Cardiovascular disease (CVD)-associated thrombosis are the most threatening cause of death worldwide. To resolve this crisis, efforts must be made to discover antithrombotic compounds for development of therapeutic agents with novel mechanisms of action, higher efficacy, and less adverse effects. It might also impact on the development of nutraceuticals to ameliorate vascular disease, and the development of appropriate diets to prevent CVDs. Recently, the research on antithrombotic compounds from edible natural sources increased swiftly by demand, and there has been remarkable progress. This review article covers bioactive components with antithrombotic activity that have been investigated in recent 5 years, more focused on the chemical structure classification (phenolics, polysaccharides, peptides, terpenes, and so on) and their original natural sources (traditional medicines, plants, animals, and foods).
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References
1.
World Health Organization: Cardiovascular Diseases. www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (accessed May17, 2017).
2.
IslamA, AlamF, KhalilI, SasongkoTH, GanSH: Natural products towards the discovery of potential future antithrombotic drugs. Curr Pharm Des, 2016; 22:2926–2946.
3.
FaresA: Winter cardiovascular diseases phenomenon. N Am J Med Sci, 2013; 5:66e279.
4.
FuentesEJ, AstudilloLA, GutiérrezMI, ContrerasSO, BustamanteLO, RubioPI, Moore-CarrascoR, AlarcónMA, FuentesJA, GonzálezDE, PalomoIF: Fractions of aqueous and methanolic extracts from tomato (Solanum lycopersicum L.) present platelet antiaggregant activity. Blood Coagul Fibrinolysis, 2012; 23:109–117.
5.
HuFB: Plant-based foods and prevention of cardiovascular disease: An overview. Am J Clin Nutr, 2003; 78:544S–551S.
6.
DasL, BhaumikE, RaychaudhuriU, ChakrabortyR: Role of nutraceuticals in human health. J Food Sci Tech, 2012; 49:173–183.
7.
GriffithsJC, AbernethyDR, SchuberS, WilliamsRL: Functional food ingredient quality: Opportunities to improve public health by compendial standardization. J Funct Foods, 2009; 1:128–130.
8.
SahebkarA, CiceroAFG, Simental-MendíaLE, AggarwalBB, GuptaSC: Curcumin downregulates human tumor necrosis factor-α levels: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res, 2016; 107:234–242.
FuentesE, PalomoI: Antiplatelet effects of natural bioactive compounds by multiple targets: Food and drug interactions. J Funct Foods, 2014; 6:73–81.
11.
CiceroAFG, CollettiA: Food and plant bioactives for reducing cardiometabolic disease: How does the evidence stack up?. Trends Food Sci Technol, 2017; 69:192–202.
12.
ShuklaSK, GuptaS, OjhaSK, SharmaSB: Cardiovascular friendly natural products: A promising approach in the management of CVD. Nat Prod Res, 2010; 24:873–898.
13.
ChaturvediSK: Natural products as the source of anti-thrombotic drugs. Acta Cienc Indica Chem, 2003; 29:81–82.
14.
BeretzA, CazenaveJP: Old and new natural products as the source of modern antithrombotic drugs. Planta Medica, 1991; 57:S68–S72.
15.
LiHX, HanSY, WangXW, MaX, ZhangK, WangL, MaZZ, TuPF: Effect of the carthamins yellow from Carthamus tinctorius L. on hemorheological disorders of blood stasis in rats. Food Chem Toxicol, 2009; 47:1797–1802.
16.
LiuY, LaiXY, LingXM, ZhaoYY, CuiJR: Interactions between thrombin with flavonoids from Abelmoschus manihot (L.) Medicus by CZE. Chromatographia, 2006; 64:45–50.
17.
SinghB, KaurP, SinghGRD, AhujaPS: Biology and chemistry of Ginkgo biloba. Fitoterapia, 2008; 79:401–418.
18.
RenaudS, De LorgerilM: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet, 1992; 339:1523–1526.
19.
De GaetanoG, De CurtisA, Di CastelnuovoA, DonatiMB, IacovielloL, RotondoS: Antithrombotic effect of polyphenols in experimental models. Ann N Y Acad Sci, 2002; 957:174–188.
20.
WangX, OuyangYY, LiuJ, ZhaoG: Flavonoid intake and risk of CVD: A systematic review and meta-analysis of prospective cohort studies. Br J Nutr, 2014; 111:1–11.
21.
YamamotoJ, NaemuraA, UraM, IjiriY, YamashitaT, KuriokaA, KoyamaA: Testing various fruits for anti-thrombotic effect: i. Mulberries. Platelets, 2006; 17:555–564.
