Phenolic Compounds as Arginase Inhibitors: New Insights Regarding Endothelial Dysfunction Treatment

Abstract

Endothelial dysfunction is characterised by the low bioavailability of nitric oxide with a relevant negative impact on the nitric oxide/cGMP pathway. The loss of nitric oxide/cGMP signaling may be caused by an increased arginase activity. Plant-derived substances, especially polyphenols, are compounds that have the potential to inhibit arginase activity and they may represent an attractive therapeutic option to combat clinical outcomes related to endothelial dysfunction. An extensive review was carried out using all available data published in English in the Pubmed database, and without restriction regarding the year of publication. Despite the increased number of new substances that have been tested as arginase inhibitors, it is rare to find a compound that satisfies all the toxicological criteria to be used in the development of a new drug. On the other hand, recent data have shown that substances from plants have great potential to be applied as arginase inhibitors, most of which are polyphenols. Of the relevant mechanisms in this process, the inhibition of arginase by natural products seems to act against endothelial dysfunction by reestablishing the vascular function and elevating nitric oxide levels (by increasing the amounts of substrate (L-arginine, and endothelial nitric oxide synthase activation and stabilisation) as well as decreasing the generation of reactive species (formed by uncoupledendothelial nitric oxide synthase). This review summarises several topics regarding arginase inhibition by natural substances as well as indicating this pathway as an emergent strategy to elevate nitric oxide levels in disorders involving endothelial dysfunction. In addition, some aspects regarding structural activity and future perspectives are discussed.

Key words

vascular disease - endothelial nitric oxide synthase - nitric oxide - arginase - natural products - polyphenols

• References

• 1 Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003; 108: 2000-2006
• 2 Durante W, Johnson FK, Johnson RA. Arginase: a critical role regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol 2007; 34: 906-911
• 3 Meurs H, Maarsingh H, Zaagsma J. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci 2003; 24: 450-455
• 4 Romero MJ, Platt DH, Tawfik HE, Labazi M, El-Remessy AB, Bartoli M, Caldwell RB, Caldwell RW. Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 2008; 102: 95-102
• 5 Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Lim HK, Sohi J, Santhanam L, Soucy K, Tuday E, Baraban E, Ilies M, Gerstenblith G, Nyhan D, Shoukas A, Christianson DW, Alp NJ, Champion HC, Huso D, Berkowitz DE. Endothelial arginase II: a novel target for the treatment of atherosclerosis. Circ Res 2008; 102: 923-932
• 6 Schade D, Kotthaus J, Clement B. Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease. Pharmacol Ther 2010; 126: 279-300
• 7 You H, Gao T, Cooper TK, Morris jr. SM, Awad AS. Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism. Kidney Int 2013; 84: 1189-1197
• 8 El-Bassossy HM, El-Fawal R, Fahmy A. Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vascul Pharmacol 2012; 57: 194-200
• 9 Shemyakin A, Kövamees O, Rafnsson A, Böhm F, Svenarud P, Settergren M, Jung C, Pernow J. Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus. Circulation 2012; 126: 2943-2950
• 10 Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87: 315-424
