Polyphenolic Flavonoids and Metalloprotease Inhibition: Applications to Health and Disease

C H A P T E R

4 Polyphenolic Flavonoids and Metalloprotease Inhibition: Applications to Health and Disease Dejan Agi
c*, Marija Abrami
c†, Vesna Rastija*, Rosemary Vukovi
c‡ *Faculty of Agriculture, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia †Division of Organic Chemistry and Biochemistry, Ruđer Bosˇkovi
c Institute, Zagreb, Croatia ‡Department of Biology, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

The chemical nature and biological activity of flavonoids depend on their structural class, number and substitution pattern of the hydroxyl groups, other substitutions and conjugations, and degree of polymerization [5]. Flavonoids have long been recognized to possess antioxidant activity. In addition, hepatoprotective, antibacterial, antiinflammatory, anticancer, and antiviral activities have been reported for flavonoids [1]. The antioxidant and free radical scavenging properties of flavonoids as typical natural polyphenols linked with their ability to act as potent metal chelators and to interact with many enzymes, including metalloproteases, are the main causes of their beneficial effects on human health [6]. Metalloproteases (metallopeptidases) are a class of proteolytic enzymes that contain a catalytic metal ion at their active site, which aids in the hydrolysis of peptide bonds leading to protein and peptide degradation [7]. Metalloproteases participate in numerous physiological processes such as cell differentiation, migration and proliferation, cellular adhesion, fertilization, and neurogenesis, and so their deregulation leads to diseases ranging from cancer, inflammation, and cardiovascular disease, to arthritis and neurological insults. To date, a great variety of synthetic and natural inhibitors with physiological and pathophysiological significance for the activity regulation of human metalloproteases are known. In fact, polyphenolic flavonoids as natural inhibitors are widely used for scientific and pharmaceutical studies [7–9]. This paper presents an overview of the investigations on the feasibility and application of flavonoids as natural inhibitors for well-known human metalloproteases: matrix metalloproteinases (MMPs) and angiotensinconverting enzyme (ACE).

Abbreviations ACE ECM EGCG HUVEC KKS MMPs OA RAS TIMPs TPA UV VEGF

angiotensin-converting enzyme extracellular matrix epigallocatechin-3-gallate human umbilical vein cells kallikrein-kinin system matrix metalloproteinases osteoarthritis renin-angiotensin system tissue inhibitors of metalloproteinase 12-O-tetradecanoylphorbol-13-acetate ultraviolet vascular endothelial growth factor

1 INTRODUCTION Flavonoids are hydroxylated polyphenolic compounds ubiquitously distributed in plants, where they perform important functions including attracting pollinating insects, combating environmental stresses, such as microbial infection, and regulating cell growth [1]. Apart from various vegetables and fruits, flavonoids are found in nuts, seeds, grains, spices, beverages like wine, tea and beer, chocolate, and other food sources and are consumed regularly with the human diet [2]. Over 9000 different naturally occurring flavonoids have been discovered [3] and the list is still growing. The basic structure of dietary flavonoids is composed of two phenyl rings (A and B rings) joined via a heterocyclic pyran ring structure (C ring) (Fig. 4.1). Based on their structural differences, flavonoids have been classified into six major subclasses, namely flavan-3-ols, anthocyanidins, flavonols, flavones, flavanones, and isoflavones [4].

Polyphenols: Mechanisms of Action in Human Health and Disease https://doi.org/10.1016/B978-0-12-813006-3.00004-0

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© 2018 Elsevier Inc. All rights reserved.

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FIG.

4.1 The basic chemical structure of six mayor subclasses of flavonoids: (A) flavan-3-ol, (B) anthocyanidin, (C) flavonol, (D) flavone, (E) flavanone, and (F) isoflavone.

2 MATRIX METALLOPROTEINASES Matrix metalloproteinases, collectively called matrixins, are zinc and calcium dependent proteases that participate in degradation of the extracellular matrix (ECM) and hence are closely linked with embryonic development, morphogenesis, tissue remodeling, tumor invasion, angiogenesis, and metastasis of cancer [10]. They are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. The propeptide is thought to keep the enzyme in latent form by the interaction of a cysteine residue in this peptide with the zinc moiety in the enzyme active site. Disruption of this interaction triggers the cysteine switch mechanism and results in activation of the enzyme [11]. On the basis of structure and in terms of substrate specificity, MMPs were classified into six groups: collagenases, gelatinases, stromelysins, matrilysins, membrane-

type MMPs, and other nonclassified MMPs. Since some MMPs have been found to have multiple targets and some members cannot be classified into existing groups, this classification system has been replaced by numerical designations MMP-1 to MMP-28 [12]. Currently there are 24 known MMPs identified in vertebrates, including 23 in humans [13]. Under normal physiological conditions, MMPs are minimally expressed and their activities are precisely regulated at the level of transcription, activation of the precursor zymogens, interaction with specific ECM components, and inhibition by endogenous inhibitors like tissue inhibitors of metalloproteinase (TIMPs) [14]. Previous studies have shown that the MMP levels often increases in various pathological conditions such as cancer [15], atherosclerosis [16], lung disease [17], skin ulceration [18], arthritis [19], and Alzheimer’s disease [20]. In addition to TIMPs, which constitute the major polypeptide inhibitors of this enzyme group, MMP inhibition

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2 MATRIX METALLOPROTEINASES

was also achieved by synthetic pharmacological agents such as diphosphonates, tetracycline derivatives, and hydroxamic peptidomimetics. These compounds have been shown to be effective in the treatment of bone diseases and dental periodontitis [21,22]. However, the negative results obtained in human clinical trials analyzing synthetic MMP inhibitors for anticancer activity stirred up the impellent need for compounds that could be more effective in cancer treatment and this search found its answer in the field of natural compounds [23].