22.
HsiaoG, ChangCY, ShenMY, ChouDS, TzengSH, ChenTF, SheuJR: Alpha-Naphthoflavone, a potent antiplatelet flavonoid, is mediated through inhibition of phospholipase C activity and stimulation of cyclic GMP formation. J Agric Food Chem, 2005; 53:5179–5186.
23.
SheuJR, HsiaoG, ChouPH, ShenMY, ChouDS: Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem, 2004; 52:4414–4418.
24.
WrightB, MoraesLA, KempCF, MullenW, CrozierA, LovegroveJA, GibbinsJM: A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids. Br J Pharm, 2010; 159:1312–1325.
25.
JinYR, ImJH, ParkES, ChoMR, HanXH, LeeJJ, LimY, KimTJ, YunYP: Antiplatelet activity of epigallocatechin gallate is mediated by the inhibition of PLCgamma2 phosphorylation, elevation of PGD2 production, and maintaining calcium-ATPase activity. J Cardiovasc Pharmacol, 2008; 51:45–54.
26.
LiPG, SunL, HanX, LingS, GanWT, XuJW: Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt-independent and PKA-dependent mechanism. Pharmacology, 2012; 89:220–228.
27.
OhWJ, EndaleM, ParkSC, ChoJY, RheeMH: Dual roles of quercetin in platelets: Phosphoinositide-3-kinase and MAP kinases inhibition, and cAMP-dependent vasodilator-stimulated phosphoprotein stimulation. Evid Based Complement Alternat Med, 2012; 2012:485262.
28.
McNicolA: The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostag Leukotr Ess, 1993; 48:379–384.
29.
MunozY, GarridoA, ValladaresL: Equol is more active than soy isoflavone itself to compete for binding to thromboxane A(2) receptor in human platelets. Thromb Res, 2009; 123:740–744.
30.
KondoK, SuzukiY, IkedaY, UmemuraK: Genistein, an isoflavone included in soy, inhibits thrombotic vessel occlusion in the mouse femoral artery and in vitro platelet aggregation. Eur J Pharmacol, 2002; 455:53–57.
31.
GuerreroJA, LozanoML, CastilloJ, Benavente-GarciaO, VicenteV, RiveraJ: Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor. J Thromb Haemost, 2005; 3:369–376.
32.
Navarro-NunezL, LozanoML, PalomoM, MartinezC, VicenteV, CastilloJ, Benavente-GarciaO, Diaz-RicartM, EscolarG, RiveraJ: Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway. J Agric Food Chem, 2008; 56:2970–2976.
33.
LeeW, BaeJS: Antithrombotic and antiplatelet activities of orientin in vitro and in vivo. J Funct Foods, 2015; 17:388–398.
34.
ZhangJ, ChuCJ, LiX, YaoS, YanB, RenHL: Isolation and identification of antioxidant compounds in Vaccinium bracteatum Thunb. by UHPLC-Q-TOF LC/MS and their kidney damage protection. J Funct Foods, 2014; 11:62–70.
35.
NairAGR, GunasegaranR, JoshiS: Chemical investigation of some South Indian plants. Ind J Chem B, 1982; 21:979–986.
36.
Uma DeviP, GanasoundariA, RaoBSS: Srinivasan KK: In vivo radioprotection by Ocimum flavonoids: Survival of mice. Radiat Res, 1999; 151:74–78.
37.
LiuZ, WangL, LiW, HuangY, XuZC: Determination of orientin and vitexin in Trollius chinesis preparation by HPLC. J Chinese Materia Medica, 2004; 29:1049–1051.
38.
ShibanoM, KakutaniK, TaniguchiM, YasudaM, BabaK: Antioxidant constituents in the dayflower (Commelina communis L.) and their α-glucosidase-inhibitory activity. J Nat Med, 2008; 62:349–353.
39.
LeeJH, KimM, ChangKH, HongCY, NaCS, DongMS, LeeD, LeeMY: Antiplatelet effects of Rhus verniciflua Stokes heartwood and its active constituents—fisetin, butein, and sulfuretin—in rats. J Med Food, 2014; 17:1–10.
40.
ChenXQ, WangXB, GuanRF, TuJ, GongZH, ZhengN, YangJH, ZhangYY, YingMM: Blood anticoagulation and antiplatelet activity of green tea (−)-epigallocatechin (EGC) in mice. Food Funct, 2013; 4:1521–1525.
41.
KuSK, YoonEK, LeeW, KwonS, LeeT, BaeJS: Antithrombotic and antiplatelet activities of pelargonidin in vivo and in vitro. Arch Pharm Res, 2016; 39:398–408.
