Resveratrol: review on therapeutic potential and recent advances in drug delivery

Introduction: Natural products have seen a wide range of acceptability for the prevention and treatment of diseases throughout history. Resveratrol, a member of the stilbene family, has been found to potentially exhibit anticancer, antiangiogenic, immunomodulatory and cardioprotective activities as well as being an antioxidant. This is in addition to its usefulness in the treatment of neurodegenerative disease, diabetes and cardiac ailments. Currently, various studies have revealed that resveratrol is a potential drug candidate with multi-spectrum therapeutic application. Areas covered: This review aims to describe the various studies supporting the wide range of pharmacological activities of resveratrol. In addition, it includes a section devoted to discussing the challenges associated with the drug and strategies to improve the properties of resveratrol such as solubility, stability and bioavailability. Expert opinion: Resveratrol demonstrated its ability to be a potential drug candidate for the treatment of different ailments due to its potent antioxidant properties. To improve the drug stability, increase the bioavailability and minimize side-effects of resveratrol, novel drug delivery systems have been formulated to bring this potential candidate to the first line of disease treatment.

[1]  T. Lockett,et al.  Nano‐ and micro‐encapsulated systems for enhancing the delivery of resveratrol , 2013, Annals of the New York Academy of Sciences.

[2]  R. Andriantsitohaina,et al.  Wine Polyphenols Decrease Blood Pressure, Improve NO Vasodilatation, and Induce Gene Expression , 2001, Hypertension.

[3]  R. Tallarida,et al.  Resveratrol in combination with other dietary polyphenols concomitantly enhances antiproliferation and UGT1A1 induction in Caco-2 cells. , 2011, Life sciences.

[4]  N. Ahmad,et al.  Prevention of Ultraviolet-B Radiation Damage by Resveratrol in Mouse Skin Is Mediated via Modulation in Survivin¶ , 2005, Photochemistry and photobiology.

[5]  I. Gülçin Antioxidant properties of resveratrol: A structure–activity insight , 2010 .

[6]  F. Figueiró,et al.  Resveratrol-loaded lipid-core nanocapsules treatment reduces in vitro and in vivo glioma growth. , 2013, Journal of biomedical nanotechnology.

[7]  P. Ho,et al.  Design of a pectin-based microparticle formulation using zinc ions as the cross-linking agent and glutaraldehyde as the hardening agent for colonic-specific delivery of resveratrol: In vitro and in vivo evaluations , 2011, Journal of drug targeting.

[8]  R. Ullrich,et al.  Resveratrol Reduces Radiation-Induced Chromosome Aberration Frequencies in Mouse Bone Marrow Cells , 2008, Radiation research.

[9]  D. Das,et al.  Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol. , 2009, Free radical biology & medicine.

[10]  U. Förstermann,et al.  Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol. , 2013, Nitric oxide : biology and chemistry.

[11]  M. Böhm,et al.  Alcohol and red wine: impact on cardiovascular risk. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  Hyo Jin Kim,et al.  Antioxidative Activity of Resveratrol and Its Derivatives Isolated from Seeds of Paeonia lactiflora , 2002, Bioscience, biotechnology, and biochemistry.

[13]  E. Talero,et al.  Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice. , 2010, European journal of pharmacology.

[14]  Thomas J. Sweet,et al.  Effect of resveratrol on herpes simplex virus vaginal infection in the mouse. , 2005, Antiviral research.

[15]  U. Förstermann,et al.  Resveratrol: A Multifunctional Compound Improving Endothelial Function , 2009, Cardiovascular Drugs and Therapy.

[16]  E. Bursal,et al.  Polyphenol contents and in vitro antioxidant activities of lyophilised aqueous extract of kiwifruit (Actinidia deliciosa) , 2011 .

[17]  N. Madhav,et al.  Review on Microparticulate Drug Delivery System , 2011 .

[18]  V. Dolinsky,et al.  Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice. , 2013, Biochimica et biophysica acta.

[19]  P. Thonart,et al.  Antioxidant phenolic compounds loss during the fermentation of Chétoui olives , 2009 .

[20]  K. Magyara,et al.  Cardioprotection by resveratrol : A human clinical trial in patients with stable coronary artery disease , 2012 .

