Protective Effects of Pomegranate in Endothelial Dysfunction

Author(s): Nathalie T.B. Delgado, Wender N. Rouver, Roger L. dos Santos*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 30 , 2020

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Background: Punica granatum L. is an infructescence native of occidental Asia and Mediterranean Europe, popularly referred to as pomegranate. It has been used in ethnomedicine for several applications, including the treatment of obesity, inflammation, diabetes, and the regulation of blood lipid parameters. Thus, pomegranate has been linked to the treatment of cardiovascular diseases that have endothelial dysfunction as a common factor acting mainly against oxidative stress due to its high polyphenol content. Its biocomponents have antihypertensive, antiatherogenic, antihyperglycemic, and anti-inflammatory properties, which promote cardiovascular protection through the improvement of endothelial function.

Methods: Different electronic databases were searched in a non-systematic way to uncover the literature of interest.

Conclusion: This review article presents updated information on the role of pomegranate in the context of endothelial dysfunction and cardiovascular diseases. We have shown that pomegranate, or rather its components (e.g., tannins, flavonoids, phytoestrogens, anthocyanins, alkaloids, etc.), have beneficial effects on the cardiovascular system, improving parameters such as oxidative stress and the enzymatic antioxidant system, reducing reactive oxygen species formation and acting in an anti-inflammatory way. Thus, this review may contribute to a better understanding of pomegranate's beneficial actions on endothelial function and possibly to the development of strategies associated with conventional treatments of cardiovascular diseases.

Keywords: Pomegranate, endothelium, cardiovascular disease, antioxidant, anti-inflammatory, alternative therapies.

Flammer AJ, Lüscher TF. Human endothelial dysfunction: EDRFs. Pflugers ArchEur J Physiol 2010; 459: 1005-13.
[] [PMID: 20383717]
Furchgott RF, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-6.
Cherry PD, Furchgott RF, Zawadzki JV, Jothianandan D. Role of endothelial cells in relaxation of isolated arteries by bradykinin. Proc Natl Acad Sci USA 1982; 79: 2106-10.
Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 2011; 164: 894-912.
Leung SWS, Vanhoutte PM. Endothelium-dependent hyperpolarization: age, gender and blood pressure, do they matter? Acta Physiol 2017; 219: 108-23.
Vanhoutte PM, Shimokawa H, Feletou M, Tang EHC. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol 2017; 219: 22-96.
Sies H. Biochemistry of oxidative stress. Angew Chemie Int Ed English 1986; 25: 1058-71.
Halliwell BB, Poulsen HE. Cigarette smoke and oxidative stress. Berlin: Springer 2006.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: Testing and clinical relevance. Circulation 2007; 115: 1285-95.
Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 2001; 37: 529-34.
Basu A, Penugonda K. Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 2009; 67: 49-56.
Meyrelles SS, Peotta VA, Pereira TMC, Vasquez EC. Endothelial dysfunction in the apolipoprotein E-deficient Mouse: insights into the influence of diet, gender and aging. Lipids Health Dis 2011; 10: 211.
Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sci 2009; 84: 705-12.
Jayakumar R, Kanthimathi MS. Inhibitory effects of fruit extracts on nitric oxide-induced proliferation in MCF-7 cells. Food Chem 2011; 126: 956-60.
Ignarro LJ, Byrns RE, Sumi D, de Nigris F, Napoli C. Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide. Nitric Oxide 2006; 15: 93-102.
Vidal A, Fallarero A, Peña BR, et al. Studies on the toxicity of Punica granatum L. (Punicaceae) whole fruit extracts. J Ethnopharmacol 2003; 89: 295-300.
Gracious Ross R, Selvasubramanian S, Jayasundar S. Immunomodulatory activity of Punica granatum in rabbits - A preliminary study. J Ethnopharmacol 2001; 78: 85-7.
Medjakovic S, Jungbauer A. Pomegranate: A fruit that ameliorates metabolic syndrome. Food Funct 2013; 4: 19-39.
Prashanth D, Asha MK, Amit A. Antibacterial activity of Punica granatum. Fitoterapia 2001; 72: 171-3.
Schubert SY, Neeman I, Resnick N. A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants. FASEB J 2002; 16: 1931-3.
Longtin R. The pomegranate: Nature's power fruit? J Natl Cancer Inst 2003; 95: 346-8.
Fawole OA, Opara UL. Developmental changes in maturity indices of pomegranate fruit: A descriptive review. Sci Hortic 2013; 159: 152-61.