• 11 Steppan J, Nyhan D, Berkowitz DE. Development of novel arginase inhibitors for therapy of endothelial dysfunction. Front Immunol 2013; 4: 278
• 12 Schmitt CA, Dirsch VM. Modulation of endothelial nitric oxide by plant-derived products. Nitric Oxide 2009; 21: 77-91
• 13 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840-844
• 14 Félétou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder. Am J Physiol Heart Circ Physiol 2006; 291: H985-H1002
• 15 Vanhoutte PM, Shimokawa H, Feletou M, Tang EHC. Endothelial dysfunction and vascular disease – a 30th anniversary update. Acta Physiol (Oxf) 2017; 219: 22-96
• 16 Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 2009; 32: S314-S321
• 17 Akinyemi AJ, Oboh G, Ademiluyi AO, Boligon AA, Athayde ML. Effect of two ginger varieties on arginase activity in hypercholesterolemic rats. J Acupunct Meridian Stud 2016; 9: 80-87
• 18 Chung JH, Moon J, Lee YS, Chung HK, Lee SM, Shin MJ. Arginase inhibition restores endothelial function in diet-induced obesity. Biochem Biophys Res Commun 2014; 451: 179-183
• 19 Colwell JA, Lopes-Virella M, Halushka PV. Pathogenesis of atherosclerosis in diabetes mellitus. Diabetes Care 1981; 4: 121-133
• 20 Cooke JP, Dzau J, Creager A. Endothelial dysfunction in hypercholesterolemia is corrected by L-arginine. Basic Res Cardiol 1991; 86: 173-181
• 21 Lüscher TF. Heterogeneity of endothelial dysfunction in hypertension. Eur Heart J 1992; 13: 50-55
• 22 Flavahan NA. Atherosclerosis or lipoprotein-induced endothelial dysfunction: potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation 1992; 85: 1927-1938
• 23 Todoki K, Okabe E, Kiyose T, Sekishita T, Ito H. Oxygen free radical-mediated selective endothelial dysfunction in isolated coronary artery. Am J Physiol 1992; 262: H806-H812
• 24 Schini-Kerth VB, Etienne-Selloum N, Chataigneau T, Auger C. Vascular protection by natural product-derived polyhenols: in vitro and in vivo evidence. Planta Med 2011; 77: 1161-1167
• 25 Ivanenkov YA, Chufarova NV. Small-molecule arginase inhibitors. Pharm Pat Anal 2014; 3: 65-85
• 26 Pernow J, Jung C. Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal?. Cardiovasc Res 2013; 98: 334-343
• 27 Girard-Thernier C, Pham TN, Demougeot C. The promise of plant-derived substances as inhibitors of arginase. Mini Rev Med Chem 2015; 15: 798-808
• 28 Romero MJ, Platt DH, Tawfik HE, Labazi M, El-Remessy AB, Bartoli M, Caldwell RB, Caldwell RW. Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 2008; 102: 95-102
• 29 Schnorr O, Brossette T, Momma TY, Kleinbongard P, Keen CL, Schroeter H, Sies H. Cocoa flavanols lower vascular arginase activity in human endothelial cells in vitro and in erythrocytes in vivo . Arch Biochem Biophys 2008; 476: 211-215
• 30 Yi B, Nguyen MC, Won MH, Kim YM, Ryoo S. Arginase inhibitor 2, 3, 5, 4′-tetrahydroxystilbene-2-O-β-D-glucoside activates endothelial nitric oxide synthase and improves vascular function. Planta Med 2016; 83: 210-216
• 31 Huynh NN, Harris EE, Chin-Dusting JFP, Andrews KL. The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries. Br J Pharmacol 2009; 156: 84-93
• 32 Minozzo BR, Lemes BM, Justo AS, Lara JE, Petry VEK, Fernandes D, Belló C, Vellosa JCR, Campagnoli EB, Nunes OC, Kitagawa RR, Avula B, Khan IA, Beltrame FL. Anti-ulcer mechanisms of polyphenols extract of Euphorbia umbellata (Pax) Bruyns (Euphorbiaceae). J Ethnopharmacol 2016; 191: 29-40
• 33 Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79: 629-661
• 34 Bordage S, Pham TN, Zedet A, Gugglielmetti AS, Nappey M, Demougeot C, Girard Thernier C. Investigation of mammal arginase inhibitory properties of natural ubiquitous polyphenols by using an optimized colorimetric microplate assay. Planta Med 2017; 83: 647-653
• 35 Dal-Ros S, Bronner C, Auger C, Schini-Kerth VB. Red wine polyphenols improve an established aging-related endothelial dysfunction in the mesenteric artery of middle-aged rats: role of oxidative stress. Biochem Biophys Res Commun 2012; 419: 381-387
• 36 Kim SW, Cuong TD, Hung TM, Ryoo S, Lee JH, Min BS. Arginase II inhibitory activity of flavonoid compounds from Scutellaria indica . Arch Pharm Res 2013; 26: 922-926
• 37 Li LC, Kan LD. Traditional Chinese medicine for pulmonary fibrosis therapy: Progress and future prospects. J Ethnopharmacol 2017; 198: 45-63
• 38 Oboh G, Ademiluyi AO, Ademosun AO, Olasehinde TA, Oyeleye SI, Boligon AA, Athayde M. Phenolic extract from Moringa oleifera leaves inhibits key enzymes linked to erectile dysfunction and oxidative stress in ratsʼ penile tissues. Biochem Res Int 2015; 2015: 175950
• 39 Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW. Crystal structure of human arginase I at 1.29 – A resolution and exploration of inhibition in the immune response. Proc Natl Acad Sci U S A 2005; 102: 13058-13063
• 40 Cama E, Pethe S, Boucher JL, Han S, Emig FA, Ash DE, Viola RE, Mansuy D, Christianson DW. Inhibitor coordination interactions in the binuclear manganese cluster of arginase. Biochemistry 2004; 43: 8987-8999
• 41 Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci 1999; 55: 1015-1028
• 42 Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW. Human arginase II: crystal structure and physiological role in male and female sexual arousal. Biochemistry 2003; 42: 8445-8451
• 43 Zamecka E, Porembska Z. Five forms of arginase in human tissues. Biochem Med Metab Biol 1988; 39: 258-266
• 44 Caldwell RB, Toque HA, Narayanan SP, Caldwell RW. Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 2015; 36: 395-405
• 45 Chen B, Calvert AE, Meng X, Nelin LD. Pharmacologic agents elevating camp prevent arginase II expression and proliferation of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 2012; 47: 218-226
• 46 Durante W. Role of arginase in vessel wall remodeling. Front Immunol 2013; 13: 111
• 47 Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comp Biochem Physiol 1996; 114: 107-132
• 48 Konarska L, Tomaszewski L, Colombo JP, Terheggen HG. Human salivary arginase and its deficiency in argininaemia. J Clin Chem Clin Biochem 1985; 23: 337-342
• 49 Morris jr. SM, Bhamidipati D, Kepka-Lenhart D. Human type II arginase: sequence analysis and tissue-specific expression. Gene 1997; 193: 157-161
• 50 Ryoo S, Bhunia A, Chang F, Shoukas A, Berkowitz DE, Romer LH. OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling. Atherosclerosis 2011; 214: 279-287
• 51 Shatanawi A, Lemtalsi T, Yao L, Patel C, Caldwell RB, Caldwell RW. Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway. Eur J Pharmacol 2015; 5: 106-114
• 52 Waddington SN, Tam FWK, Cook HT, Cattell V. Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells. Am J Physiol 1998; 274: F473-F480
• 53 Adeva MM, Souto G, Blanco N, Donapetry C. Ammonium metabolism in humans. Metabolism 2012; 61: 1495-1511
• 54 Gotoh T, Araki M, Mori M. Chromosomal localization of the human arginase II gene and tissue distribution of its mRNA. Biochem Biophys Res Commun 1997; 233: 487-491
• 55 Maarsingh H, Zaagsma J, Meurs H. Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. Br J Pharmacol 2009; 158: 652-664
