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Evidence-Based Complementary and Alternative Medicine
Volume 2013 (2013), Article ID 861786, 10 pages
http://dx.doi.org/10.1155/2013/861786
Review Article

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products

1Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Programa de Investigacion de Excelencia Interdisciplinaria en Envejecimiento Saludable (PIEI-ES), Universidad de Talca, 3460000 Talca, Chile
2Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule, R09I2001 Talca, Chile

Received 14 June 2013; Accepted 23 September 2013

Academic Editor: Vassya Bankova

Copyright © 2013 Eduardo Fuentes and Iván Palomo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Platelets are no longer considered simply as cells participating in thrombosis. In atherosclerosis, platelets are regulators of multiple processes, with the recruitment of inflammatory cells towards the lesion sites, inflammatory mediators release, and regulation of endothelial function. The antiplatelet therapy has been used for a long time in an effort to prevent and treat cardiovascular diseases. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy. In this context, a large number of natural products (polyphenols, terpenoids, alkaloids, and fatty acids) have been reported with antiplatelet activity. In this sense, the present paper describes mechanisms of antiplatelet action of natural products on platelet P-selectin expression through cAMP levels and its role as peroxisome proliferator-activated receptors agonists.

1. Introduction

Cardiovascular diseases (CVD) result in >19 million deaths annually and coronary heart disease accounts for the majority of this toll. Actually a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms [1]. The incidence and prevalence of CVD have increased significantly in recent years [24] and are regulated by both genetic and environmental factors (dyslipidemia, hypertension, smoking, diabetes, and obesity) [5, 6].

Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis and the activation is a critical component of atherothrombosis [7]. Thus patients with unstable complex lesions had a fivefold higher expression of the platelet activation epitope CD63 than patients with stable angina, indicating an intense thrombogenic potential [8]. Platelets also interact directly with other cells of the immune system in physiological and pathological conditions [9, 10]. Platelet-derived P-selectin seems to contribute to atherosclerotic lesion development and arterial thrombogenesis by forming large stable platelet-leukocyte aggregates [11]. In this context, the percentage of neutrophil-platelet conjugates increased by 22% in patients with unstable angina pectoris [12]. Also platelets can be directly involved in the plaque unstable by the production and release of proinflammatory molecules, including a variety of cytokines, such as TGF-β, IL-1β, and sCD40L, and chemokines, such as CXCL7, CXCL4, CXCL4L1, CCl5, CXCL1, CXCL8, CXCL5, CXCL12, CCL2, and CCL3 [13, 14].

The antiplatelet therapy has been used for a long time in an effort to prevent and treat CVD [15, 16]. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy [17, 18]. Therefore, there is much room for further improvement of antiplatelet treatment and search of novel antiplatelet agents with increased efficacy and safety profile. In this context, a large number of natural products (polyphenols, terpenoids, alkaloids, and fatty acids, among others) have been reported with an inhibitory activity on platelets function [19].

Interestingly, some natural compounds consumed regularly in the diet may have protective effects in primary and secondary prevention of CVD [20, 21]. In this context, a great deal of interest has been paid by consumers towards natural bioactive compounds as functional ingredients in diets due to their various beneficial health effects [2225]. Natural bioactive compounds from fruit, vegetables, beverages, and grass among others have antiplatelet effects and may thus affect the development of CVD [26].

In this sense, the present paper describes mechanisms of antiplatelet action of natural products by PPARs signaling pathway and inhibit of platelet P-selectin expression through of cAMP.

2. Regulation of Platelet cAMP Levels by PPARs

The PPARs consist of three nuclear receptor isoforms (γ, β/δ, and α) [27]. PPARs are key regulators of metabolic syndrome and play an important role in the processes that govern chronic inflammatory diseases [28, 29]. Thus PPARs remain attractive therapeutic targets for the development of drugs used in the treatment of chronic inflammatory diseases such as atherosclerosis [30]. PPAR-δ antagonizes multiple proinflammatory pathways [31] and is pivotal to control the program for fatty acid oxidation in the skeletal muscle [32].

PPARs modulate atherosclerosis development by acting at both metabolic and vascular levels [33]. Thus PPARs activation is a key mechanism for improving cardiovascular function resulting from weight loss [3436]. PPARs are expressed in human platelets [37]. In this context, PPARs appear to play a major role in the regulation of atherogenesis by countering the inflammation-provoking action of platelet adhesion and activation [38]. The antiplatelet activity of statins and fibrates on platelet function is mediated by PPARs activation via a novel mechanism that involves the inhibition of protein kinase-α (PKC-α) [39]. In addition, statins by increasing both cAMP as well as cGMP pathways could inhibit platelet activation [39]. cAMP increased by PPAR activation is due to the repression of PKC that allows greater activity of adenylyl cyclase (ATP to cAMP) [40, 41]. Meanwhile, cAMP-induced inhibition of platelet P-selectin expression is through activation of protein kinase A (PKA) [42].