Tsuyuki H, Itoh S, Nakatsukasa Y. Studies on the lipids in pomegranate seeds Bulletin of the College of Agriculture and Veterinary Medicine Nihon University. 1981.
Kaufman M, Wiesman Z. Pomegranate oil analysis with emphasis on MALDI-TOF/MS triacylglycerol fingerprinting. J Agric Food Chem 2007; 55: 10405-13.
Elfalleh W, Ying M, Nasri N, Sheng-Hua H, Guasmi F, Ferchichi A. Fatty acids from Tunisian and Chinese pomegranate (Punica granatum L.) seeds. Int J Food Sci Nutr 2011; 62: 200-6.
Viuda-Martos M, Fernández-Lóaez J, Pérez-álvarez JA. Pomegranate and its many functional components as related to human health: A Review. Compr Rev Food Sci Food Saf 2010; 9: 635-54.
Rosenberg Zand RS, Jenkins DJA, Diamandis EP. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat 2000; 62: 35-49.
Lansky EP, Newman RA. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol 2007; 109: 177-206.
Sharma P, McClees SF, Afaq F. Pomegranate for prevention and treatment of cancer: An update. Molecules 2017; 22: 1-18.
[ PMID: 28125044]
Sadeghi F, Nematbakhsh M, Noori-Diziche A, et al. Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats. J Ren Inj Prev 2015; 4: 45-50.
Huang THW, Yang Q, Harada M, et al. Pomegranate flower extract diminishes cardiac fibrosis in zucker diabetic fatty rats: Modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways. J Cardiovasc Pharmacol 2005; 46: 856-62.
Al-Muammar MN, Khan F. Obesity: the preventive role of the pomegranate (Punica granatum). Nutrition 2012; 28: 595-604.
Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol 2015; 71: 40-56.
Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 29-38.
Delgado NTB, Rouver W do N, et al. Pomegranate extract enhances endothelium-dependent coronary relaxation in isolated perfused hearts from spontaneously hypertensive ovariectomized rats. Front Pharmacol 2017; 7: 1-12.
Bagri P, Ali M, Aeri V, Bhowmik M, Sultana S. Antidiabetic effect of Punica granatum flowers: effect on hyperlipidemia, pancreatic cells lipid peroxidation and antioxidant enzymes in experimental diabetes. Food Chem Toxicol 2009; 47: 50-4.
Althunibat OY, Al-Mustafa AH, Tarawneh K, Khleifat KM, Ridzwan BH, Qaralleh HN. Protective role of Punica granatum L. peel extract against oxidative damage in experimental diabetic rats. Process Biochem 2010; 45: 581-5.
Mohan M, Waghulde H, Kasture S. Effect of pomegranate juice on angiotensin II-induced hypertension in diabetic wistar rats. Phyther Res 2010; 24: 196-203.
Veiskarami S, Fathi Nasri MH, Ahmadvand H, Rashidi L, Hadipur Moradi F. Effect of pomegranate peel hydroAlcoholic extract and vitamin E supplementation on strengthens antioxidant defense system in rats submitted to exhaustive exercise stress. Pars Jahrom Univ Med Sci 2016; 14: 34-42.
Sun W, Yan C, Frost B, et al. Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Sci Rep 2016; 6: 1-12.
Scapagnini G, Sonya V, Nader AG, Calogero C, Zella D, Fabio G. Modulation of Nrf2/ARE pathway by food polyphenols: A nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol 2011; 44: 192-201.
García-Niño WR, Zazueta C. Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection. Pharmacol Res 2015; 97: 84-103.
Huang K, Chen C, Hao J, et al. Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating Sirt1 to resist AGEs-induced upregulation of fibronetin and transforming growth factor-β1 in rat glomerular messangial cells. Mol Cell Endocrinol 2015; 399: 178-89.
Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 2000; 273: 793-8.
Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem 2004; 73: 417-35.
Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011; 15: 1583-606.
Zhao F, Pang W, Zhang Z, et al. Pomegranate extract and exercise provide additive benefits on improvement of immune function by inhibiting inflammation and oxidative stress in high-fat-diet induced obesity rats. J Nutr Biochem 2016; 32: 20-8.
Li X, Liu L, Pischetsrieder M. Pomegranate (Punica granatum L.) wine polyphenols affect Nrf2 activation and antioxidant enzyme expression in human neuroblastoma cells (SH-SY5Y). J Funct Foods 2017; 38: 140-50.