• 56 Sparkers RS, Dizikes GJ, Klisak I, Grody WW, Mohandas T, Heinzmann C, Zollman S, Lusis AJ, Cederbaum SD. The gene for human liver arginase (ARG1) is assigned to chromosome band 6q23. Am J Hum Genet 1986; 39: 186-193
• 57 Chen F, Lucas R, Fulton D. The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction. Front Immunol 2013; 9: 184
• 58 André C, Herlem G, Ghardi T, Guillaume YC. A new arginase enzymatic reactor: development and application for the research of plant-derived inhibitors. J Pharm Biomed Anal 2011; 55: 48-53
• 59 We LH, Wu G, Morris jr. SM, Ignarro LJ. Elevated arginase I expression in rat aortic smooth muscle cell increases cell proliferation. Proc Natl Acad Sci U S A 2001; 98: 9260-9264
• 60 Yoon J, Ryoo S. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production. Biochem Biophys Res Commun 2013; 435: 428-433
• 61 Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Santhanam L, Webb A, Camara A, Sikka G, Nyhan D, Shoukas AA, Ilies M, Christianson DW, Champion HC, Berkowitz DE. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol 2009; 107: 1249-1257
• 62 Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 2010; 23: 75-93
• 63 Morris jr. SM. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol 2009; 157: 922-930
• 64 Louis CA, Mody V, Henry jr. WL, Reichner JS, Albina JE. Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages. Am J Physiol 1999; 276: R237-R242
• 65 Woo A, Min B, Ryoo S. Piceatannol-3′-O-β-D-glucopyranoside as an active component of rhubarb activates endothelial nitric oxide synthase through inhibition of arginase activity. Exp Mol Med 2010; 42: 524-532
• 66 El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher U, Koo MS, Kaplan G, Fitzgerald K, Tuomanen EI, Orme IM, Kanneganti TD, Bodgan C, Wynn TA, Murray PJ. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 2008; 9: 1399-1406
• 67 Lucas R, Yang G, Gorshkov BA, Zemskov EA, Sridhar S, Umapathy NS, Jezierska-Drutel A, Alieva IB, Leustik M, Hossain H, Fischer B, Catravas JD, Verin AD, Pittet JF, Caldwell RB, Mitchell TJ, Cederbaum SD, Fulton DJ, Matthay MA, Caldwell RW, Romero MJ, Chakraborty T. Protein kinase C-α and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Respir Cell Mol Biol 2012; 47: 445-453
• 68 Wang C, Chen H, Luo H, Zhu L, Zhao Y, Tian H, Wang R, Shang P, Zhao Y. Microgravity activates p 38 MAPK-C/EBPβ pathway to regulate the expression of arginase and inflammatory cytokines in macrophages. Inflamm Res 2015; 64: 303-311
• 69 Corraliza IM, Modolell M, Ferber E, Soler G. Involvement of protein kinase A in the induction of arginase in murine bone marrow-derived macrophages. Biochim Biophys Acta 1997; 1334: 123-128
• 70 Chang CI, Zoghi B, Liao J, Kuo L. The involvement of tyrosine kinases, cyclic AMP/protein kinase A, and p 38 mitogen-activated protein kinase in IL-13-mediated arginase I induction in macrophages: its implications in IL-13-inhibited nitric oxide production. J Immunol 2000; 165: 2134-2141
• 71 Nelin LD, Chicoine LG, Reber KM, English BK, Young TL, Liu Y. Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. Am J Respir Cell Mol Biol 2005; 33: 394-401
• 72 Chem Gonzalez-Garrido JA, Olivares-Corichi IM, Tovar-Rodriguez JM, Hernández-Santana NA, Méndez-Bolaina E, Ceballos-Reyes GM, García-Sánchez JR. Influence of the AT2 receptor on the L-arginine–nitric oxide pathway and effects of (−)-epicatechin on HUVECs from women with preeclampsia. J Hum Hypertens 2013; 27: 355-361
• 73 Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increase nitric oxide signaling in cardiovascular disease. Nat Rev Drug Discov 2015; 14: 623-641