3. Relationship between cAMP Levels and Platelet P-Selectin Expression

It has been shown that cAMP and cGMP-dependent protein kinases not only inhibit platelet pathways leading to activation and aggregation, but also those resulting in enhanced surface expression of protein ligands involved in inflammation [43]. Also, Ca2+ in human platelets is directly downregulated by cGMP and cAMP by a mechanism involving the inhibition of cytoskeletal reorganization via the activation of protein tyrosine phosphatases [44].

Moreover, platelet shape change can be antagonized by PKA (cAMP-dependent) activation but not by protein kinase G (PKG) (cGMP-dependent), which may occur with particular efficiency by the formation of a local compartment of cAMP through the inhibition of phosphodiesterase-3 (PDE3) [45]. In fact, activation/phosphorylation of PDE3 via Akt signaling pathway participates in regulating cAMP during thrombin activation of platelets [46]. Together, these results indicate that cAMP is persistently formed in platelets [47].

cAMP-induced inhibition of platelet P-selectin expression is, in large part, mediated through the activation of PKA [42]. While P-selectin expression was found to be independent of mitogen-activated protein kinase (MAPK) activation, since it was not inhibited by specific MAPK inhibitors [43]. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation was inhibited by clopidogrel and AR-C69931MX but not by aspirin [48, 49]. Prolonged cyclooxygenase-2 (COX-2) inhibition attenuates C-reactive protein and IL-6, but does not modify P-selectin [50]. ARC69931MX and clopidogrel by cAMP levels can inhibit human platelet aggregation through the activation of a separate G protein-coupled pathway (presumably involving Gs) and platelet P2Y12 receptor, respectively [51, 52]. Andersen et al. showed that levels of soluble P-selectin were significantly higher in aspirin responders and nonresponders [53]. Despite the above, measurement of circulating P-selectin has been suggested for remote testing of platelet function in patients treated with clopidogrel and aspirin [54].

4. Mechanism of Antiplatelet Action of Natural Products

In the context of atherosclerosis CVD, platelets can adhere to endothelial cells and leukocytes and contribute to vascular inflammation and thrombosis formation [55, 56]. In this sense, the inhibition of the platelet function has been used for long time in an effort to prevent and treat CVD [57]. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy [17, 18]. Moreover, epidemiological studies have provided evidence of a protective role of healthy diets in the prevention of CVD [58, 59].

The consumption of a diet containing 30% green and yellow vegetables results in a substantial inhibition of atherosclerosis progression [60]. Preliminary studies have demonstrated the platelet antiaggregation activity of fruit (red grapes, strawberries, kiwis, and pineapples) and vegetables (garlic, onions, green onions, melons, and tomatoes) [61, 62]. In this context, consuming two or three kiwi fruits per day for 28 days reduces platelet aggregation induced by collagen and ADP [63]. Strawberries are likely to exert significant protective effects in thromboembolic-related disorders by inhibiting platelet aggregation [64, 65]. Organo sulfur compounds in onion extracts are formed following the lysis of the S-alk(en)yl-L-cysteine sulfoxides by alliinase. These compounds inhibit the aggregation of human blood platelets and offer the potential for positive cardiovascular health benefits [66]. The raw form of garlic and some of its preparations are widely recognized as antiplatelet agents that may contribute to the prevention of CVD. Antithrombotic activities of garlic have been demonstrated by blood fibrinolytic and coagulation systems, and inhibition of platelet aggregation [67]. With respect to platelet function, allicin and thiosulfinates are responsible for in vitro antiaggregatory activity from garlic [68]. Furthermore, recently galactolipid and a phytosterol from garlic were identified as exhibiting an inhibitory action on ADP-induced aggregation in human blood platelets [69].

In fact, a large number of natural products have been reported with apparent inhibitory activity on human platelets and each constituent may possess multiply targets, and they may exert pleiotropic and synergistic effects (Table 1) [7072].

tab1
Table 1: Antiplatelet effects induced by various agonists of natural products and mechanisms described.

4.1. Antiplatelet Activity of Natural Products by PPARs

Due to high levels of toxicity associated with the first generation of drugs, there is renewed search for newer PPAR drugs that exhibit better efficacy but lesser toxicity [110]. Moreover, there has been a definite increase in the consumption of fruits and vegetables, due to the possible health benefits associated with these bioactive components [74, 111]. Thus, dietary components that act as ligands of PPARs include dietary lipids such as n-3 and n-6 fatty acids and their derivatives, polyphenols, and terpenoids, among others [112114] (Table 2).

tab2
Table 2: Natural products PPARs agonists.

In this sense, the present paper describes the mechanism of antiplatelet action of natural products as PPARs agonists and increased of intraplatelet levels of cAMP. As shown in Figure 1, the mechanism of antiplatelet action by natural products PPARs agonists is mediated by the following signaling pathways: (i) inhibition of PCK-α/increased of cAMP levels/stimulation of PKA (increased of cAMP levels), (ii) stimulation of Akt/NOS/NO/PKG (increased of cGMP levels), and (iii) inhibition of cyclooxygenase-1 (COX-1), thromboxane A2 (TXA2), and Ca2+ mobilization.

861786.fig.001
Figure 1: Mechanism of antiplatelet action by natural products on PPARs. cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; TXA2 = thromboxane A2; PKC = protein kinase C; PLC = phospholipase; COX-1 = cyclooxygenase-1; PPARs = peroxisome proliferator-activated receptors; AKT = also known as protein kinase B; NO = nitric oxide; cGMP = cyclic guanosine monophosphate; PKG = protein kinase G; NOS = nitric oxide synthase.

Magnolol is the major bioactive constituent of Magnolia officinalis (2–11% of the bark's dry weight) [115, 116]. Magnolol could improve insulin sensitivity through the activation of PPAR-γ [117]. Also Magnolol presents antiplatelet activity by PPAR-β/γ activation with upregulation of Akt/NOS/NO/cGMP/PKG cascade and suppression of PKC-α and COX-1 and Ca2+ mobilization [96].

Linolenic acid impairs arterial thrombus formation, tissue factor expression, and platelet activation and thereby represents an attractive nutritional intervention with direct dual antithrombotic effects [118]. These effects could be because both oleic and linoleic acids are PPARs agonists [119]. Meanwhile α-lipoic acid is PPAR-α/γ agonist and the mechanism of action involves the inhibition of Ca2+ mobilization, TXA2, PKC-α, and COX-1 expression, and elevation of cAMP levels [104, 105].

α- and γ-tocopherols have been shown to activate PPAR-γ expression and γ-tocopherol is a better modulator of PPAR-γ expression than α-tocopherol [106, 107]. In this context, α-tocopherol inhibits platelet aggregation through a PKC-dependent mechanism, which may explain a decrease in the expression of P-selectin and interactions platelet-mononuclear cells ex vivo [108, 109].

Curcumin, the major component of food spice turmeric (Curcuma longa), inhibits platelet aggregation induced by PAF and arachidonic acid with inhibitory effects on TXA2 and Ca2+ mobilization and also prevents the adhesion of platelets to brain microvascular endothelial cells [8486]. The beneficial effect of curcumin on platelet activation appears to be mediated by the upregulation of PPAR-γ [87].

4.2. Antiplatelet Activity of Natural Products by cAMP Levels

Here we describe one possible mechanism of action of natural products on platelet P-selectin expression through cAMP.

The natural products caffedymine (clovamide-type phenylpropenoic acid amide found in cocoa), N-caffeoyl tyramine, N-feruloyl tyramine, 5-caffeoylquinic acid, caffeic acid, and gallic acid were able to suppress P-selectin expression on platelets and were found to be very potent compounds able to inhibit COX-1 and 2 enzymes [73, 78, 81, 120122]. Moreover, previous studies indicate that caffedymine and N-caffeoyl tyramine inhibit P-selectin expression by increasing cAMP through beta-2 adrenoceptors [79, 80, 123]. Gallic acid, in a concentration-dependent manner, prevents the elevation of intracellular calcium and attenuate phosphorylation of PKCα/p38 MAPK and Akt/GSK3β on platelets stimulated by the stimulants ADP or U46619 [70]. Based on the function of other cell (mast cells), the mode of action of gallic acid is likely related with the elevation of the intracellular cAMP level by the inhibition of the cAMP phosphodiesterase [124].

Adenosine is another natural product with antiplatelet activity [74, 75]. Adenosine through G-protein linked receptors to activate adenylate cyclase and increase cellular cAMP levels, showing the inhibition of platelet P-selectin expression [76, 77]. However, chlorogenic acid, an antiplatelet compound, presented increase of cAMP and cGMP levels and strong inhibition of COX-1 [125] and COX-2 [126] but did not have effect on P-selectin expression [127].

Moreover, sanguinarine, alkaloid present in the root of Sanguinaria canadensis and Poppy fumaria species, is a potent antiplatelet agent, which activates adenylate cyclase with cAMP production, inhibits platelet Ca2+ mobilization and TXA2 production as well as suppresses COX-1 enzyme activity (whereas its effect on COX-2 activity was minimal) [99]. Similar antiplatelet effect had girinimbine that presented the inhibition of COX activity and elevation of the cAMP level [93].

Being increased of intraplatelet levels of Ca2+ involves phosphorylation of both pleckstrin (47 kDa) and myosin light chain (20 kDa) via Ca2+-dependent PKC and Ca2+/calmodulin-dependent protein kinase (CaM-PK), respectively. The phosphorylation of these proteins participates in the release of platelet aggregation factors such as serotonin and ADP [128, 129]. In this context, the effect of cordycepin on platelet aggregation might be associated with the inhibition of phosphorylation of these proteins to suppress the release of serotonin and ADP out of dense body in platelets, which is associated with the inhibition of Ca2+ mobilization by cordycepin-elevated cAMP [82, 83]. Whereas the ODQ (NO-sensitive guanylyl cyclase inhibitor) did not alter the cordycepin-induced upregulation of cGMP, the adenylyl cyclase inhibitor SQ22536 completely blocked the cAMP enhancement mediated by cordycepin [82]. Sulforaphane possesses potent antiplatelet activity, which may initially activate adenylate cyclase/cAMP, followed by inhibiting intracellular signals (such as the PI3-kinase/Akt and PLCγ2-PKC-p47 cascades) [102, 103]. Furthermore epigallocatechin-3-gallate increases cAMP via adenylate cyclase activation and subsequently phosphorylates VASP-Ser-157 through A-kinase activation to inhibit Ca2+ mobilization and TXA2 production on collagen-induced platelet aggregation [91]. Sesamol possesses potent antiplatelet activity, which may involve the activation of the cAMP-eNOS/NO-cGMP pathway, resulting in the inhibition of the PLCγ2-PKC-p38MAPK-TXA2 cascade [100]. Also, sesamol activates cAMP-PKA signaling, followed by the inhibition of the NF-κB-PLC-PKC cascade. The inhibition of NF-κB which interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases [101]. The inhibition of platelet aggregation by α-lipoic acid is mediated by PPARα/γ-dependent processes, which involve interaction with PKC and COX-1, increase of cAMP formation, and inhibition of intracellular Ca2+ mobilization [104]. However, the effects of α-lipoic acid on the above platelet responses were markedly reversed by the addition of 2′5′-ddAdo, an adenylate cyclase inhibitor [105]. Meanwhile, quercetin-mediated antiplatelet activity involves PI3K/Akt inactivation, cAMP elevation, and VASP stimulation that, in turn, suppresses MAPK phosphorylations [98]. Intraplatelet cAMP production was quickly increased by quercetin stimulation and probably through the adenylate cyclase signaling pathway [130].

According to natural products as caffedymine, N-caffeoyl tyramine, quercetin, and adenosine, which increase the intraplatelet cAMP levels and inhibit platelet P-selectin expression. It is possible to consider that those natural products (sanguinarine, α-Lipoic acid, sesamol, sulforaphane, epigallocatechin-3-gallate, and cordycepin) which increase the intraplatelet cAMP levels and lose their antiplatelet activity after adenylate cyclase blockaded would be able to inhibit platelet P-selectin expression. Even only an increase in the intraplatelet cAMP Levels may establish that dicentrine and girinimbine could inhibit P-selectin expression. Thus, the relationship between cAMP levels and P-selectin expression is because cAMP via the activation of PKA is capable of inhibiting platelet P-selectin expression [42, 77]. Furthermore, natural products that inhibited platelet aggregation stimulated by ADP and collagen with increased of cAMP levels is because cAMP downregulates P2Y1R expression [131] and GPVI-maintained in a monomeric form on resting platelets [132].

Finally, it is possible to establish that natural products that show antiplatelet activity by increasing levels of cAMP are able to inhibit platelet-leukocyte interactions through P-selectin inhibition (Figure 2). This makes it possible to consider that natural products in addition to platelet function inhibitors are compounds capable of preventing atherothrombosis/atheroinflammation.