Aviram M, Rosenblat M. Pomegranate protection against cardiovascular diseases. Evid Based Complement Alternat Med 2012; 2012: 382763.
[ PMID: 23243442]
Bouchet N, Barrier L, Fauconneau B. Radical scavenging activity and antioxidant properties of tannins from Guiera senegalensisi (Combretaceae). Phyther Res 1998; 12: 159-62.
Kulkarni AP, Aradhya SM, Divakar S. Isolation and identification of a radical scavenging antioxidant - Punicalagin from pith and carpellary membrane of pomegranate fruit. Food Chem 2004; 87: 551-7.
Omar U, Aloqbi A, Yousr MK, Howell N. Punicalagin induce the production of nitric oxide and inhibit angiotensin converting enzyme in endothelial cell line EA.hy926. Univers J Public Heal 2016; 4: 268-77.
Aviram M, Dornfeld L, Rosenblat M, et al. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr 2000; 71: 1062-76.
Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001; 158: 195-8.
Liu W, Ma H, Frost L, Yuan T, Dain JA, Seeram NP. Pomegranate phenolics inhibit formation of advanced glycation endproducts by scavenging reactive carbonyl species. Food Funct 2014; 5: 2996-3004.
Steffen Y, Gruber C, Schewe T, Sies H. Mono-O-methylated flavanols and other flavonoids as inhibitors of endothelial NADPH oxidase. Arch Biochem Biophys 2008; 469: 209-19.
Sánchez M, Galisteo M, Vera R, et al. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens 2006; 24: 75-84.
Lin JK, Chen PC, Ho CT, Lin-Shiau SY. Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin-3,3&'-digallate, (-)-epigallocatechin-3-gallate, and propyl gallate. J Agric Food Chem 2000; 48: 2736-43.
Loke WM, Proudfoot JM, Hodgson JM, et al. Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction. Arterioscler Thromb Vasc Biol 2010; 30: 749-57.
Schubert SY, Lansky EP, Neeman I. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J Ethnopharmacol 1999; 66: 11-7.
Shingai Y, Fujimoto A, Nakamura M, Masuda T. Structure and function of the oxidation products of polyphenols and identification of potent lipoxygenase inhibitors from Fe-catalyzed oxidation of resveratrol. J Agric Food Chem 2011; 59: 8180-6.
Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1β generation. Clin Exp Immunol 2007; 147: 227-35.
Biswas SK. Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxid Med Cell Longev 2016; 2016: 17-9.
Gimbrone MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118: 620-36.
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 2045-51.
Geovanini GR, Libby P. Atherosclerosis and inflammation: Overview and updates. Clin Sci 2018; 132: 1243-52.
Ghavipour M, Sotoudeh G, Tavakoli E, Mowla K, Hasanzadeh J, Mazloom Z. Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation and oxidative stress in Rheumatoid Arthritis patients. Eur J Clin Nutr 2017; 71: 92-6.
Panichayupakaranant P, Tewtrakul S, Yuenyongsawad S. Antibacterial, anti-inflammatory and anti-allergic activities of standardised pomegranate rind extract. Food Chem 2010; 123: 400-3.
Lee SI, Kim BS, Kim KS, Lee S, Shin KS, Lim JS. Immune suppressive activity of punicalagin via inhibition of NFAT activation. Biochem Biophys Res Commun 2008; 371: 799-803.
Romier B, Van De Walle J, During A, Larondelle Y, Schneider YJ. Modulation of signalling nuclear factor-κB activation pathway by polyphenols in human intestinal Caco-2 cells. Br J Nutr 2008; 100: 542-51.
Colombo E, Sangiovanni E, Dell'Agli M. A review on the anti inflammatory activity of pomegranate in the gastrointestinal tract. Evidence-based Complement Altern Med 2013; 2013: 247145.
Shukla M, Gupta K, Rasheed Z, Khan KA, Haqqi TM. Consumption of hydrolyzable tannins-rich pomegranate extract suppresses inflammation and joint damage in rheumatoid arthritis. Nutrition 2008; 24: 733-43.
Zhao C, Sakaguchi T, Fujita K, et al. Pomegranate-derived polyphenols reduce reactive oxygen species production via SIRT3- mediated SOD2 activation. Oxid Med Cell Longev 2016; 2016: 2927131.