2.1 Inhibition of Matrix Metalloproteases by Flavonoids The ability to use flavonoids as MMP inhibitors in regulating severe pathological conditions has been studied over the past two decades and most of the flavonoids have proved to be effective in suppressing the activity of MMPs. The effects of ultraviolet (UV) irradiation from sunlight on skin photoaging have been widely studied, and it has been shown that UV irradiation of human skin fibroblasts, either in vitro or on human skin in vivo stimulate the overexpression of genes of MMPs, including matrix metalloproteinase-1 (MMP-1, collagenase-1), which play an important role in the degradation of ECM components during skin photoaging [24]. In order to develop new antiphotoaging agents, Kim et al. [25] examined the inhibitory effect of extracts from the marine product Zostera marina on MMP-1 and found that luteolin suppressed the expression of MMP-1 in human skin fibroblasts (Hs68) cells, while Aslam et al. [26] demonstrated that MMP-1 accumulation in the fibroblastconditioned medium was dramatically reduced in the presence of quercetin, luteolin, kaempferol, and naringenin, major constituents of pomegranate peel extract. Likewise, flavonoids, such as quercetin, kaempferol, apigenin and wogonin, were proved to be MMP-1 inhibitors, and also inhibited MMP-1 induction by suppressing activation of the transcription factor, activator protein-1 (AP1) in 12-O-tetradecanoylphorbol-13-acetate (TPA) treated human neonatal dermal fibroblast culture. Therefore, certain plant flavonoids may be beneficial to treat some inflammatory skin disorders and to protect skin from photo-aging [27]. Furthermore, flavonoids apigenin and luteolin suppress UV-A-induced MMP-1 expression via mitogen-activated protein kinase and AP-1-dependent signaling in human keratinocytes HaCaT cells [28] while methoxyflavonoid isosakuranetin inhibits UV-B-induced MMP-1 expression in HaCaT cells through the suppression of ERK1/2 kinase pathways [29]. To investigate the structure-activity relationship of flavonoid compounds on their inhibitory effects against the MMP-1 activity, Sim et al. [30] examined the effects of several

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flavonoids in vitro and in human dermal fibroblasts induced by UV-A and demonstrated that myricetin, quercetin, kaempferol, luteolin, apigenin and chrysin inhibited collagenase activities, in a dose-dependent manner, and MMP-1 expression. Also, they showed that the inhibitory effects of flavonoids on expression of MMP-1 in human dermal fibroblasts depends on the number and order of OH groups in the flavonoid structure. In order to fit for the demands for MMP-1 inhibitor screening and the further structural and biochemical characterization of enzyme-inhibitor complex studies, Lu et al. [31] reported an improved method for high-level expression of soluble human MMP-1 catalytic domain (cd-MMP-1) in Escherichia coli. For this purpose 17 structure-related flavonoids were tested for their inhibitory effect on soluble cd-MMP-1 and six compounds (luteolin, fisetin, kaempferol, morin, myricetin, and quercetin) were active with an IC50 value less than 10 μM. Among them, fisetin, the most potent inhibitor, was identified as a mixed-type inhibitor of cd-MMP-1. Osteoarthritis (OA) is a chronic progressive disease associated with complicated mechanisms that involve synovitis and articular cartilage destruction [32]. Proinflammatory cytokines, such as interleukin-1β (IL-1β), are suspected of causing damage to OA cartilage by inducing MMP expression in chondrocytes in an autocrine/paracrine manner [33]. Zheng et al. [34] for the first time showed that the flavonoid chrysin significantly inhibited the IL-1β-induced expression of MMP-1, MMP-3, and MMP-13 in human OA chondrocytes. Similarly, baicalin, a predominant flavonoid isolated from the dry root of Scutellaria baicalensis Georgi, notably prevented IL-1β-induced MMP-1, MMP-3, and MMP-13 expression at the mRNA and protein levels [32,35]. To identify the therapeutic potential for cartilage degradation and its action mechanisms, Lim et al. [36] examined the effects of apigenin and wogonin on MMP-13 induction and showed that these naturally occurring flavonoids down-regulate MMP-13 expression in interleukin IL-1β-treated human chondrocyte SW1353 cells. The results of these studies have shown that inhibiting the expression and activity of MMPs is an attractive strategy to counteract OA. MMPs, in particular gelatinases MMP-2 and MMP-9, play an important role in cancer invasion and were found to be overexpressed in almost all types of cancers [16]. The association of green tea consumption with prevention of cancer development is based on several epidemiologic observations. The effect of the main flavanol present in green tea, epigallocatechin-3-gallate (EGCG), on two gelatinases most frequently overexpressed in cancer and angiogenesis (MMP-2 and MMP-9) and on tumor cell invasion and chemotaxis were examined [37]. The results from this study showed that EGCG inhibited in

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a dose-dependent, precipitation-independent manner the activity of both basement membrane collagen- and gelatin-degrading metalloproteinases, MMP-2 and MMP-9, and it also increased the expression of TIMP-1 and TIMP-2, which block the activity of activated MMPs. Moreover, Cheng et al. [38] showed that EGCG forms a reversible complex with MMP-2, thus inhibiting enzymatic activity. Specifically, EGCG did not interfere with the binding of MMP-2 to type I collagen, but it significantly enhanced both pro- and activated-MMP-2 binding to TIMP-2. To investigate interaction of flavonoids with the secretion of MMPs, Huang et al. [39] reported that quercetin suppressed the epidermal growth factor-induced production of MMP-2 and MMP-9 in human squamous carcinoma A431 cells. Furthermore, Lin et al. [40] showed that quercetin effectively suppressed MMP-9 gene expression induced by TPA via suppressing the protein kinase C/extracellular signal-regulated kinase and cJun/activator protein-1 cascades with consequent suppression of colony formation, tumor migration, and invasion by human breast carcinoma cells. By using docking and molecular dynamics simulations, Saragusti et al. [41] showed that quercetin interacted in the S10 subsite of the MMP-9 active site. Moreover, the structure-activity relationship analysis demonstrated that flavonoid R 30 OH and R 40 -OH substitutions were relevant to the inhibitory property against MMP-9 activity. Recently, Lan et al. [42] demonstrated that this flavonoid inhibited cell migration and invasion in human osteosarcoma cell line by regulating hypoxia-inducible factor, HIF-1α, vascular endothelial cell growth factor, VEGF, MMP-2 and MMP-9 expression in vitro and that quercetin ameliorated tumor metastasis in vivo in the osteosarcoma nude mouse model. Genistein, an isoflavonoid of the leguminosae family, also regulates cell invasion and the metastatic process by inhibiting MMP-2 and MMP-9 activity in prostate cell lines [43,44]. Among the natural compounds that help to protect from pathological states such as cancer, other flavonoids have been analyzed, including the citrus flavonoid nobiletin. This polymethoxy flavonoid inhibited an in vitro invasion of human fibrosarcoma HT1080 cells in the Matrigel model and transcriptionally down-regulated the expression of MMP-1 and MMP-9 but up-regulated that of TIMP-1, suggesting that nobiletin prevents tumor invasion not only by suppressing the production of MMPs but also by augmenting TIMP-1 production in tumor cells [45]. Also, nobiletin has a distinct ability to strongly suppress MMP-7 expression and production, presumably by blocking AP-1 activity in HT-29 human colorectal cancer cells [46]. In order to find novel MMPs inhibitors from natural resources, Matchett et al. [47] demonstrated that flavonoid-enriched fractions from lowbush blueberries (Vaccinium angustifolium) can down-regulate the activities

of MMP-2 and MMP-9 in DU145 human prostate cancer cells, suggesting that further understanding of the complex properties of flavonoids, in particular those from lowbush blueberry, may allow for the further development and refinement of the role of flavonoids in the prevention of carcinogenesis and metastasis. Furthermore, Zheng et al. [48] explored the effects of deguelin, a flavonoid isolated from several plant species, such as Derris trifoliata and Mundulea sericea, and demonstrated that this natural compound was capable of modulating migration and invasion in human pancreatic cancer cells by downregulating the expression of MMP-2 and MMP-9. The effects of baicalein in inhibiting MMP-2 and MMP9 expression were studied in vitro, showing that baicalein inhibits colorectal cancer cell migration and invasion by reducing the expression of MMP-2 and MMP-9 via suppression of the protein kinase B and extracellular signal regulated kinases signaling pathway [49,50]. Likewise, baicalein significantly inhibits migration and invasion in B16F10 melanoma cells by suppressing MMP-2 and MMP-9 expression and activity. Thus, baicalein could be a potential candidate for the development of chemotherapeutic treatments for colorectal cancer and melanoma [51]. Diosmin, a glycosylated flavonoid from citrus species and olive leaves, exhibits cytotoxic potential by suppressing overexpression of MMP-2 and MMP-9 in A431 skin cancer cells, which indicates the antiinvasive potential of this polyphenolic compound [52]. The significant inhibitory effect on MMP-2 and MMP-9 in human fibrosarcoma cell line HT-1080 was also shown for glycosylated flavonoids from the halophyte Salicornia herbacea, isorhamnetin 3-O-b-D-glucoside, and quercetin 3-O-b-D-glucoside [53]. More recently, Crascì et al. [54] reported that flavones apigenin, luteolin, and their respective glucosides show different selectivity against MMP-1, MMP-3, MMP-8, MMP-9, and MMP-13. In particular, the aglycones apigenin and luteolin are very selective toward both the MMP-9 and MMP-13 in respect to the other MMPs. However, these flavones have a good ability to interact with metalloproteases and can also be lead compounds for further development.

3 ANGIOTENSIN-CONVERTING ENZYME Angiotensin-converting enzyme (ACE) is a transmembrane zinc metallopeptidase that hydrolyzes peptides by the removal of dipeptide from the C-terminus. It is a central component of the renin-angiotensin system (RAS), which converts the inactive decapeptide angiotensin I to the potent vasoconstrictor angiotensin II [55]. ACE is present in different cell types, but its principal location is on the surface of endothelial and epithelial cells [56]. In humans, ACE is encountered in two distinct isoforms, the somatic and the germinal isoform. Somatic ACE

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isoform is a large glycoprotein comprising two homologous domains, N and C, joined by an interdomain linker. Both domains are capable of cleaving angiotensin I and bradykinin [57]. This isoform is a key regulator of blood pressure, expressed in various tissues, mainly in lung, and cell types including cardiovascular system, liver, kidneys, intestine and adrenal gland [58]. Germinal ACE isoform is a lower-molecular-mass glycoform found exclusively in sperm cells and is thought to play a role in sperm maturation and the binding of sperm to the oviduct epithelium [59]. The most significant physiological substrates of ACE are angiotensin I, which is converted into angiotensin II by removal of the C-terminal HisLeu, and the potent vasodilator bradykinin, which is inactivated by ACE cleavage of the penultimate ProPhe bond. As a nonspecific metalloprotease, ACE was able to cleave neuropeptides such as neurotensin and substance P as well as luteinize hormone-releasing hormone (luliberin) [60]. As a bioactive component of RAS and the kallikrein-kinin system (KKS), ACE plays a significant role in blood pressure regulation and fluid and electrolyte balance [61]. The broad spectrum of ACE substrates, and its wide tissue distribution, indicate that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in (patho)physiologic processes such as fertilization, atherosclerosis, and kidney and lung fibrosis. ACE levels are increased in many forms of vascular and cardiac hypertrophy, and the administration of ACE inhibitors has led to regression of hypertrophy. ACE inhibitors have achieved widespread use in the treatment of hypertension [56]. However, all of these synthetic drugs produced some side effects, such as angioedema and cough, when they are used for a long time [62]. Therefore, ACE inhibitors from natural sources, particularly dietary sources, are potentially beneficial.

3.1 Inhibition of Angiotensin-Converting Enzyme by Flavonoids Abundant literature has reported that high fruit and vegetable consumption displays positive correlations in cardiovascular and cerebrovascular disease reduction, due to the antioxidant potential of phenolic compounds present in them [63–65]. A number of extracts obtained from Australian and Iranian medicinal plants rich in phytochemicals were found to be effective in ACE inhibition [66,67]. To investigate if the connection between tea and ACE might be an explanation of the pharmacological effects of tea on the cardiovascular system, Persson et al. [68] incubated cultured endothelial cells from human umbilical veins (HUVEC) with extracts of Japanese Sencha (green tea), Indian Assam Broken Orange Pekoe (black tea), and Rooibos tea, respectively. After

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incubation a significant and dose-dependent inhibition of ACE activity in HUVEC was seen with the green tea and the black tea, but no significant effect was seen with the Rooibos tea. Also, the authors have shown that the inhibitory effect on ACE activity was associated with the four major flavanols, epicatechin, epigallocatechin, epicatechingallate and epigallocatechingallate, isolated from tea. The ability of flavonoids to inhibit ACE through the generation of chelate complexes within the active center of ACE [69] may explain the action of green and black tea as ACE inhibitors. Flavan-3-ols and proanthocyanidins are of great interest in nutrition and medicine because of their potent antioxidant capacity and other protective efects on human health. In a search for potential ACE inhibitors from plants, Lacaille-Dubois et al. [70] prepared methanolic extracts, fractions, and pure substances from Musanga cecropioides, Cecropia, and Crataegus species and demonstrated that proanthocyanidins from these plants exhibited inhibitory activity against ACE. Furthermore, Actis-Goretta et al. [71] have determined that flavan-3-ols and procyanidins have an inhibitory effect on ACE activity, and the effect was dependent on the number of epicatechin units forming the procyanidin. To investigate the effect of bilberry (Vaccinium myrtillus) extracts on ACE activity, Persson et al. [72] treated the human endothelial cell culture with prepared extracts (rich in flavonoids i.e., cyanidin, delphinidin, and malvidin) and showed that the ACE activity had been significantly reduced in a dose-dependent manner. Several anthocyanins (anthocyanidin glycosides) such as cyanidin-3-O-β-glucoside isolated from rose (Rosa damascene) and cyanidin-3-O-sambubiosides and delphinidin-3-O-sambubiosides isolated from hibiscus (Hibiscus sabdariffa) extracts have shown ACE inhibition in vitro [73,74]. Ethanolic extracts of Senecio gibbosus subsp. gibbosus and S. vulgaris exhibit ACE inhibitory activity [75]. Since Senecio species contain polyphenols such as quercetin, isoquercetrin, isorhamnetin-3-O-rutinoside, and quercetin-3-O-glucoside, the authors believed that flavonoids are responsible for the observed ACE inhibitory activity. Likewise, the flavonoids quercetin, quercetin-3-glucoside, quercetin-3-galactoside, and cyanidin-3-galactoside from apple skin extract exhibit a capacity to inhibit ACE with IC50 values in the 71 to 206 μM range [76] while quercetin 3-O-(600 -galloyl)galactoside and kaempferol-3-O-(600 -p-coumaroyl)glucoside from willow herb (Epilobium angustifolium) inhibit ACE in a dose-dependent manner [77]. The in vitro ACE inhibitory activity was also shown for apigenin, luteolin, kaempferol-3-O-α-arabinopyranoside, kaempferol-3-O-β-galactopyranoside, quercetin-3-O-αarabinopyranoside, and luteolin-7-O-β-glucopyranoside isolated from Ailanthus excelsa with IC50 values in the 260 to 320 μM range [78]. In the cases when bioassayguided fractionation of extract of Sedum sarmentosum

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was performed, a new flavonoid, quercetin-3-O-α-(6000 -caffeoylglucosyl-β-1,2-rhamnoside), along with four known flavonoids, quercetin 3-O-α-(6000 -p-coumaroylglucosylβ-1,2-rhamnoside), isorhamnetin-3-β-glucopyranoside, quercetin-3-β-glucopyranoside, and kaempferol-3-αarabinopyranoside, was found to exhibit distinctive ACE inhibitory activity [79]. When evaluating the content of individual phenolics and ACE activity of the extracts of selected plants of the Rutaceae family, Alu’datt et al. [80] found that the highest ACE inhibitory activity of the extracted phenolics from lemon was associated with free phenolic extracts obtained at 30°C. Contrarily, Kwon et al. [81] reported that the strong ACE-inhibitory activity in water extracts of rosemary clonal line (Rosemary LA) and lemon balm (Melissa officinalis) did not correlate well with the total soluble phenolic content, antioxidant activity, or the concentration of individual phenolics in the extracts. Furthermore, Pinto et al. [82] reported that water extracts of red currents (Ribes rubrum) and black currents (Ribes nigrum) had ACE inhibitory activity but not the extracts of red and green gooseberries (Ribes uva-crispa). Although black currants had the highest quercetin derivatives content among all berries no correlation was found between ACE inhibition and quercetin content. The ACE inhibitory activity had been reported for several brown seaweed species such as Ecklonia cava and Ecklonia stolonifera [83,84]. More recently, Nagappan et al. [85] reported that crude extracts and fucoxanthin-rich fractions of Sargassum siliquosum and Sargassum polycystum are able to inhibit ACE activity. The results of a systematic screening of 21 flavonoids for the inhibition of ACE showed that luteolin, diosmin, quercetin and naringenin (inhibition approx. 45%) are the most effective compounds [86]. Finally, study of structure-activity relationships of the flavonoids and inhibitory activity of ACE showed that the combination of substructures in the framework of flavonoids that enhances the activity of ACE inhibitors consists of the following elements: a double bond between C2 and C3 on the C-ring, 40 -O-methoxylation on B-ring, 4-carbonyl group on C-ring, 3-hydroxylation on C-ring, and 3-Oglycosylation on C-ring [87]. These results suggested that flavonoids are an excellent source of antihypertensive compounds.

4 CONCLUSION Flavonoids belong to polyphenolic compounds ubiquitously distributed in plants, many of which have been used in traditional herbal medicine for thousands of years. The data from ex vivo and in vitro experiments clearly indicate that flavonoids possess antioxidant, antibacterial, and antiviral activities. Moreover, the direct or indirect inhibitory action of flavonoids on metalloproteases such as MMPs, which participate in degradation

of the extracellular matrix, and ACE, which plays a significant role in blood pressure regulation, allows these naturally occurring compounds to be considered as potential candidates for the prevention and treatment of skin disorders, osteoarthritis, cancer, and cardiovascular diseases.

