Flavonoids and Their Metabolites: Prevention in Cardiovascular Diseases and Diabetes
Total Page：16
File Type：pdf, Size：1020Kb
diseases Perspective Flavonoids and Their Metabolites: Prevention in Cardiovascular Diseases and Diabetes Keti Zeka 1,*,†, Ketan Ruparelia 1,†, Randolph R. J. Arroo 1, Roberta Budriesi 2 and Matteo Micucci 2 1 Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK; [email protected] (K.R.); [email protected] (R.R.J.A.) 2 Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; [email protected] (R.B.); [email protected] (M.M.) * Correspondence: [email protected]; Tel.: +44-075-0647-3809 † These authors contributed equally to the present work. Received: 2 August 2017; Accepted: 3 September 2017; Published: 5 September 2017 Abstract: The occurrence of atherosclerosis and diabetes is expanding rapidly worldwide. These two metabolic disorders often co-occur, and are part of what is often referred to as the metabolic syndrome. In order to determine future therapies, we propose that molecular mechanisms should be investigated. Once the aetiology of the metabolic syndrome is clear, a nutritional intervention should be assessed. Here we focus on the protective effects of some dietary flavonoids, and their metabolites. Further studies may also pave the way for development of novel drug candidates. Keywords: antioxidants; atherosclerosis; diabetes; flavonoids; metabolites 1. Atherosclerosis Atherosclerosis is known to predispose patients to myocardial infarction and stroke, and it is responsible for cardiovascular ailments that represent the main cause of death in industrialised societies. Disorders related to atherosclerosis, e.g., vascular inflammation and metabolic alterations, strongly favour the onset and progression of a range of chronic diseases. The onset of these pathological events is linked to several factors such as age, hypertension, diabetes mellitus, smoking, and dyslipidemia. Atherosclerosis is a chronic, inflammatory, fibro-proliferative disorder, primarily of the large- and medium-sized conduit arteries. The vascular production of reactive oxygen species (ROS), such as − O2 , derived from NADPH oxidase (NOX)-catalysed oxidations, represents a key event on the − road to endothelial dysfunction [1,2]. In fact, O2 and H2O2 stimulate vascular smooth muscle cell (VSMC) hyperplasia and hypertrophy occurring along with intracellular alkalinization, increase of the intracellular free calcium concentration, activation of MAP kinase, and induction of proto-oncogene expression [3–6]. Endogenous and exogenous oxidants continuously trigger ROS generation in the vascular tissue which results in atherosclerosis, neointimal hyperplasia, and hypertension [7–9]. Different authors have reported that Angiotensin II-induced hypertension is, at least in part, due to oxidative stress [10,11]. Several natural extracts, e.g., from leaves of Olea europea L., or calyces of Hibiscus sabdariffa L. [12], exert multiple effects that result in an inhibition of atherosclerosis and hypertension. The effects include vasorelaxant, antioxidant and antinflammatory activities. Also, vegetal extracts rich in hydrolyzable tannins, such as Castanea sativa Mill. bark [13] and Punica granatum L. extracts [14] exert anti-atherogenic effects through several mechanisms including the suppression of inflammation and oxidative stress, the inhibition of adhesion molecules such as VCAM-1 and ICAM-1, and the lipid-lowering properties [15]. In addition, diets rich in flavonoids are consistently linked with beneficial effects in the primary prevention of cardiovascular events. Diseases 2017, 5, 19; doi:10.3390/diseases5030019 www.mdpi.com/journal/diseases Diseases 2017, 5, 19 2 of 18 Diseases 2017, 5, 19 2 of 19 lipid-lowering properties [15]. In addition, diets rich in flavonoids are consistently linked with beneficial effects in the primary prevention of cardiovascular events. The main aim of this perspective is to critically explore flavonoidsflavonoids (Figure1 1a:a: StructuresStructures ofof thethe flavonoidsflavonoids discusseddiscussed fromfrom this this perspective; perspective; Figure Figure1b: 1b: Structures Structures of theof the isoflavones isoflavones discussed discussed from from this perspective)this perspective) and their and antioxidanttheir antioxidant activities, activities, and their and ability their to affectability lipid to affect levels andlipid the levels development and the ofdevelopment plaque, atherosclerosis, of plaque, atherosc and itslerosis, progression. and its progression. (a) Figure 1. Cont. Diseases 2017, 5, 19 3 of 18 19 Diseases 2017, 5, 19 3 of 18 (b) (b) Figure 1. (a) Structures of the flavonoids discussed in this perspective; (b) Structures of the isoflavonesFigure 1.1.