Kim H, Banerjee N, Ivanov I, et al. Comparison of anti inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis. Mol Nutr Food Res 2016; 60: 1912-23.
Larrosa M, González-Sarrías A, Yáñez-Gascón MJ, et al. Anti inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem 2010; 21: 717-25.
Asgary S, Sahebkar A, Afshani MR, Keshvari M, Haghjooyjavanmard S, Rafieian-Kopaei M. Clinical evaluation of blood pressure lowering, endothelial function improving, hypolipidemic and anti inflammatory effects of pomegranate juice in hypertensive subjects. Phyther Res 2014; 28: 193-9.
Park S, Seok JK, Kwak JY, Suh HJ, Kim YM, Boo YC. Anti inflammatory effects of pomegranate peel extract in THP-1 cells exposed to particulate matter PM10. Evidence-based Complement Altern Med 2016; 2016: 6836080.
Liu X, Cao K, Lv W, et al. Punicalagin attenuates endothelial dysfunction by activating FoxO1, a pivotal regulating switch of mitochondrial biogenesis. Free Radic Biol Med 2019; 135: 251-60.
Batumalaie K, Amin MA, Murugan DD, Sattar MZA, Abdullah NA. Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation. Sci Rep 2016; 6: 1-11.
Guillermo Gormaz J, Valls N, Sotomayor C, Turner T, Rodrigo R. Potential role of polyphenols in the prevention of cardiovascular diseases: Molecular bases. Curr Med Chem 2016; 23: 115-28.
[ PMID: 26630919]
Yılmaz B, Usta C. Ellagic acid-induced endothelium-dependent and endothelium-independent vasorelaxation in rat thoracic aortic rings and the underlying mechanism. Phytother Res 2013; 27: 285-9.
Fitzpatrick DF, Hirschfield SL, Coffey RG. Endothelium dependent vasorelaxing activity of wine and other grape products Am J Physiol - Hear Circ Physiol. 1993; 265: H774-8.
Al-Habib O, Adam L. Effects of Punica granatum seed hydromethanol extract on contractility of isolated aorta in female albino rats. Sci J Univ Zakho 2017; 5: 37-43.
de Nigris F, Balestrieri ML, Williams-Ignarro S, et al. The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats. Nitric Oxide 2007; 17: 50-4.
Yilmaz B, Usta C. Ellagic acid-induced endothelium-dependent and endothelium-independent vasorelaxation in rat thoracic aortic rings and the underlying mechanism. Phyther Res 2013; 27: 285-9.
Machha A, Mustafa MR. Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta. J Cardiovasc Pharmacol 2005; 46: 36-40.
Neyrinck AM, Catry E, Taminiau B, et al. Chitin-glucan and pomegranate polyphenols improve endothelial dysfunction. Sci Rep 2019; 9: 1-12.
Silva BR, Paula TD, Paulo M, Bendhack LM. Nitric oxide signaling and the cross talk with prostanoids pathways in vascular system. Med Chem 2017; 13: 319-33.
Hurtado-Barroso S, Quifer-Rada P, de Alvarenga JFR, Pérez-Fernández S, Tresserra-Rimbau A, Lamuela-Raventos RM. Changing to a low-polyphenol diet alters vascular biomarkers in healthy men after only two weeks. Nutrients 2018; 10: 1-14.
Polagruto JA, Schramm DD, Wang-polagruto JF, Lee L, Keen CL. Human aortic endothelial cells: association with ex vivo platelet function. Annu Rev Nutr 2003; 6: 301-8.
Ndiaye M, Chataigneau T, Andriantsitohaina R, Stoclet JC, Schini-Kerth VB. Red wine polyphenols cause endothelium-dependent EDHF-mediated relaxations in porcine coronary arteries via a redox-sensitive mechanism. Biochem Biophys Res Commun 2003; 310: 371-7.
Ndiaye M, Chataigneau T, Chataigneau M, Schini-Kerth VB. Red wine polyphenols induce EDHF-mediated relaxations in porcine coronary arteries through the redox-sensitive activation of the PI3-kinase/Akt pathway. Br J Pharmacol 2004; 142: 1131-6.
Félétou M, Vanhoutte PM. EDHF: an update. Clin Sci 2009; 117: 139-55.
Schini-Kerth VB, Auger C, Étienne-Selloum N, Chataigneau T. Polyphenol-induced endothelium-dependent relaxations. Role of NO and EDHF. Adv Pharmacol 2010; 60: 133-75.
[ PMID: 21081218]
Auger C, Said A, Nguyen PN, Chabert P, Idris-Khodja N, Schini-Kerth VB. Potential of food and natural products to promote endothelial and vascular health. J Cardiovasc Pharmacol 2016; 68: 11-8.
Li HF, Chen SA, Wu SN. Evidence for the stimulatory effect of resveratrol on Ca(2+)-activated K+ current in vascular endothelial cells. Cardiovasc Res 2000; 45: 1035-45.
Stoclet JC, Chataigneau T, Ndiaye M, et al. Vascular protection by dietary polyphenols. Eur J Pharmacol 2004; 500: 299-313.
Horrigan LA, Holohan CA, Lawless GA, Murtagh MA, Williams CT, Webster CM. Blueberry juice causes potent relaxation of rat aortic rings via the activation of potassium channels and the H2S pathway. Food Funct 2013; 4: 392-400.
Promprom W, Kupittayanant P, Indrapichate K, Wray S, Kupittayanant S. The effects of pomegranate seed extract and β-Sitosterol on Rat Uterine Contractions. Reprod Sci 2010; 17: 288-96.
Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 2007-18.
Wong MSK, Vanhoutte PM. COX-mediated endothelium dependent contractions: From the past to recent discoveries. Acta Pharmacol Sin 2010; 31: 1095-102.
Nemzer BV, Rodriguez LC, Hammond L, Disilvestro R, Hunter JM, Pietrzkowski Z. Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol rich beverage; A pilot clinical study with phytochemical and in vitro antioxidant characterization. Nutr J 2011; 10: 67.
Fukunaga M, Yura T, Badr KF. Stimulatory effect of 8-Epi-PGF2 alpha, an F2-isoprostane, on endothelin-1 release. J Cardiovasc Pharmacol 1995; 26(Suppl 3): S51-2.
Mattiello T, Trifiró E, Jotti GS, Pulcinelli FM. Effects of pomegranate juice and extract polyphenols on platelet function. J Med Food 2009; 12: 334-9.
Kusumawati W, Keman K, Soeharto S. Inhibitory effect of the Punica granatum fruit extract on angiotensin-II type I receptor and thromboxane B2 in endothelial cells induced by plasma from preeclamptic patients. Adv Prev Med 2016; 2016: 1-6.
Yanagisawa M. The endothelin system: A new target for therapeutic intervention. Circulation 1994; 89: 1320-2.
Wu D, Zhang Q, Yu Y, et al. Oleanolic acid, a novel endothelin a receptor antagonist, alleviated high glucose-induced cardiomyocytes injury. Am J Chin Med 2018; 46: 1187-201.
[ PMID: 30149760]
Rey FE, Cifuentes ME. Kiarasha., Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 2001; 89: 408-14.
Androwiki ACD, Camargo L de L, Sartoretto S, et al. Protein disulfide isomerase expression increases in resistance arteries during hypertension development. Effects on Nox1 NADPH oxidase signaling. Front Chem 2015; 3: 1-10.
Beswick RA, Dorrance AM, Leite R, Webb RC. NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 2001; 38: 1107-11.
Shah AM. Free radicals and redox signalling in cardiovascular disease. Heart 2004; 90: 486-7.
dos Santos RL, Dellacqua LO, Delgado NTB, et al. Pomegranate peel extract attenuates oxidative stress by decreasing coronary angiotensin- converting enzyme (ACE) activity in hypertensive female rats. J Toxicol Environ HealPart A 2016; 79: 998-1007.
Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001; 158: 195-8.
Shiuchi T, Cui TX, Wu L, et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension 2002; 40: 329-34.
Halliwell B, Gutteridge JM. The importance of free radicals and catalytic metal ions in human diseases. Mol Aspects Med 1985; 8: 89-193.
Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán FA, Espín JC. Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J Agric Food Chem 2006; 54: 1611-20.
Förstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J 2012; 33: 829-37., 837a-837d.
Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1-12.
de Nigris F, Williams-Ignarro S, Lerman LO, et al. Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress. Proc Natl Acad Sci USA 2005; 102: 4896-901.
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update: A report from the American Heart Association. Circulation 2011; 123: 18-209.
Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease and stroke statistics-2016 update. Circulation 2016; 133: 447-54.
Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: A report from the american heart association. Circulation 2018; 137: e67-492.