[21]  C. Carratelli,et al.  Effect of resveratrol and quercetin in experimental infection by Salmonella enterica serovar Typhimurium. , 2011, International immunopharmacology.

[22]  A. Falcão,et al.  Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. , 2009, Molecular nutrition & food research.

[23]  I. Gülçin,et al.  Synthesis, Antioxidant, and Antiacetylcholinesterase Activities of Sulfonamide Derivatives of Dopamine‐Related Compounds , 2013, Archiv der Pharmazie.

[24]  R. S. Lee,et al.  Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. , 2000, Cardiovascular research.

[25]  D. Wei,et al.  Phytochemical profiles of different mulberry (Morus sp.) species from China. , 2009, Journal of agricultural and food chemistry.

[26]  I. Gülçin,et al.  Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. , 2013, Mini reviews in medicinal chemistry.

[27]  Thomas J. Sweet,et al.  Resveratrol inhibition of varicella-zoster virus replication in vitro. , 2006, Antiviral research.

[28]  F. Wang,et al.  Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants , 2005, Journal of Asian natural products research.

[29]  I. Villegas,et al.  Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. , 2005, Molecular nutrition & food research.

[30]  N. Başaran,et al.  Protective effects of resveratrol on sepsis-induced DNA damage in the lymphocytes of rats , 2013, Human & experimental toxicology.

[31]  A. Akaike,et al.  Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. , 2007, Biochemical pharmacology.

[32]  H. Jeong,et al.  An anticancer/cytotoxic activity of resveratrol is not hampered by its ability to induce the expression of the antioxidant/cytoprotective heme oxygenase-1 in RAW264.7 cells , 2011 .

[33]  M. Chan Antimicrobial effect of resveratrol on dermatophytes and bacterial pathogens of the skin. , 2002, Biochemical pharmacology.

[34]  Jiankun Cui,et al.  Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells , 2013, Journal of Neuroinflammation.

[35]  KyungMann Kim,et al.  Anti-tumor and immunomodulatory activity of resveratrol in vitro and its potential for combining with cancer immunotherapy. , 2011, International immunopharmacology.

[36]  James L. Thomas,et al.  Extraction of resveratrol from polygonum cuspidatum with magnetic orcinol-imprinted poly(ethylene-co-vinyl alcohol) composite particles and their in vitro suppression of human osteogenic sarcoma (HOS) cell line , 2012 .

[37]  G. Szabó A glass of red wine to improve mitochondrial biogenesis? Novel mechanisms of resveratrol. , 2009, American journal of physiology. Heart and circulatory physiology.

[38]  Z. Zaheer,et al.  Nanosponges – a completely new nano-horizon: pharmaceutical applications and recent advances , 2013, Drug development and industrial pharmacy.

[39]  F. García-Carmona,et al.  Aggregation state and pKa values of (E)-resveratrol as determined by fluorescence spectroscopy and UV-visible absorption. , 2008, Journal of agricultural and food chemistry.

[40]  J. Barrett,et al.  Mechanisms of multistep carcinogenesis and carcinogen risk assessment. , 1993, Environmental health perspectives.

[41]  Shujuan Ma,et al.  Selective on-line extraction of trans-resveratrol and emodin from Polygonum cuspidatum using molecularly imprinted polymer. , 2008, Journal of chromatographic science.

[42]  B. Bonavida,et al.  Resveratrol and cancer: chemoprevention, apoptosis, and chemo-immunosensitizing activities. , 2003, Current medicinal chemistry. Anti-cancer agents.

[43]  J. Bhatt,et al.  Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. , 2012, Nutrition research.

[44]  Jeng-Feng Lin,et al.  Resveratrol reduces infarct size and improves ventricular function after myocardial ischemia in rats. , 2008, Life sciences.

[45]  Y. K. Agrawal,et al.  Nanosuspension: An approach to enhance solubility of drugs , 2011, Journal of advanced pharmaceutical technology & research.

[46]  S. F. Zawadzki,et al.  PHBV/PCL Microparticles for Controlled Release of Resveratrol: Physicochemical Characterization, Antioxidant Potential, and Effect on Hemolysis of Human Erythrocytes , 2012, TheScientificWorldJournal.