42.
ThompsonK, PederickW, SinghI, SanthakumarAB: Anthocyanin supplementation in alleviating thrombogenesis in overweight and obese population: A randomized, double-blind, placebo-controlled study. J Funct Foods, 2017; 32:131–138.
43.
SanthakumarAB, KundurAR, SabapathyS, StanleyR, SinghI: The potential of anthocyanin-rich Queen Garnet plum juice supplementation in alleviating thrombotic risk under induced oxidative stress conditions. J Funct Foods, 2015; 14:747–757.
44.
LeeW, BaeJS: Antithrombotic and antiplatelet activities of vicenin-2. Blood Coagul Fibrinolysis, 2015; 26:628–634.
45.
YoonEK, KuSK, LeeW, KwakS, KangH, JungB, BaeJS: Antitcoagulant and antiplatelet activities of scolymoside. BMB Rep, 2015; 48:577–582.
46.
KwonSU, LeeHY, XinM, JiSJ, ChoHK, KimDS, KimDK, LeeYM: Antithrombotic activity of Vitis labrusca extract on rat platelet aggregation. Blood Coagul Fibrinolysis, 2016; 27:141–146.
47.
Del TurcoS, SartiniS, CigniS, SentieriC, SbranaS, BattagliaD, PapaA, Da SettimoF, La MottaC, BastaG: Synthetic analogues of flavonoids with improved activity against platelet activation and aggregation as novel prototypes of food supplements. Food Chem, 2014; 175:494–499.
48.
LuzakB, GolanskiJ, PrzygodzkiT, BonclerM, SosnowskaD, OszmianskiJ, WatalaC, RozalskiM: Extract from spent hop (Humulus lupulus L.) reduces blood platelet aggregation and improves anticoagulant activity of human endothelial cells in vitro. J Funct Foods, 2016; 22:257–269.
49.
LeeW, KuSK, KimMA, BaeJS: Anti-factor Xa activities of zingerone with anti-platelet aggregation activity. Food Chem Tox, 2017; 105:186–193.
50.
VeachD, HoskingH, ThompsonK, SanthakumarAB: Anti-platelet and anti-thrombogenic effects of shikimic acid in sedentary population. Food Funct, 2016; 7:3609–3616.
51.
ChoiJH, KimS: Mechanisms of attenuation of clot formation and acute thromboembolism by syringic acid in mice. J Funct Foods, 2018; 43:112–122.
KhannaS, DasA, SpieldennerJ, RinkC, RoyS: Supplementation of a standardized extract from Phyllanthus emblica improves cardiovascular risk factors and platelet aggregation in overweight/class-1 obese adults. J Med Food, 2015; 18:415–420.
54.
FuentesE, AlarcónM, FuentesM, CarrascoG, PalomoI: A novel role of Eruca sativa Mill. (rocket) extract: Antiplatelet (NF-κB inhibition) and antithrombotic activities. Nutrients, 2014; 6:5839–5852.
55.
OlsonST, BjorkI: Mechanism of action of heparin and heparin-like antithrombotics. Perspect Drug Discov, 1993; 1:479–501.
56.
KeltonJG, WarkentinTE: Heparin-induced thrombocytopenia: A historical perspective. Blood, 2008; 112:2607–2616.
AnandS, YusufS, PogueJ, GinsbergJ, HirshJ: Relationship of activated partial thromboplastin time to coronary events and bleeding in patients with acute coronary syndromes who receive heparin. Circulation, 2003; 107:2884–2888.
59.
OlsonST, HalvorsonHR, BjörkI: Quantitative characterization of the thrombin-heparin interaction. Discrimination between specific and nonspecific binding models. J Biol Chem, 1991; 266:6342–6352.
60.
MinSJ, KwonOC, LeeS, ParkKH, KimJK: An antithrombotic fucoidan, unlike heparin, does not prolong bleeding time in a murine arterial thrombosis model: A comparative study of Undaria pinnatifida sporophylls and Fucus vesiculosus. Phytother Res, 2012; 26:752–757.
61.
DoreCM, das C Faustino AlvesMG, WillLS, CostaTG, SabryDA, de Souza RêgoLA, AccardoCM, RochaHA, FilgueiraLG, LeiteEL: A sulfated polysaccharide, fucans, isolated from brown algae Sargassum vulgare with anticoagulant, antithrombotic, antioxidant and anti-inflammatory effects. Carbohydr Polym, 2013; 91:467–475.
62.
WangJ, LianP, YuQ, WeiJ, KangW: Antithrombotic mechanism of polysaccharides in blackberry (Rubus spp.) seeds. Food Nutr Res, 2017; 61:1379862.