Al-Jarallah A, Igdoura F, Zhang Y, et al. The effect of pomegranate extract on coronary artery atherosclerosis in SR-BI/APOE double knockout mice. Atherosclerosis 2013; 228: 80-9.
Neyrinck AM, Van Hée VF, Bindels LB, De Backer F, Cani PD, Delzenne NM. Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota. Br J Nutr 2013; 109: 802-9.
Hossin FLA. Effect of pomegranate peels (Punica granatum) peels and it's extract on obese hypercholesterolemic rats. Pak J Nutr 2009; 8: 1251-7.
Fuhrman B, Volkova N, Aviram M. Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients. Nutrition 2010; 26: 359-66.
Estrada-Luna D, Martínez-Hinojosa E, Cancino-Diaz JC, Belefant-Miller H, López-Rodríguez G, Betanzos-Cabrera G. Daily supplementation with fresh pomegranate juice increases paraoxonase 1 expression and activity in mice fed a high-fat diet. Eur J Nutr 2018; 57: 383-9.
Hashemi M, Kelishadi R, Hashemipour M, et al. Acute and long-term effects of grape and pomegranate juice consumption on vascular reactivity in paediatric metabolic syndrome. Cardiol Young 2010; 20: 73-7.
Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998; 15: 539-53.
Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur Heart J 2013; 34: 2436-46.
Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis epidemiology, pathophysiology, and management. JAMA 2002 May 15; 287: 2570-81.
Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 2004; 24: 816-23.
Martín-Gallán P, Carrascosa A, Gussinyé M, Domínguez C. Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications. Free Radic Biol Med 2003; 34: 1563-74.
Whiteside CI. Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species. Curr Hypertens Rep 2005; 7: 148-54.
Johnson JS, Harns AK, Rychly DJ, Ergel A. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical pratice. Card Diabetol 2005; 4: 5-11.
Sharma A, Rizky L, Stefanovic N, et al. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction. Cardiovasc Diabetol 2017; 16: 1-13.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a position statement of the American diabetes association and the European association for the study of diabetes. Diabetes Care 2015; 38: 140-9.
Banihani S, Swedan S, Alguraan Z. Pomegranate and type 2 diabetes. Nutr Res 2013; 33: 341-8.
Banihani SA, Makahleh SM, El-Akawi Z, et al. Fresh pomegranate juice ameliorates insulin resistance, enhances β-cell function, and decreases fasting serum glucose in type 2 diabetic patients. Nutr Res 2014; 34: 862-7.
Kaur C, Pal RK, Kar A, et al. Characterization of antioxidants and hypoglycemic potential of pomegranate grown in India: A preliminary investigation. J Food Biochem 2014; 38: 397-406.
Li Y, Wen S, Kota BP, et al. Punica granatum flower extract, a potent alpha-glucosidase inhibitor, improves postprandial hyperglycemia in Zucker diabetic fatty rats. J Ethnopharmacol 2005; 99: 239-44.
Bekir J, Cazaux S, Mars M, Bouajila J. In vitro anti-cholinesterase and anti-hyperglycemic activities of flowers extracts from seven pomegranate varieties. Ind Crops Prod 2016; 81: 176-9.
Nekooeian AA, Eftekhari MH, Adibi S, Rajaeifard A. Effects of pomegranate seed oil on insulin release in rats with type 2 diabetes. Iran J Med Sci 2014; 39: 130-5.
Esmaillzadeh A, Tahbaz F, Gaieni I, Alavi-Majd H, Azadbakht L. Concentrated pomegranate juice improves lipid profiles in diabetic patients with hyperlipidemia. J Med Food 2004; 7: 305-8.
Xu KZY, Zhu C, Kim MS, Yamahara J, Li Y. Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity. J Ethnopharmacol 2009; 123: 280-7.
Shishehbor F, Shahi MM, Zarei M, et al. Effects of concentrated pomegranate juice on subclinical inflammation and cardiometabolic risk factors for type 2 diabetes: A quasi-experimental study. Int J Endocrinol Metab 2016; 14: e33835.
Faghihimani Z, Mirmiran P, Sohrab G, Iraj B, Faghihimani E. Effects of pomegranate seed oil on metabolic state of patients with type 2 diabetes mellitus. Int J Prev Med 2016; 7: 124.
Sohrab G, Ebrahimof S, Sotoudeh G, et al. Effects of pomegranate juice consumption on oxidative stress in patients with type 2 diabetes: a single-blind, randomized clinical trial. Int J Food Sci Nutr 2017; 68: 249-55.