[47]  F. Domingues,et al.  Anti-Helicobacter pylori and urease inhibitory activities of resveratrol and red wine , 2011 .

[48]  Kaige Peng,et al.  The Parkinson's disease-related genes act in mitochondrial homeostasis , 2012, Neuroscience & Biobehavioral Reviews.

[49]  E. Naderali,et al.  Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs. , 2000, Clinical science.

[50]  F. Zhang,et al.  Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. , 2010, European journal of pharmacology.

[51]  A. Agarwal,et al.  Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. , 2005, Indian journal of experimental biology.

[52]  Junmo Kang,et al.  Synthesis of novel trans-stilbene derivatives and evaluation of their potent antioxidant and neuroprotective effects. , 2009, European journal of medicinal chemistry.

[53]  M. Beal,et al.  Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease , 2009, Neurochemistry International.

[54]  B. Sümegi,et al.  Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. , 2011, The British journal of nutrition.

[55]  G. Bronchti,et al.  Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[56]  L. Pernomian,et al.  Antioxidant Protective Effects of the Resveratrol on the Cardiac and Vascular Tissues from Renal Hypertensive Rats , 2012 .

[57]  S. Klahr The role of nitric oxide in hypertension and renal disease progression. , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[58]  J. Kristl,et al.  The evidence for solid lipid nanoparticles mediated cell uptake of resveratrol. , 2010, International journal of pharmaceutics.

[59]  M. Lee,et al.  Identification, characterisation, and quantification of phenolic compounds in the antioxidant activity-containing fraction from the seeds of Korean perilla (Perilla frutescens) cultivars. , 2013, Food chemistry.

[60]  J. Crowell,et al.  Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent , 2007, Cancer Epidemiology Biomarkers & Prevention.

[61]  Manavalan Rajappan,et al.  Nanosponges: a novel class of drug delivery system--review. , 2012, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[62]  B. Aggarwal,et al.  Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer , 2010, International journal of cancer.

[63]  T. Kokubun,et al.  Antibacterial and antifungal activity of cicerfuran and related 2-arylbenzofurans and stilbenes. , 2009, Microbiological research.

[64]  F. Figueiró Resveratrol-loaded nanocapsules treatment reduces in vitro and in vivo glioma growth , 2010 .

[65]  N. Mignet,et al.  Bioavailability of Polyphenol Liposomes: A Challenge Ahead , 2013, Pharmaceutics.

[66]  A. Waterhouse,et al.  Principal Phenolic Phytochemicals in Selected California Wines and Their Antioxidant Activity in Inhibiting Oxidation of Human Low-Density Lipoproteins , 1995 .

[67]  G. Gutiérrez,et al.  Preparation and characterization of niosomes containing resveratrol , 2013 .

[68]  Donald J L Jones,et al.  Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. , 2010, Cancer research.

[69]  Y. Miura,et al.  Hypoglycemic effect of resveratrol in type 2 diabetic model db/db mice and its actions in cultured L6 myotubes and RIN-5F pancreatic β-cells , 2011, Journal of clinical biochemistry and nutrition.

[70]  P. Ho,et al.  The Impact of Aqueous Solubility and Dose on the Pharmacokinetic Profiles of Resveratrol , 2008, Pharmaceutical Research.

[71]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. , 1996, Journal of pharmaceutical sciences.

[72]  Ananda Sen,et al.  Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. , 2010, Cancer research.

[73]  P. O S I T I O N S T A T E M E N T,et al.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[74]  A. Novaković,et al.  The mechanism of endothelium-independent relaxation induced by the wine polyphenol resveratrol in human internal mammary artery. , 2006, Journal of pharmacological sciences.

[75]  P. Langcake,et al.  The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injury , 1976 .

[76]  S. Renaud,et al.  Wine, alcohol, platelets, and the French paradox for coronary heart disease , 1992, The Lancet.

[77]  R. Cavalli,et al.  Cyclodextrin-Based Nanosponges for Delivery of Resveratrol: In Vitro Characterisation, Stability, Cytotoxicity and Permeation Study , 2011, AAPS PharmSciTech.

[78]  A. Bhardwaj,et al.  Stable free radical scavenging and antiperoxidative properties of resveratrol compared in vitro with some other bioflavonoids. , 2003, Indian journal of biochemistry & biophysics.

[79]  B. Muguerza,et al.  Antioxidant properties of polyphenol-rich cocoa products industrially processed , 2010 .

[80]  R. Holcombe,et al.  Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer , 2009, Cancer management and research.

[81]  A. Banday,et al.  Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats. , 2011, European journal of pharmacology.

[82]  J. Lamas,et al.  The anti-inflammatory activity of the polyphenol resveratrol may be partially related to inhibition of tumour necrosis factor-alpha (TNF-alpha) pre-mRNA splicing. , 2010, Molecular immunology.

[83]  D. Kletsas,et al.  Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[84]  K. Suh,et al.  Stabilization of resveratrol immobilized in monodisperse cyano-functionalized porous polymeric microspheres , 2005 .

[85]  Tetsuro Ito,et al.  New resveratrol oligomers in the stem bark of Vatica pauciflora , 2003 .

[86]  L. Hung,et al.  Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. , 2006, American journal of physiology. Endocrinology and metabolism.

[87]  D. Baker,et al.  The value of natural products to future pharmaceutical discovery. , 2007, Natural product reports.

[88]  Sacheen Kumar,et al.  High melting lipid based approach for drug delivery: solid lipid nanoparticles. , 2013, Materials science & engineering. C, Materials for biological applications.

[89]  R. Andriantsitohaina,et al.  Red wine polyphenols induce vasorelaxation by increased nitric oxide bioactivity. , 2003, Physiological research.

[90]  Orsu Prabhakar,et al.  Cerebroprotective effect of resveratrol through antioxidant and anti-inflammatory effects in diabetic rats , 2013, Naunyn-Schmiedeberg's Archives of Pharmacology.

[91]  J. A. Gabaldón,et al.  Complexation of resveratrol by native and modified cyclodextrins: Determination of complexation constant by enzymatic, solubility and fluorimetric assays , 2008 .

[92]  I. Gülçin Antioxidant activity of food constituents: an overview , 2012, Archives of Toxicology.

[93]  C. Diniz,et al.  New insights on the anticancer properties of dietary polyphenols , 2006, Medicinal research reviews.

[94]  L. Subramanian,et al.  Resveratrol: Challenges in Translation to the Clinic — A Critical Discussion , 2010, Clinical Cancer Research.

[95]  N. Davies,et al.  Pharmacometrics of stilbenes: seguing towards the clinic. , 2006, Current clinical pharmacology.

[96]  J. Marier,et al.  Metabolism and Disposition of Resveratrol in Rats: Extent of Absorption, Glucuronidation, and Enterohepatic Recirculation Evidenced by a Linked-Rat Model , 2002, Journal of Pharmacology and Experimental Therapeutics.

[97]  Yitao Wang,et al.  Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma. , 2013, Journal of ethnopharmacology.

[98]  S. Madhyastha,et al.  Neuroprotective effect of resveratrol against prenatal stress induced cognitive impairment and possible involvement of Na+, K+-ATPase activity , 2013, Pharmacology Biochemistry and Behavior.

[99]  Hua Xiong,et al.  Vanillin cross-linked chitosan microspheres for controlled release of resveratrol , 2010 .

[100]  A. Virmani,et al.  Food, Nutrigenomics, and Neurodegeneration—Neuroprotection by What You Eat! , 2013, Molecular Neurobiology.

[101]  T. Devasagayam,et al.  Radioprotective properties of polyphenols from Phyllanthus amarus Linn. , 2009, Journal of radiation research.

[102]  A. Buczyński,et al.  Antioxidant activity of resveratrol in endotoxin-stimulated blood platelets , 2004, Cell Biology and Toxicology.

[103]  G. P. Kumar,et al.  Nonionic surfactant vesicular systems for effective drug delivery—an overview , 2011 .

[104]  A. Novaković,et al.  Potassium channels-mediated vasorelaxation of rat aorta induced by resveratrol. , 2006, Basic & clinical pharmacology & toxicology.

[105]  Peter Davies,et al.  Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides* , 2005, Journal of Biological Chemistry.

[106]  M. Miksits,et al.  Antitumor activity of resveratrol and its sulfated metabolites against human breast cancer cells. , 2009, Planta medica.

[107]  P. Barnes,et al.  Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[108]  C. Sinico,et al.  Host–Guest Interaction Study of Resveratrol With Natural and Modified Cyclodextrins , 2006 .

[109]  Raj Kumar,et al.  Resveratrol in cancer management: where are we and where we go from here? , 2011, Annals of the New York Academy of Sciences.

[110]  G. Lippi,et al.  Red wine and cardiovascular health the "French Paradox" revisited , 2010 .

[111]  H. W. Bedell,et al.  Resveratrol is cidal to both classes of Haemophilus ducreyi. , 2013, International journal of antimicrobial agents.

[112]  R. V. van Breemen,et al.  An LC-MS method for analyzing total resveratrol in grape juice, cranberry juice, and in wine. , 2002, Journal of agricultural and food chemistry.

[113]  G. Sandri,et al.  Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: evaluation of antioxidant potential for dermal applications , 2012, International journal of nanomedicine.

[114]  E. D. Valle,et al.  Cyclodextrins and their uses: a review , 2004 .

[115]  G. Valacchi,et al.  Free radicals and antioxidants: how to reestablish redox homeostasis in chronic diseases? , 2013, Current medicinal chemistry.

[116]  F. Villarroya,et al.  Resveratrol induces nuclear factor-κB activity in human cardiac cells. , 2013, International journal of cardiology.

[117]  A. Fadda,et al.  Nanocarriers for antioxidant resveratrol: formulation approach, vesicle self-assembly and stability evaluation. , 2013, Colloids and surfaces. B, Biointerfaces.

[118]  J. Pezzuto,et al.  Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorbol Ester-treated Human Mammary Epithelial Cells* , 1998, The Journal of Biological Chemistry.

[119]  P. Gariglio,et al.  Resveratrol induces cell death in cervical cancer cells through apoptosis and autophagy , 2013, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[120]  T. Walle,et al.  HIGH ABSORPTION BUT VERY LOW BIOAVAILABILITY OF ORAL RESVERATROL IN HUMANS , 2004, Drug Metabolism and Disposition.

[121]  Sameer Al-harthi,et al.  Chemosensetizing and cardioprotective effects of resveratrol in doxorubicin- treated animals , 2013, Cancer Cell International.

[122]  J. Pezzuto,et al.  Human, Rat, and Mouse Metabolism of Resveratrol , 2002, Pharmaceutical Research.

[123]  R. Müller,et al.  Resveratrol nanosuspensions for dermal application--production, characterization, and physical stability. , 2009, Die Pharmazie.

[124]  Norman R. Farnsworth,et al.  Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes , 1997, Science.

[125]  G. Fabbrocini,et al.  Nanocarriers for topical administration of resveratrol: a comparative study. , 2013, International journal of pharmaceutics.

[126]  S. Subramanian,et al.  Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. , 2008, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[127]  Zhong Lu,et al.  Complexation of resveratrol with cyclodextrins: Solubility and antioxidant activity , 2009 .

[128]  Tan Li,et al.  Resveratrol induces apoptosis, influences IL-6 and exerts immunomodulatory effect on mouse lymphocytic leukemia both in vitro and in vivo. , 2007, International immunopharmacology.

[129]  A. Ray,et al.  Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type‐2 diabetes , 2011, Phytotherapy research : PTR.

[130]  L. Ciani,et al.  Using Liposomes as Carriers for Polyphenolic Compounds: The Case of Trans-Resveratrol , 2012, PloS one.

[131]  V. Schini-Kerth,et al.  Red wine polyphenols prevent angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase. , 2006, Cardiovascular research.

[132]  J. Cervera,et al.  Radioprotective activity and cytogenetic effect of resveratrol in human lymphocytes: an in vitro evaluation. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[133]  Anjali U. Patel,et al.  Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan , 2011, Journal of advanced pharmaceutical technology & research.

[134]  P. Elliott,et al.  Phase I Randomized, Double-Blind Pilot Study of Micronized Resveratrol (SRT501) in Patients with Hepatic Metastases—Safety, Pharmacokinetics, and Pharmacodynamics , 2011, Cancer Prevention Research.