References [1] Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J 2013;2013:162750. [2] Kuhnau J. The flavanoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 1976;24:117–91. [3] Williams CA, Grayer RG. Anthocyanins and other flavonoids. Nat Prod Rep 2004;21(4):539–73. [4] Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79 (5):727–47. [5] Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002;13(10):572–84. [6] Robak J, Gryglewski RJ. Bioactivity of flavonoids. Pol J Pharmacol 1996;48(6):555–64. [7] Thomas NV, Kim SK. Metalloproteinase inhibitors: status and scope from marine organisms. Biochem Res Int 2010;2010:845975. [8] Nancy J, Brown MD, Douglas E, Vaughan MD. Angiotensinconverting enzyme inhibitors. Circulation 1998;97:1411–20. [9] Bauvois B, Dauzonne D. Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev 2006;26(1):88–130. [10] Nagase H, Woessner Jr. JF. Matrix metalloproteinases. J Biol Chem 1999;274(31):21491–4. [11] Vu T, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 2000;14(17):2123–33. [12] Puente XS, Sanchez LM, Overall CM, Lopez-Otin C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 2003;4(7):544–58. [13] Jabło
nska-Trypu
c A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhibit Med Chem 2016;31(Suppl 1):177–83. [14] Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69(3):562–73. [15] Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloproteinases in cancer: bringing new life to old ideas. Genes Dis 2015;2 (1):26–34. [16] Noji Y, Kajinami K, Kawashiri MA, Todo Y, Horita T, Nohara A, et al. Circulating matrix metalloproteinases and their inhibitors in premature coronary atherosclerosis. Clin Chem Lab Med 2001;39(5):380–4. [17] Molet S, Belleguic C, Lena H, Germain N, Bertrand CP, Shapiro SD, et al. Increase in macrophage elastase (MMP-12) in lungs from patients with chronic obstructive pulmonary disease. Inflamm Res 2005;54(1):31–6. [18] Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY. Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med 2008;25(4):419–26. [19] Yoshihara Y, Obata K, Fujimoto N, Yamashita K, Hayakawa T, Shimmei M. Increased levels of stromelysin-1 and tissue inhibitor of metalloproteinases-1 in sera from patients with rheumatoid arthritis. Arthritis Rheum 1995;38(7):969–75.

I. OVERVIEW OF POLYPHENOLS AND HEALTH

REFERENCES

[20] Lorenzl S, Albers DS, Relkin N, Ngyuen T, Hilgenberg SL, Chirichigno J, et al. Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int 2003;43(3):191–6. [21] Teronen O, Heikkil€a P, Konttinen YT, Laitinen M, Salo T, Hanemaaijer R, et al. MMP inhibition and downregulation by bisphosphonates. Ann N Y Acad Sci 1999;878:453–65. [22] Soory M. A role for non-antimicrobial actions of tetracyclines in combating oxidative stress in periodontal and metabolic diseases: a literature review. Open Dent J 2008;2:5–12. [23] Mannello F. Natural bio-drugs as matrix metalloproteinase inhibitors: new perspectives on the horizon? Recent Pat Anticancer Drug Discov 2006;1(1):91–103. [24] Scharffetter-Kochanek K, Brenneisen P, Wenk J, Herrmann G, Ma W, Kuhr L, et al. Photoaging of the skin from phenotype to mechanisms. Exp Gerontol 2000;35(3):307–16. [25] Kim JH, Cho YH, Park SM, Lee KE, Lee JJ, Lee BC, et al. Antioxidants and inhibitor of matrix metalloproteinase-1 expression from leaves of Zostera marina L. Arch Pharm Res 2004;27 (2):177–83. [26] Aslam MN, Lansky EP, Varani J. Pomegranate as a cosmeceutical source: pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells. J Ethnopharmacol 2006;103(3):311–8. [27] Lim H, Kim HP. Inhibition of mammalian collagenase, matrix metalloproteinase-1, by naturally-occurring flavonoids. Planta Med 2007;73(12):1267–74. [28] Hwang YP, Oh KN, Yun HJ, Jeong HG. The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cells. J Dermatol Sci 2011;61(1):23–31. [29] Jung H, Lee EH, Lee TH, Cho MH. The methoxyflavonoid isosakuranetin suppresses UV-B-induced matrix metalloproteinase-1 expression and collagen degradation relevant for skin photoaging. Int J Mol Sci 2016;17(9):1449. [30] Sim GS, Lee BC, Cho HS, Lee JW, Kim JH, Lee DH, et al. Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVAirradiated human dermal fibroblast. Arch Pharm Res 2007;30 (3):290–8. [31] Lu W, Zhu J, Zou S, Li X, Huang J. The efficient expression of human fibroblast collagenase in Escherichia coli and the discovery of flavonoid inhibitors. J Enzyme Inhibit Med Chem 2013;28 (4):741–6. [32] Chen C, Zhang C, Cai L, Xie H, Hu W, Wang T, et al. Baicalin suppresses IL-1β-induced expression of inflammatory cytokines via blocking NF-κB in human osteoarthritis chondrocytes and shows protective effect in mice osteoarthritis models. Int Immunopharmacol 2017;52:218–26. [33] Kobayashi M, Squires GR, Mousa A, Tanzer M, Zukor DJ, Antoniou J, et al. Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum 2005;52(1):128–35. [34] Zheng W, Tao Z, Cai L, Chen C, Zhang C, Wang Q, et al. Chrysin attenuates IL-1β-induced expression of inflammatory mediators by suppressing NF-κB in human osteoarthritis chondrocytes. Inflammation 2017;40(4):1143–54. [35] Xing D, Gao H, Liu Z, Zhao Y, Gong M. Baicalin inhibits inflammatory responses to interleukin-1β stimulation in human chondrocytes. J Interf Cytokine Res 2017;37(9):398–405. [36] Lim H, Park H, Kim HP. Effects of flavonoids on matrix metalloproteinase-13 expression of interleukin-1β-treated articular chondrocytes and their cellular mechanisms: inhibition of c-Fos/ AP-1 and JAK/STAT signaling pathways. J Pharmacol Sci 2011;116(2):221–31.