Rosenblat M, Hayek T, Aviram M. Anti-oxidative effects of pomegranate juice (PJ) consumption by diabetic patients on serum and on macrophages. Atherosclerosis 2006; 187: 363-71.
Harzallah A, Hammami M, Kępczyńska MA, et al. Comparison of potential preventive effects of pomegranate flower, peel and seed oil on insulin resistance and inflammation in high-fat and high sucrose diet-induced obesity mice model. Arch Physiol Biochem 2016; 122: 75-87.
Mollazadeh H, Sadeghnia HR, Hoseini A, Farzadnia M, Boroushaki MT. Effects of pomegranate seed oil on oxidative stress markers, serum biochemical parameters and pathological findings in kidney and heart of streptozotocin-induced diabetic rats. Ren Fail 2016; 38: 1256-66.
Sun Y-L, Zhou F-M, Wang H-R. Mechanism of pomegranate ellagic polyphenols reducing insulin resistance on gestational diabetes mellitus rats. Am J Transl Res 2019; 11: 5487-500.
Sohrab G, Nasrollahzadeh J, Tohidi M, Zand H, Nikpayam O. Pomegranate juice increases sirtuin1 protein in peripheral blood mononuclear cell from patients with type 2 diabetes: A randomized placebo controlled clinical trial. Metab Syndr Relat Disord 2018; 16: 446-51.
Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-κB dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004; 23: 2369-80.
Ambigaipalan P, De Camargo AC, Shahidi F. Phenolic compounds of Pomegranate byproducts (outer skin, mesocarp, divider membrane) and their antioxidant activities. J Agric Food Chem 2016; 64: 6584-604.
Ambigaipalan P, de Camargo AC, Shahidi F. Identification of phenolic antioxidants and bioactives of pomegranate seeds following juice extraction using HPLC-DAD-ESI-MSn. Food 2017; 221: 1883-94.
Hopkins CY, Chisholm MJ. A survey of the conjugated fatty acids of seed oils. J Am Oil Chem Soc 1968; 45: 176-82.
Hornung E, Pernstich C, Feussner I. Formation of conjugated Delta11Delta13-double bonds by Delta12-linoleic acid (1,4)-acyl lipid- desaturase in pomegranate seeds. Eur J Biochem 2002; 269: 4852-9.
Bonzanini F, Bruni R, Palla G, et al. Identification and distribution of lignans in Punica granatum L. fruit endocarp, pulp, seeds, wood knots and commercial juices by GC-MS. Food Chem 2009; 117: 745-9.
Viladomiu M, Hontecillas R, Lu P, et al. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. Evidence-based Complement Altern Med 2013; 2013: 1-18.
Wang RF, Xie WD, Zhang Z, et al. Bioactive compounds from the seeds of Punica granatum (pomegranate). J Nat Prod 2004; 67: 2096-8.
Wafa BA, Makni M, Ammar S, et al. Antimicrobial effect of the Tunisian Nana variety Punica granatum L. extracts against Salmonella enterica (serovars Kentucky and Enteritidis) isolated from chicken meat and phenolic composition of its peel extract. Int J Food Microbiol 2017; 241: 123-31.
Fischer UA, Carle R, Kammerer DR. Identification and quantification of phenolic compounds from pomegranate (Punica granatum L.) peel, mesocarp, aril and differently produced juices by HPLC DAD-ESI/MSn. Food Chem 2011; 127: 807-21.
de Pascual-Teresa S, Santos-Buelga C, Rivas-Gonzalo JG. Quantitative analysis of flavan-3-ols in Spanish foodstuffs and beverages. J Agric Food Chem 2000; 48: 5331-7.
Van Elswijk DA, Schobel UP, Lansky EP, et al. Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry 2004; 65: 233-41.
Wang R, Ding Y, Liu R, et al. Pomegranate: constituents, bioactivities and pharmacokinetics. Fruit. Veg Cereal Sci Biotechnol 2010; 4: 77-87.
Hasnaoui N, Wathelet B, Jiménez-Araujo A. Valorization of pomegranate peel from 12 cultivars: Dietary fibre composition, antioxidant capacity and functional properties. Food Chem 2014; 160: 196-203.
Tzulker R, Glazer I, Bar-Ilan I, et al. Antioxidant activity, polyphenol content, and related compounds in different fruit juices and homogenates prepared from 29 different pomegranate accessions. J Agric Food Chem 2007; 55: 9559-70.