• 74 Li H, Förstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol 2013; 13: 161-167
• 75 Frombaum M, Le Clanche S, Bonnefont-Rousselot D, Borderie D. Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and •NO bioavailability: potential benefits to cardiovascular diseases. Biochimie 2012; 94: 269-276
• 76 Mitjavila MT, Moreno JJ. The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases. Biochem Pharmacol 2012; 84: 1113-1122
• 77 Pereira TMC, Pimenta FS, Porto ML, Baldo MP, Campagnaro BP, Gava AL, Meyrelles SS, Vasquez EC. Coadjuvants in the diabetic complications: nutraceuticals and drugs with pleiotropic effects. Int J Mol Sci 2016; 17: 1-24
• 78 Suganya S, Bhakkiyalakshmi E, Sarada DVL, Ramkumar KM. Reversibility of endothelial dysfunction in diabetes: role of polyphenols. Br J Nutr 2016; 116: 223-246
• 79 Yoon J, Park M, Lee JH, Min BS, Ryoo S. Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice. Vascul Pharmacol 2014; 60: 102-109
• 80 Hardy TA, May JM. Coordinate regulation of L-arginine uptake and nitric oxide synthase activity in cultured endothelial cells. Free Radic Biol Med 2002; 32: 122-131
• 81 Sahach VF, Baziliuk OV, Kotsiuruba AV, Buzhanevich OM. Disorders of endothelium-dependent vascular reactions and of the arginase and NO-synthase pathways of L-arginine metabolism in arterial hypertension. Fiziol Zh 2000; 46: 3-13
• 82 Demougeot C, Prigent-Tessier A, Marie C, Berthelot A. Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens 2005; 23: 971-978
• 83 White AR, Ryoo LD, Champion HC, Steppan J, Wang D, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE. Knockdown of arginase I restores NO signaling in the vasculature of old rats. Hypertension 2006; 47: 245-251
• 84 Abdelkawy KS, Lack K, Elbarbry F. Pharmacokinetics and pharmacodynamics of promising arginase inhibitors. Eur J Drug Metab Pharmacokinet 2016; DOI: 10.1007/s13318-016-0381-y.
• 85 Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011; 11: 239-253
• 86 Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012; 75: 311-335
• 87 Akanni OO, Owumi SE, Adaramoye OA. In vitro studies to assess the antioxidative, radical scavenging and arginase inhibitory potentials of extracts from Artocarpus altilis, Ficus exasperate and Kigelia africana . Asian Pac J Trop Biomed 2014; 4: S492-S499
• 88 Nikolić J, Cvetković T, Sokolović D. Role of quercetin on hepatic urea production in acute renal failure. Ren Fail 2003; 25: 149-155
• 89 Duffy CF, Killeen GF, Connolly CD, Power RF. Effects of dietary supplementation with Yucca schidigera Roezl ex Ortgies and its saponin and non-saponin fractions on rat metabolism. J Agric Food Chem 2001; 49: 3408-3413
• 90 Shin W, Cuong TD, Lee JH, Min B, Jeon BH, Lim HK, Ryoo S. Arginase inhibition by ethylacetate extract of Caesalpinia sappan lignum contributes to activation of endothelial nitric oxide synthase. Korean J Physiol Pharmacol 2011; 15: 123-128
• 91 Shin W, Yoon J, Oh GT, Ryoo S. Korean red ginseng inhibits arginase and contributes to endothelium-dependent vasorelaxation through endothelial nitric oxide synthase coupling. J Ginseng Res 2013; 37: 64-73
• 92 Choi K, Yoon J, Lim HK, Ryoo S. Korean red ginseng water extract restores impaired endothelial function by inhibiting arginase activity in aged mice. Korean J Physiol Pharmacol 2014; 18: 95-101
• 93 Caldwell RB, Toque HA, Narayanan SP, Caldwell RW. Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 2015; 36: 396-405