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[37] Garbisa S, Sartor L, Biggin S, Salvato B, Benelli R, Albini A. Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate. Cancer 2001;91(4):822–32. [38] Cheng XW, Kuzuya M, Kanda S, Maeda K, Sasaki T, Wang QL, et al. Epigallocatechin-3-gallate binding to MMP-2 inhibits gelatinolytic activity without influencing the attachment to extracellular matrix proteins but enhances MMP-2 binding to TIMP-2. Arch Biochem Biophys 2003;415(1):126–32. [39] Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, et al. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties inA431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 1999;128(5):999–1010. [40] Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, et al. Quercetin inhibition of tumor invasion via suppressing PKC delta/ ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 2008;29(9):1807–15. [41] Saragusti AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando GA. Inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur J Pharmacol 2010;644(1-3):138–45. [42] Lan H, Hong W, Fan P, Qian D, Zhu J, Bai B. Quercetin inhibits cell migration and invasion in human osteosarcoma cells. Cell Physiol Biochem 2017;43(2):553–67. [43] Huang X, Chen S, Xu L, Liu Y, Deb DK, Platanias LC, et al. Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 2005;65(8):3470–8. [44] Li Y, Che M, Bhagat S, Ellis KL, Kucuk O, Doerge DR. Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia 2004;6(4):354–63. [45] Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y, et al. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res 2002;62(4):1025–9. [46] Kawabata K, Murakami A, Ohigashi H. Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells. Biosci Biotechnol Biochem 2005;69(2):307–14. [47] Matchett MD, MacKinnon SL, Sweeney MI, Gottschall-Pass KT, Hurta RA. Blueberry flavonoids inhibit matrix metalloproteinase activity in DU145 human prostate cancer cells. Biochem Cell Biol 2005;83(5):637–43. [48] Zheng W, Lu S, Cai H, Kang M, Qin W, Li C, et al. Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway. Oncol Lett 2016;12(4):2761–5. [49] Rui X, Yan XI, Zhang K. Baicalein inhibits the migration and invasion of colorectal cancer cells via suppression of the AKT signaling pathway. Oncol Lett 2016;11(1):685–8. [50] Chai Y, Xu J, Yan B. The anti-metastatic effect of baicalein on colorectal cancer. Oncol Rep 2017;37(4):2317–23. [51] Choi EO, Cho EJ, Jeong JW, Park C, Hong SH, Hwang HJ. Baicalein inhibits the migration and invasion of B16F10 mouse melanoma cells through inactivation of the PI3K/Akt signaling pathway. Biomol Ther 2017;25(2):213–21. [52] Buddhan R, Manoharan S. Diosmin reduces cell viability of A431 skin cancer cells through apoptotic induction. J Cancer Res Ther 2017;13(3):471–6. [53] Kong CS, Kim YA, Kim MM, Park JS, Kim JA, Kim SK, et al. Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells. Toxicol in Vitro 2008;22(7):1742–8.

I. OVERVIEW OF POLYPHENOLS AND HEALTH

40

4. POLYPHENOLIC FLAVONOIDS AND METALLOPROTEASE INHIBITION

[54] Crascì L, Basile L, Panico A, Puglia C, Bonina FP, Basile PM, et al. Correlating in vitro target-oriented screening and docking: inhibition of matrix metalloproteinases activities by flavonoids. Planta Med 2017;83(11):901–11. [55] Sun X, Becker M, Pankow K, Krause E, Ringling M, Beyermann M, et al. Catabolic attacks of membrane-bound angiotensin-converting enzyme on the N-terminal part of species-specific amyloid-beta peptides. Eur J Pharmacol 2008;588(1):18–25. [56] Igi
c R, Behnia R. Properties and distribution of angiotensin I converting enzyme. Curr Pharm Des 2003;9(9):697–706. [57] Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domainspecific inhibitor design. J Mol Biol 2006;357(3):964–74. [58] Anthony CS, Masuyer G, Sturrock ED, Acharya KR. Structure based drug design of angiotensin-I converting enzyme inhibitors. Curr Med Chem 2012;19(6):845–55. [59] Hagaman JR, Moyer JS, Bachman ES, Sibony M, Magyar PL, Welch JE, et al. Angiotensin-converting enzyme and male fertility. Proc Natl Acad Sci U S A 1998;95(5):2552–7. [60] Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 2002;23(4):177–83. [61] Zhao Y, Xu C. Structure and function of angiotensin converting enzyme and its inhibitors. Chin J Biotechnol 2008;24(2):171–6. [62] Sica DA. Angiotensin-converting enzyme inhibitors side effects— physiologic and non-physiologic considerations. J Clin Hypertens 2004;6(7):410–6. [63] Jiang F, Dusting GJ. Natural phenolic compounds as cardiovascular therapeutics: potential role of their antiinflammatory effects. Curr Vasc Pharmacol 2003;1(2):135–56. [64] Gan RY, Xu XR, Song FL, Kuang L, Li HB. Antioxidant activity and total phenolic content of medicinal plants associated with prevention and treatment of cardiovascular and cerebrovascular diseases. J Med Plants Res 2010;4(22):2438–44. [65] Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001;158(1):195–8. [66] Deo P, Hewawasam E, Karakoulakis A, Claudie DJ, Nelson R, Simpson BS, et al. In vitro inhibitory activities of selected Australian medicinal plant extracts against protein glycation, angiotensin converting enzyme (ACE) and digestive enzymes linked to type II diabetes. BMC Complement Altern Med 2016;16(1):435. [67] Sharifi N, Souri E, Ziai SA, Amin G, Amanlou M. Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay. Daru 2013;21 (1):74. [68] Persson IA, Josefsson M, Persson K, Andersson RG. Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells. J Pharm Pharmacol 2006;58(8):1139–44. [69] Wagner H, Elbl G, Lotter H, Guinea M. Evaluation of natural products as inhibitors of angiotensin-I-converting enzyme (ACE). Pharm Pharmacol Lett 1991;1:15–8. [70] Lacaille-Dubois FU, Wagner H. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants. Phytomedicine 2001;8(1):47–52. [71] Actis-Goretta L, Ottaviani JI, Keen CL, Fraga CG. Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett 2003;555(3):597–600.

[72] Persson IA, Persson K, Andersson RG. Effect of Vaccinium myrtillus and its polyphenols on angiotensin-converting enzyme activity in human endothelial cells. J Agric Food Chem 2009;57(11):4626–9. [73] Kwon EK, Lee DY, Lee H, Kim DO, Baek NI, Kim YE, et al. Flavonoids from the buds of Rosa damascena inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme a reductase and angiotensin I-converting enzyme. J Agric Food Chem 2010;58 (2):882–6. [74] Ojeda D, Jim
enez-Ferrer E, Zamilpa A, Herrera-Arellano A, Tortoriello J, Alvarez L. Inhibition of angiotensin converting enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. J Ethnopharmacol 2010;127(1):7–10. [75] Loizzo MR, Tundis R, Conforti F, Statti GA, Menichini F. Inhibition of angiotensin converting enzyme activity by Senecio Species. Pharm Biol 2009;47(6):516–20. [76] Balasuriya BWN, Rupasinghe HPV. Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension. Funct Foods Health Dis 2011;1(5):172–88. [77] Kiss A, Kowalski J, Melzig MF. Compounds from Epilobium angustifolium inhibit the specific metallopeptidases ACE, NEP and APN. Planta Med 2004;70(10):919–23. [78] Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A, et al. Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (simaroubaceae). Phytother Res 2007;21(1):32–6. [79] Oh H, Kang DG, Kwon JW, Kwon TO, Lee SY, Lee DB, et al. Isolation of angiotensin converting enzyme (ACE) inhibitory flavonoids from Sedum sarmentosum. Biol Pharm Bull 2004;27(12):2035–7. [80] Alu’datt MH, Rababah T, Alhamad MN, Al-Mahasneh MA, Ereifej K, Al-Karaki G. Profiles of free and bound phenolics extracted from Citrus fruits and their roles in biological systems: content, and antioxidant, anti-diabetic and anti-hypertensive properties. Food Funct 2017;8:3187–97. [81] Kwon YI, Vattem DA, Shetty K. Evaluation of clonal herbs of Lamiaceae species for management of diabetes and hypertension. Asia Pac J Clin Nutr 2006;15(1):107–18. [82] Pinto MDS, Kwon YI, Apostolidis E, Lajolo FM, Genovese MI, Shetty K. Evaluation of red currants (Ribes rubrun L.), black currents (Ribes nigrum L.), red and green gooseberries (Ribes uva-crispa) for potential management of type 2 diabetes and hypertension using in vitro models. J Food Biochem 2010;34:639–60. [83] Jung HA, Hyun SK, Kim HR, Choi JS. Angiotensin-converting enzyme inhibitory activity of phlorotannins from Ecklonia stolonifera. Fish Sci 2006;72(6):1292–9. [84] Wijesinghe WA, Ko SC, Jeon YJ. Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity. Nutr Res Pract 2011;5(2):93–100. [85] Nagappan H, Pee PP, Kee SHY, Ow JT, Yan SW, Chew LY, Kong KW. Malaysian brown seaweeds Sargassum siliquosum and Sargassum polycystum: low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and αglucosidase inhibition activities. Food Res Int 2017;99(Pt 2):950–8. [86] Bormann H, Melzig MF. Inhibition of metallopeptidases by flavonoids and related compounds. Pharmazie 2000;55(2):129–32. [87] Guerrero L, Castillo J, Quiñones M, Garcia-Vallv
e S, Arola L, Pujadas G, et al. Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PLoS One 2012;7(11):e49493.

I. OVERVIEW OF POLYPHENOLS AND HEALTH