63.
LiuX, HaoJ, ShanX, ZhangX, ZhaoX, LiQ, WangX, CaiC, LiG, YuG: Antithrombotic activities of fucosylated chondroitin sulfates and their depolymerized fragments from two sea cucumbers. Carbohydr Polym, 2016; 152:343–350.
64.
LiY, LiJ, LiuT, WangY, ZhouZ, ChengF, FengC, ChengX, LiuH, ChenX: Preparation and antithrombotic activity identification of Perinereis aibuhitensis extract: A high temperature and wide pH range stable biological agent. Food Funct, 2017; 8:3533–3541.
65.
WangY, ShaoJ, YaoS, ZhangS, YanJ, WangH, ChenY: Study on the antithrombotic activity of Umbilicaria esculenta polysaccharide. Carbohydr Polym, 2014; 105:231–236.
66.
SumiH, HamadaH, TsushimaH, MiharaH, MurakiH: A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia, 1987; 43:1110–1111.
67.
RyuGH, ParkS, HanDK, KimYH, MinB: Antithrombotic activity of a lumbrokinase immobilized polyurethane surface. ASAIO J, 1993; 39:M314–M318.
68.
ChakrabartiS, JahandidehF, WuJ: Food-derived bioactive peptides on inflammation and oxidative stress. Biomed Res Int, 2014; 2014:608979.
69.
YuG, WangF, ZhangB, FanJ: In vitro inhibition of platelet aggregation by peptides derived from oat (Avena sativa L.), highland barley (Hordeum vulgare Linn. var. nudum Hook. f.), and buckwheat (Fagopyrum esculentum Moench) proteins. Food Chem, 2016; 194:577–586.
70.
TuM, FengL, WangZ, QiaoM, ShahidiF, LuW, DuM: Sequence analysis and molecular docking of antithrombotic peptides from casein hydrolysate by trypsin digestion. J Funct Foods, 2017; 32:313–323.
71.
ZhangSB: In vitro antithrombotic activities of peanut protein hydrolysates. Food Chem, 2016; 202:1–8.
72.
SabbioneAC, NardoAE, AñónMC, ScilingoA: Amaranth peptides with antithrombotic activity released by simulated gastrointestinal digestion. J Funct Foods, 2016; 20:204–214.
73.
Herrera-ChaléF, Ruiz-RuizJC, Betancur-AnconaD, Segura-CamposMR: Potential therapeutic applications of Mucuna pruriens peptide fractions purified by high-performance liquid chromatography as angiotensin-converting enzyme inhibitors, antioxidants, antithrombotic and hypocholesterolemic agents. J Med Food, 2016; 19:187–195.
74.
Herrera-ChaléF, Ruiz-RuizJC, Betancur-AnconaD, Acevedo-FernándezJJ, Segura-CamposMR: The hypolipidemic effect and antithrombotic activity of Mucuna pruriens protein hydrolysates. Food Funct, 2016; 7:434–444.
75.
KongY, HuangSL, ShaoY, LiS, WeiJF: Purification and characterization of a novel antithrombotic peptide from Scolopendra subspinipes mutilans. J Ethnopharmacol, 2013; 145:182–186.
76.
KongY, LiS, ShaoY, HeZ, ChenM, MingX, WeiJ: Antithrombotic peptides from Scolopendra subspinipes mutilans hydrolysates, Int J Pept Res Ther, 2014; 20:245–252.
77.
BiQ, HanB, FengY, JiangZ, YangY, LiuW: Antithrombotic effects of a newly purified fibrinolytic protease from Urechis unicinctus. Thromb Res, 2013; 132:e135–e144.
78.
Mendes-SilvaW, AssafimM, RutaB, MonteiroRQ, GuimarãesJA, ZingaliRB: Antithrombotic effect of Glycyrrhizin, a plant-derived thrombin inhibitor. Thromb Res, 2003; 112:93–98.
79.
ZhangPC, ZhouYJ, XuSX: Two novel flavonoid glycosides from Crataegus pinnatifida Bge.var.major N.E.Br. J Asian Nat Prod Res, 2001; 3:77–82.
80.
ZhouCC, HuangXX, GaoPY, LiFF, LiDM, LiLZ, SongSJ: Two new compounds from Crataegus pinnatifida and their antithrombotic activities. J Asian Nat Prod Res, 2014; 16:169–174.
81.
GaoPY, LiLZ, LiuKC, SunC, SunX, WuYN, SongSJ: Natural terpenoid glycosides with in vitro/vivo antithrombotic profiles from the leaves of Crataegus pinnatifida. RSC Adv, 2017; 7:48466.
82.
LiLZ, GaoPY, SongSJ, YuanYQ, LiuCT, HuangXX, LiuQB: Monoterpenes and flavones from the leaves of Crataegus pinnatifida with anticoagulant activities. J Funct Foods, 2015; 12:237–245.
83.
KooHJ, LimKH, JungHJ, ParkEH: Anti-inflammatory evaluation of Gardenia extract, geniposide and genipin. J Ethnopharmacol, 2006; 103:496–500.
84.
SuzukiY, KondoK, IkedaY, UmemuraK: Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. Planta Med, 2001; 67:807–810.
85.
ZhangHY, LiuH, YangM, WeiSF: Antithrombotic activities of aqueous extract from Gardenia jasminoides and its main constituent. Pharm Biol, 2013; 51:221–225.
86.
TangW, CaoJ, ZhangX, ZhaoY: Osmanthus fragrans seeds, a source of secoiridoid glucosides and its antioxidizing and novel platelet-aggregation inhibiting function, J Funct Foods, 2015; 12:337–344.
87.
DahmerT, BergerM, BarletteAG, ReckJJr., SegalinJ, VerzaS, OrtegaGG, GnoattoSC, GuimarãesJA, VerliH, GosmannG: Antithrombotic effect of chikusetsusaponin IVa isolated from Ilex paraguariensis (maté). J Med Food, 2012; 15:1073–1080.
88.
XieP, ZhangY, WangX, WeiJ, KangW: Antithrombotic effect and mechanism of Rubus spp. blackberry. Food Funct, 2017; 8:2000–2012.
89.
BadimonL, VilahurG, PadroT: Nutraceuticals and atherosclerosis: Human trials. Cardiovasc Ther, 2010; 28:202–215.
90.
KontogianniVG, TsoumaniME, KelliciTF, MavromoustakosT, GerothanassisIP, TselepisAD, TzakosAG: Deconvoluting the dual antiplatelet activity of a plant extract. J Agri Food Chem, 2016; 64:4511–4521.
91.
ShibataM, NoguchiR, SuzukiM, et al.: Pharmacological studies on medicinal plant components. I. On the extracts of Ophiopogon and some folk medicine. Proc Hoshi Pharm, 1979; 13:66–76.
92.
ZhangYL, XiMZ, ChoiYB, LeeBH: Antithrombotic effect of fermented Ophiopogon japonicas in thrombosis-induced rat models. J Med Food, 2017; 20:637–645.
93.
LeeW, LeeJ, KulkarniR, KimMA, HwangJS, NaM, BaeJS: Antithrombotic and antiplatelet activities of small-molecule alkaloids from Scolopendra subspinipes mutilans. Sci Rep, 2016; 6:21956.
94.
LeeW, KimMA, ParkI, HwangJS, NaM, BaeJS: Novel direct factor Xa inhibitory compounds from Tenebrio molitor with anti-platelet aggregation activity. Food Chem Toxicol, 2017; 105:9–27.
95.
LeeJ, LeeW, KimMA, HwangJS, NaM, BaeJS: Inhibition of platelet aggregation and thrombosis by indole alkaloids isolated from the edible insect Protaetia brevitarsis seulensis (Kolbe). J Cell Mol Med, 2017; 21:1217–1227.
96.
WuJN, HoSC, ZhouC, LingWH, ChenWQ, WangCL, ChenYM: Coffee consumption and risk of coronary heart diseases: A meta-analysis of 21 prospective cohort studies. Int J Cardiol, 2009; 137:216−225.
97.
KalaskaB, PiotrowskiL, LeszczynskaA, MichalowskiB, KramkowskiK, KaminskiT, AdamusJ, MarcinekA, GebickiJ, MogielnickiA, BuczkoW: Antithrombotic effects of pyridinium compounds formed from trigonelline upon coffee roasting. J Agric Food Chem, 2014; 62:2853–2860.
98.
KuSK, KimJA, HanCK, BaeJS: Antithrombotic activities of epi-sesamin in vitro and in vivo. Am J Chin Med, 2013; 41:1313–1327.
99.
ShiYN, ShiYM, YangL, LiXC, ZhaoJH, QuY, ZhuHT, WangD, ChengRR, YangCR, XuM, ZhangYJ: Lignans and aromatic glycosides from Piper wallichii and their antithrombotic activities. J Ethnopharmacol, 2015; 162:87–96.
100.
LeeDS, KimTH, JungYS: Inhibitory effect of allyl isothiocyanate on platelet aggregation. J Agric Food Chem, 2014; 62:7131–7139.