• 94 Reis MBG, Manjolin LC, Maquiaveli CC, Santos-Filho OA, Silva ER. Inhibition of Leishmania (Leishmania) amazonensis and rat arginases by green tea EGCG, (+)-catechin and (−)-epicatechin: a comparative structural analysis of enzyme-inhibitor interactions. PLoS One 2013; 8: 1-9
• 95 Lim CJ, Cuong TD, Hung TM, Ryoo S, Lee JH, Kim EH, Woo MH, Choi JS, Min BS. Arginase II inhibitory activity of phenolic compounds from Saururus chinensis . Bull Korean Chem Soc 2012; 33: 3079-3082
• 96 Hwang HM, Lee JH, Min BS, Jeon BH, Hoe KL, Kim YM, Ryoo S. A novel arginase inhibitor derived from Scutellavia indica restored endothelial function in ApoE-null mice fed a high-cholesterol diet. J Pharmacol Exp Ther 2015; 355: 57-65
• 97 Tang YL, Chan SW. A review of the pharmacological effects of piceatannol on cardiovascular diseases. Phytother Res 2014; 28: 1581-1588
• 98 Frombaum M, Therond P, Djelidi R, Beaudeux JL, Bonnefont-Rousselot D, Borderie D. Piceatannol is more effective than resveratrol in restoring endothelial cell dimethylarginine dimethylaminohydrolase expression and activity after high-glucose oxidative stress. Free Radical Res 2011; 45: 293-302
• 99 Woo A, Shin W, Cuong TD, Min B, Lee JH, Jeon BH, Ryoo S. Arginase inhibition by piceatannol-3′-O-β-D-glucopyranoside improves endothelial dysfunction via activation of endothelial nitric oxide synthase in ApoE-null mice fed a high-cholesterol diet. Int J Mol Med 2013; 31: 801-810
• 100 Nguyen MC, Ryoo S. Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice. Korean J Physiol Pharmacol 2017; 21: 83-90
• 101 Joe Y, Zheng M, Kim HJ, Kim S, Uddin J, Park C, Ryu DG, Kang SS, Ryoo S, Ryter SW, Chang KC, Chung HT. Salvianolic acid B exerts vasoprotective effects through the modulation of heme oxygenase-1 and arginase activities. J Pharmacol Exp Ther 2012; 341: 850-858
• 102 García-Niño WR, Zazueta C. Ellagic acid: pharmacological activities and molecular mechanisms involved in liver protection. Pharmacol Res 2015; 97: 84-103
• 103 Hernández-Trejo M, Montoya-Estrada A, Torres-Ramos Y, Espejel-Núñez A, Guzmán-Grenfell A, Morales-Hernández R, Tolentino-Dolores M, Laresgoiti-Servitje E. Oxidative stress biomarkers and their relationship with cytokine concentrations in overweight/obese pregnant women and their neonates. BMC Immunol 2017; 18: 3
• 104 Hussein RH, Khalifa FK. The protective role of ellagitannins flavonoids pretreatment against N-nitrosodiethylamine induced-hepatocellular carcinoma. Saudi J Biol Sci 2014; 21: 589-596
• 105 Stolarczyk M, Piwowarski JP, Granica S, Stefańska S, Naruszewicz M, Kiss AK. Extracts from Epilobium sp. herbs, their components and gut microbiota metabolites of Epilobium ellagitannins, urolithins, inhibit hormone-dependent prostate cancer Cells- (LNCaP) proliferation and PSA secretion. Phytother Res 2013; 27: 1842-1848
• 106 Cerdá B, Llorach R, Cerón JJ, Espín JC, Tomás-Barberán FA. Evaluation of the bioavailability and metabolism in the rat of punicalagin, and antioxidant polyphenol from pomegranate juice. Eur J Nutr 2003; 42: 18-28
• 107 Landete JM. Ellagitannins, ellagic acid and their derived metabolites: a review about source, metabolism, functions and health. Food Res Int 2011; 44: 1150-1160
• 108 Engler MB, Engler MM, Chen CY, Malloy MJ, Browne A, Chiu EY, Kwak HK, Milbury P, Paul SM, Blumberg J, Mietus-Snyder ML. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr 2004; 23: 197-204
• 109 Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH, Kelm M. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A 2006; 103: 1024-1029
• 110 Zhang S, Li X, Yang X. Drug-likeness prediction of chemical constituents isolated from Chinese materia medica Ciwujia. J Ethnopharmacol 2017; 198: 131-138