( a( )discusseda Structures) Structures in of this theof perspective. flavonoidsthe flavonoids discussed discussed in this in perspective; this perspective; (b) Structures (b) Structures of the isoflavones of the discussedisoflavones in discussed this perspective. in this perspective. 2. Flavonoids and Atherosclerosis 2. Flavonoids and Atherosclerosis 2. Flavonoids and Atherosclerosis 2.1. Direct Antioxidant Effects of Flavonoids 2.1. Direct Antioxidant Effects of Flavonoids Dietary flavonoids commonly exert good antioxidant activity with the extent depending on the structureDietary of the flavonoidsflavonoids flavonoid commonly [16]. It is exert generally good antioxidantantioxidanaccepted thatt activity the number with the and extent position depending of hydroxyl on the groupsstructure on of B theand flavonoidflavonoid A rings, [[16].and16]. theIt is extent generally of co acceptednjugation that between the number the B and and C position rings are of hydroxylthe main featuresgroups on onaffecting BB and and A theA rings, rings, flavonoids’ and and the the extentantioxidant extent of conjugation of activityconjugation [17]. between between the B the and B C and rings C are rings the mainare the features main affectingfeaturesThe affecting thestructural flavonoids’ the features flavonoids’ antioxidant of flavonoids antioxidant activity that [ 17activity are]. necessary [17]. to exert radical scavenging and/or the antioxidativeThe structural actions features are described ofof flavonoidsflavonoids by the thatthat three areare necessarycriteria:necessary (1) toto the exertexert ortho radicalradical-dihydroxy scavengingscavenging (3′,4′-diOH, and/orand/or i.e., the catechol)antioxidative structure actions in arethe described B ring, giving by thethe high threethree st criteria:criteria:ability to (1) the the flavonoidorthoortho-dihydroxy-dihydroxy phenoxyl (3(30′,4 radicals′0-diOH,-diOH, i.e., via hydrogencatechol) structure structurebonding in inor the theby B ring, Bexpanded ring, giving giving highelectron stabilityhigh destabilitylocalization; to the flavonoidto the (2)flavonoid phenoxylthe C2-C3 phenoxyl radicals double viaradicals hydrogenbond via(in conjugationbondinghydrogen or bonding bywith expanded the 4-oxoor by electron group), expanded delocalization; which electron confers (2) dethelocalization; the co-planarity C2-C3 double (2)of thethe bond hetero-ring C2-C3 (in conjugation double and contributes bond with the(in to4-oxoconjugation radical group), stabilization with which the confers 4-oxo via electron group), the co-planarity delocalization which confers of the ov th hetero-ringere co-planarity all three and ring of contributes systems; the hetero-ring (3) to the radical presence and stabilization contributes of both via3-OHto radical electron and stabilization 5-OH delocalization (Figure via 2) overelectron groups all three delocalization for ringthe systems;maximal over (3) radical all the three presence scavenging ring ofsystems; both capacity 3-OH (3) the and and presence 5-OH the strongest (Figure of both2) radicalgroups3-OH and absorption. for the5-OH maximal (Figure radical 2) groups scavenging for the capacitymaximal and radical the strongest scavenging radical capacity absorption. and the strongest radicalIn absorption. addition, the lack of o-dihydroxy structure in the B ring can be compensated by hydroxyl substituentsIn addition, in a the catechol lack ofstructure o-dihydroxy on the structure A ring:ring: inthis the feature B ring represents can be compensated a larger determinant by hydroxyl of flavonoidflavonoidsubstituents antiradical in a catechol activity. structure The basic on theflavonoid flavonoid A ring :ststructure thisructure feature is essential represents for a the larger antioxidant determinant activity of onlyflavonoid when antiradical a catechol configuration configurationactivity. The basicis absent. flavonoid Glycosylation structure of is flavonoids flavonoids essential fordecreases the antioxidant their antioxidant activity activity.only when TheThe a block catecholblock or or theconfiguration the removal removal of is the of absent. C3the OH C3 Glycosylation group OH group results ofresults in flavonoids a reduction in a reductiondecreases of antioxidative theirof antioxidative antioxidant properties propertiesofactivity. flavonoids The of flavonoids [block17,18 ].or the [17,18]. removal of the C3 OH group results in a reduction of antioxidative properties of flavonoids [17,18]. FigureFigure 2. 2. StructuralStructural features features of of flavonoids flavonoids wi withth high antioxidant activity, from Ami´cetAmić et al. [[18].18]. Figure 2. Structural features of flavonoids with high antioxidant activity, from Amić et al. [18]. Diseases 2017, 5, 19 4 of 19 2.2. Indirect Antioxidant Effects of Flavonoids: