an Adjuvant in Glioblastoma Therapy.

Glioblastoma (GB) represents the most common and malignant form of glioma cancer. The Gold Standard in Glioblastoma is neurosurgical tumor removal and radiotherapy treatment in concomitant with temozolomide (TMZ). Unfortunately, because of tumor chemo and radio-resistance during this therapy, the patient's outcome remains very poor, with a median overall survival of about 14.6 months. Resveratrol is a natural polyphenol with a stilbene structure with chemopreventive and anticancer properties. In the present review, we evaluated data from preclinical studies conducted with resveratrol as a possible adjuvant during the standard protocol of GB. Resveratrol can reach the brain parenchyma at sub-micromolar concentrations when administrated through conventional routes. In this way, resveratrol reduces cell invasion and increases the efficacy of radiotherapy (radiosensitizer effects) and temozolomide. The molecular mechanism of the adjuvant action of resveratrol may depend upon the reduction of PI3K/AKT/NF-κB axis and downstream targets O-6-methylguanine-DNA methyltransferase (MGMT) and metalloproteinase-2 (MMP-2). It has been reported that redox signaling plays an important role in the regulation of autophagy. Resveratrol administration by External Carotid Artery (ECA) injection or by Lumbar Puncture (LP) can reach micromolar concentrations in tumor mass where it would inhibit tumor growth by STAT-3 dependent mechanisms. Preclinical evidences indicate a positive effect on the use of resveratrol as an adjuvant in anti-GB therapy. Ameliorated formulations of resveratrol with a favorable plasmatic profile for a better brain distribution and timing sequences during radio and chemotherapy could represent a critical aspect for resveratrol use as an adjuvant for a clinical evaluation.

Recent Review on Role of Resveratrol in Diabetes and its Complication

Resveratrol, a nonflavanoid, is a trans-stilbene derivative and is a compound of great interest because of its wide pharmacological actions in disease such as cancer,diabetes and its complications, cardiac diseases etc. Resveratrol has been working effectively by acting as an antioxidant and interfere in the generation of free radicals, which in turn is the main cause of various diseases. Resveratrol has shown very effective in Diabetes and its complications such as Diabetic Retinopathy, Coronary Artery Disease, Diabetic cardiomyopathy,vascular dysfunction, Chronic Renal Failure and others. Though the main challenge comes in formulating Resveratrol as it has low solubility, low stability and less bioavailability. This review focuses on antioxidants being an essential class of compounds in the treatment of diabetes.Role of various antioxidants being studied along with showcasing their combined effect with resveratrol and also the mechanism of resveratrol in diabetes and its complications. Lastly, it also highlights various formulations of resveratrol which have shown improvement in solubility, stability and bioavailability. Thus Resveratrol is identified as an essential compound in the treatment of diabetes and its complications.

Resveratrol for adults with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic disorder that is characterised by insulin resistance and hyperglycaemia, which over time may give rise to vascular complications. Resveratrol is a plant-derived nutritional supplement shown to have anti-diabetic properties in many animal models. Less evidence is available on its safety and efficacy in the management of T2DM in humans. To assess the efficacy and safety of resveratrol formulations for adults with type 2 diabetes mellitus. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and International Pharmaceutical Abstracts, as well as the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. The date of the last search was December 2018 for all databases. No language restrictions were applied. All randomised controlled trials (RCTs) comparing effects of oral resveratrol (any dose or formulation, duration, or frequency of administration) with placebo, no treatment, other anti-diabetic medications, or diet or exercise, in adults with a diagnosis of T2DM. Two review authors independently identified and included RCTs, assessed risk of bias, and extracted study-level data. Study authors were contacted for any missing information or for clarification of reported data. We assessed studies for certainty of the evidence using the GRADE instrument. We identified three RCTs with a total of 50 participants. Oral resveratrol not combined with other plant polyphenols was administered at 10 mg, 150 mg, or 1000 mg daily for a period ranging from four weeks to five weeks. The comparator intervention was placebo. Overall, all three included studies had low risk of bias. None of the three included studies reported long-term, patient-relevant outcomes such as all-cause mortality, diabetes-related complications, diabetes-related mortality, health-related quality of life, or socioeconomic effects. All three included studies reported that no adverse events were observed, indicating that no deaths occurred (very low-quality evidence for adverse events, all-cause mortality, and diabetes-related mortality). Resveratrol versus placebo showed neutral effects for glycosylated haemoglobin A1c (HbA1c) levels (mean difference (MD) 0.1%, 95% confidence interval (CI) -0.02 to 0.2; P = 0.09; 2 studies; 31 participants; very low-certainty evidence). Due to the short follow-up period, HbA1c results have to be interpreted cautiously. Similarly, resveratrol versus placebo showed neutral effects for fasting blood glucose levels (MD 2 mg/dL, 95% CI -2 to 7; P = 0.29; 2 studies; 31 participants), and resveratrol versus placebo showed neutral effects for insulin resistance (MD -0.35, 95% CI -0.99 to 0.28; P = 0.27; 2 studies; 36 participants). We found eight ongoing RCTs with approximately 800 participants and two studies awaiting assessment, which, when published, could contribute to the findings of this review. Currently, research is insufficient for review authors to evaluate the safety and efficacy of resveratrol supplementation for treatment of adults with T2DM. The limited available research does not provide sufficient evidence to support any effect, beneficial or adverse, of four to five weeks of 10 mg to 1000 mg of resveratrol in adults with T2DM. Adequately powered RCTs reporting patient-relevant outcomes with long-term follow-up periods are needed to further evaluate the efficacy and safety of resveratrol supplementation in the treatment of T2DM.

Role of Resveratrol in Transmitochondrial AMD RPE Cells.

Resveratrol is a phytoalexin, stilbenoid compound with antioxidant properties attributable to its bioactive trans-resveratrol content. This study characterized the effects of over-the-counter (OTC) resveratrol nutritional supplements and a HPLC-purified resveratrol formulation, in human transmitochondrial age-related macular degeneration (AMD) retinal pigment epithelial (RPE) patient cell lines. These cell lines, which were created by fusing blood platelets obtained from dry and wet AMD patients with mitochondria-deficient (Rho0) ARPE-19 cells, had identical nuclei (derived from ARPE-19 cells) but different mitochondria that were derived from AMD patients. After resveratrol treatment, the levels of cell viability and reactive oxygen species production were measured. Results demonstrated that treatment with different resveratrol formulations improved cell viability and decreased reactive oxygen species generation in each AMD patient cell line. Although further studies are required to establish the cytoprotective potential of resveratrol under different physiological conditions, this novel study established the positive effects of OTC resveratrol supplements in macular degeneration patient cybrid cell lines in vitro.

Improvement of Resveratrol Effects When Combined with Rice Oil in Rat Models of Inflammation.

This study investigated the effects of systemic treatment with a new formulation of resveratrol (RSV) vehicled in rice oil (RSVO) in experimental rat models of inflammation. Male Wistar rats were evaluated in the following in vivo models: carrageenan-induced acute edema, complete Freund's adjuvant (CFA)-evoked sub-chronic edema, and CFA-induced polyarthritis. The animals were treated orally with RSVO (10-15 mg/kg) or RSV (100-200 mg/kg), depending on the experimental protocol. RSV was more effective than RSVO in carrageenan-elicited acute edema when dosed in either prophylactic or therapeutic schemes of administration. However, the repeated RSVO administration, at 10-fold lower doses, exhibited superior anti-inflammatory actions in either the sub-chronic edema or the chronic polyarthritis model elicited by CFA, when compared with RSV. The novel formulation RSVO displayed a lower plasma biotransformation when compared with the RSV-treated group-46% versus 88% of metabolites, respectively. RSVO also prevented polyarthritis-related cartilage destruction, an effect that might rely on the inhibition of the pro-inflammatory cytokine interleukin-6 (IL-6), associated with an increase of the anti-inflammatory cytokine interleukin-10 (IL-10). Noteworthy, the long-term administration of RSVO did not elicit any gastrointestinal harm. Our study revealed that RSVO was notably effective in the long-term inflammatory and degenerative responses triggered by CFA. This innovative formulation might well represent a promising alternative for treating chronic inflammatory diseases, such as arthritis.

Resveratrol supported on magnesium DiHydroxide (Resv@MDH, REVIFAST) represents an improved formulation of resveratrol with fast absorption and bioavailability in humans

The RolA protein belongs to the RolB class of plant T-DNA oncogenes, and shares structural similarity with the papilloma virus E2 DNA-binding domain. It has potentially as an inducer of plant secondary metabolism, although its role in biotechnology has yet to be realised. In this investigation, a Rubia cordifolia callus culture transformed with the rolA plant oncogene for more than 10 years was analysed. Expression of the rolA gene in the callus line was stable during long-term cultivation, and growth parameters were both elevated and stable, exceeding those of the non-transformed control culture. The rolA-transformed calli not only demonstrated remarkably stable growth, but also the ability to increase the yield of anthraquinones (AQs) in long-term cultivation. After ten years of cultivating rolA callus lines, we observed an activation of AQ biosynthesis from 200 mg/l to 874 mg/l. The increase was mainly due to activation of ruberitrinic acid biosynthesis. The expression of key AQ biosynthesis genes was strongly activated in rolA-transgenic calli. We compared the effects of the rolA gene with those of the rolB gene, which was previously considered the most potent inducer of secondary metabolism, and showed that rolA was more productive under conditions of long-term cultivation.

Effect of resveratrol on non‑alcoholic fatty liver disease

The aim of the present study was to investigate the effect of a micronized formulation of trans-resveratrol in humans with non-alcoholic fatty liver disease (NAFLD). Trans-Resveratrol has been used in the form of micronized formulation, which is better absorbed, has strong antioxidants effects, is more effective than plain resveratrol formulations and is circulated on the market as a food supplement. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid and a phytoalexin produced by several plants. NAFLD is an increasing clinical problem involving the liver for which effective treatments are required. The present study was based on two patient groups. The study, which commenced on April 2013 and finished on April 2015, included 44 patients, aged 29–70 years, with an average weight of 84.6 kg (n=22 per group; 28 men and 16 women) who were randomly assigned to groups and given 50 mg Evelor capsule (n=22) and 200 mg Evelor H tablet (n=22) correspondingly on a daily basis. The patients were followed up for 6 months. Quantity fat measurements, with ultrasound on the liver and kidney, were carried out. There was an initial measurement (time 1) and one after six months (time 2). The study results showed the effects of Trans-resveratrol micronized formulation in reducing the liver fat, as well as decreasing hepatic enzymes, serum glutamate pyruvic transaminase (SGPT) and gamma-glutamyl transpeptidase (g-GT) and insulin resistance. At the end of the study, the statistical analysis showed a statistically significant reduction on the liver fat. These data demonstrate that use of Trans-resveratrol micronized formulation improves features of NAFLD, and prevents liver damage. Thus, Trans-resveratrol micronized formulation can be a new treatment method for NAFLD.