• 111 Egert S, Wolffram S, Bosy-Westphal A, Boesch-Saadatmandi C, Wagner AE, Frank J, Rimbach G, Mueller MJ. Daily quercetin supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr 2008; 138: 1615-1621
• 112 Schramm DD, Karim M, Schrader HR, Holt RR, Kirkpatrick NJ, Polagruto JA, Ensunsa JL, Schmitz HH, Keen CL. Food effects on the absorption and pharmacokinetics of cocoa flavanols. Life Sci 2003; 73: 857-869
• 113 Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Res 1998; 56: 317-333
• 114 Ozdal T, Capanoglu E, Altay F. A review on protein-phenolic interactions and associated changes. Food Res Int 2013; 51: 954-970
• 115 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutri 2000; 130: 2073S-2085S
• 116 Piskula MK, Terao J. Quercetinʼs solubility affects its accumulation in rat plasma after oral administration. J Agric Food Chem 1998; 46: 4313-4317
• 117 Manach C, Williamson G, Morand C, Scalbert A, Rémésy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies1–3. Am J Clin Nutr 2005; 81: 230S-242S
• 118 Jakobek L. Interactions of polyphenols with carbohydrates, lipids and proteins. Food Chem 2015; 175: 556-567
• 119 Sanguinetti MC, Tristani-Firouzi M. Review article hERG potassium channels and cardic arrhythmia. Nature 2006; 440: 463-469
• 120 Williamson G, Holst B. Dietary reference intake (DRI) value for dietary polyphenols: are we heading in the right direction?. Br J Nutr 2008; 99: S55-S58
• 121 Pham TN, Bordage S, Pudlo M, Demougeot C, Thai KM, Girard-Thernier C. Cinnamide derivates as mammalian arginase inhibitors: synthesis, biological evaluation and molecular docking. Int J Mol Sci 2016; DOI: 10.3390/ijms17101656.
• 122 Pernow J, Kissa A, Tratsiakovich Y, Climent B. Tissue-specific up-regulation of arginase I and II induced by p38 MAPK mediates endothelial dysfunction in type 1 diabetes mellitus. Br J Pharmacol 2015; 172: 4684-4698
• 123 Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginase I and II: do their functions overlap?. Mol Genet Metab 2004; 81: S38-S44
• 124 Pudlo M, Demougeot C, Girard-Thernier C. Arginase inhibitors: a rational approach over one century. Med Res Rev 2017; 37: 475-513
• 125 Bagnost T, Ma L, da Silva RF, Rezakhaniha R, Houdayer C, Stergiopulos N, André C, Guillaume Y, Berthelot A, Demougeot C. Cardiovascular effects of arginase inhibition in spontaneously hypertensive rats with fully developed hypertension. Cardiovasc Res 2010; 87: 569-577
• 126 Wang L, Bhatta A, Toque HA, Rojas M, Yao L, Xu Z, Patel C, Caldwell RB, Caldwell RW. Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia. Microvasc Res 2015; 98: 1-18
• 127 Kavalukas SL, Uzgare AR, Bivalacqua TJ, Barbul A. Arginase inhibition promotes wound healing in mice. Surgery 2011; DOI: 10.1016/j.surg.2011.07.012.
• 128 Williamson G. The role of polyphenols in modern nutrition. Nutr Bull 2017; 42: 226-235
• 129 Santos AC, Costa G, Veiga F, Figueiredo IV, Batista MT, Ribeiro AJ. Advance in methods studying the pharmacokinetics of polyphenols. Curr Drug Metab 2014; 15: 96-115
• 130 Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004; 79: 727-747
• 131 Chen Z, Zheng S, Li L, Jiang H. Metabolism of flavonoids in human: a comprehensive review. Cur Drug Metab 2014; 15: 48-61
• 132 Lodi F, Jimenez R, Moreno L, Kroon PA, Needs PW, Hughes DA, Santos-Buelga C, Gonzalez-Paramas A, Cogolludo A, Lopez-Sepulveda R, Duarte J, Perez-Vizcaino F. Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta. Atherosclerosis 2009; 204: 34-39