Nawwar MAM, Hussein SAM, Merfort I. NMR spectral analysis of polyphenols from Punica granatum. Phytochemistry 1994; 36: 793-8.
Zhang L, Gao Y, Zhang Y, et al. Changes in bioactive compounds and antioxidant activities in pomegranate leaves. Sci Hortic (Amsterdam) 2010; 123: 543-6.
Miguel MG, Dandlen S, Neves MA. Antioxidant activities of flower extract and pomegranate juice. Acta Hortic 2009; (818): 389-94.
Zhang L, Fu Q, Zhang Y. Composition of anthocyanins in pomegranate flowers and their antioxidant activity. Food Chem 2011; 127: 1444-9.
Wang R, Wei Wang, Wang L, et al. Constituents of the flowers of Punica granatum. Fitoterapia 2006; 77: 534-7.
Xu J, Zhao Y, Aisa HA. Anti-inflammatory effect of pomegranate flower in lipopolysaccharide (Lps)-stimulated raw264.7 macrophages. Pharm Biol 2017; 55: 2095-101.
Huang THW, Peng G, Kota BP, et al. Anti-diabetic action of Punica granatum flower extract: Activation of PPAR-γ and identification of an active component. Toxicol Appl Pharmacol 2005; 207: 160-9.
Batta AK, Rangaswami S. Crystalline chemical components of some vegetable drugs. Phytochemistry 1973.
Huang THW, Peng G, Kota BP, et al. Pomegranate flower improves cardiac lipid metabolism in a diabetic rat model: Role of lowering circulating lipids. Br J Pharmacol 2005; 145: 767-74.
Yuan T, Wan C, Ma H, et al. New phenolics from the flowers of punica granatum and their in vitro α-glucosidase inhibitory activities. Planta Med 2013; 79: 1674-9.
Liu Y, Seeram NP. Liquid chromatography coupled with time-of-flight tandem mass spectrometry for comprehensive phenolic characterization of pomegranate fruit and flower extracts used as ingredients in botanical dietary supplements. J Sep Sci 2018; 41: 3022-33.
Gil MI, Tomás-Barberán FA, Hess-Pierce B, et al. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 2000; 48: 4581-9.
Pérez-Vicente A, Gil-Izquierdo A, García-Viguera C. In vitro gastrointestinal digestion study of pomegranate juice phenolic compounds, anthocyanins, and vitamin C. J Agric Food Chem 2002; 50: 2308-12.
Conidi C, Cassano A, Caiazzo F, et al. Separation and purification of phenolic compounds from pomegranate juice by ultrafiltration and nanofiltration membranes. J Food Eng 2017; 195: 1-13.
Poyrazoğlu E, Gökmen V, Artιk N. Organic acids and phenolic compounds in pomegranates (Punica granatum L.) Grown in Turkey. J Food Compos Anal 2002; 15: 567-75.
Colantuono A, Vitaglione P, Manzo N, et al. Evaluation of microfiltration and heat treatment on the microbiological characteristics, phenolic composition and volatile compound profile of pomegranate (Punica granatum L.) juice. J Sci Food Agric 2018; 98: 3324-32.
Long J, Guo Y, Yang J, et al. Bioavailability and bioactivity of free ellagic acid compared to pomegranate juice. Food Funct 2019; 10: 6582-8.
Mphahlele RR, Stander MA, Fawole OA, et al. Effect of fruit maturity and growing location on the postharvest contents of flavonoids, phenolic acids, vitamin C and antioxidant activity of pomegranate juice. Sci Hortic (Amsterdam) 2014; 179: 36-45.
Kelishadi R, Gidding SS, Hashemi M, et al. Acute and long term effects of grape and pomegranate juice consumption on endothelial dysfunction in pediatric metabolic syndrome. J Res Med Sci 2011; 16: 245-53.
Borges G, Crozier A. HPLC-PDA-MS fingerprinting to assess the authenticity of pomegranate beverages. Food Chem 2012; 135: 1863-7.
Vázquez-Araújo L, Chambers E, Adhikari K, et al. Physico-chemical and sensory properties of pomegranate juices with pomegranate albedo and carpellar membranes homogenate. LWT - Food Sci Technol 2011; 44: 2119-25.

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Article Details

Year: 2020
Published on: 03 September, 2020
Page: [3684 - 3699]
Pages: 16
DOI: 10.2174/1381612826666200406152147
Price: $65

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