861786.fig.002
Figure 2: Mechanism of antiplatelet action of natural products by cAMP levels. PDE3: phosphodiesterase-3; PKA: protein kinase A; PLC: phospholipase; DAG: diacylglycerol; IP3: inositol trisphosphate; PIP2: phosphatidylinositol 4,5-bisphosphate; PKC: protein kinase C; PSGL-1: P-selectin glycoprotein ligand-1.

5. Conclusions

According to this paper it is possible to establish that the antiplatelet activity by PPARs agonist and increased cAMP levels are not defined by one specific group of bioactive compounds. Also the data presented in this paper demonstrate that natural products with antiplatelet activity through of increase cAMP levels are able to inhibit the platelet-leukocyte interactions in atheroinflammation.

Conflict of Interests

The authors report no conflict of interests.

Acknowledgments

This work was funded by CONICYT REGIONAL/GORE MAULE/CEAP/R09I2001, Programa de Investigación de Excelencia Interdisciplinaria en Envejecimiento Saludable (PIEI-ES), and supported by grant no. 1130216 (I.P., M.G., R.M., M.A., J.C.) from Fondecyt, Chile.

References

  1. M. Naghavi, P. Libby, E. Falk et al., “From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies—part I,” Circulation, vol. 108, no. 14, pp. 1664–1672, 2003. View at Publisher · View at Google Scholar · View at Scopus
  2. “WHO publishes definitive atlas on global heart disease and stroke epidemic,” Indian Journal of Medical Sciences, vol. 58, pp. 405–406, 2004.
  3. H. A. Swartz and B. L. Rollman, “Managing the global burden of depression: lessons from the developing world,” World Psychiatry, vol. 2, pp. 162–163, 2003.
  4. I. F. Palomo, G. I. Torres, M. A. Alarcón, P. J. Maragaño, E. Leiva, and V. Mujica, “High prevalence of classic cardiovascular risk factors in a population of university students from South Central Chile,” Revista Espanola de Cardiologia, vol. 59, no. 11, pp. 1099–1105, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. K. S. Reddy and S. Yusuf, “Emerging epidemic of cardiovascular disease in developing countries,” Circulation, vol. 97, no. 6, pp. 596–601, 1998. View at Scopus
  6. M. E. Marenberg, N. Risch, L. F. Berkman, B. Floderus, and U. De Faire, “Genetic susceptibility to death from coronary heart disease in a study of twins,” New England Journal of Medicine, vol. 330, no. 15, pp. 1041–1046, 1994. View at Publisher · View at Google Scholar · View at Scopus
  7. D. D. Wagner and P. C. Burger, “Platelets in inflammation and thrombosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 12, pp. 2131–2137, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. E. Y. Chakhtoura, F. E. Shamoon, J. I. Haft, G. R. Obiedzinski, A. J. Cohen, and R. M. Watson, “Comparison of platelet activation in unstable and stable angina pectoris and correlation with coronary angiographic findings,” American Journal of Cardiology, vol. 86, no. 8, pp. 835–839, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. P. A. Da Costa Martins, J. M. Van Gils, A. Mol, P. L. Hordijk, and J. J. Zwaginga, “Platelet binding to monocytes increases the adhesive properties of monocytes by up-regulating the expression and functionality of β1 and β2 integrins,” Journal of Leukocyte Biology, vol. 79, no. 3, pp. 499–507, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. P. Da Costa Martins, N. Van Den Berk, L. H. Ulfman, L. Koenderman, P. L. Hordijk, and J. J. Zwaginga, “Platelet-monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 1, pp. 193–199, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. P. C. Burger and D. D. Wagner, “Platelet P-selectin facilitates atherosclerotic lesion development,” Blood, vol. 101, no. 7, pp. 2661–2666, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. P. B. Patel, S. E. Pfau, M. W. Cleman et al., “Comparison of coronary artery specific leukocyte-platelet conjugate formation in unstable versus stable angina pectoris,” American Journal of Cardiology, vol. 93, no. 4, pp. 410–413, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. E. Galliera, M. M. Corsi, and G. Banfi, “Platelet rich plasma therapy: inflammatory molecules involved in tissue healing,” Journal of Biological Regulators & Homeostatic Agents, vol. 26, pp. 35S–42S, 2012.
  14. Q. E. Fuentes, Q. F. Fuentes, V. Andres, O. M. Pello, J. F. de Mora, and G. I. Palomo, “Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis,” Platelets, vol. 24, pp. 255–262, 2013. View at Publisher · View at Google Scholar
  15. B. Collins and C. Hollidge, “Antithrombotic drug market. Market indicators,” Nature Reviews Drug Discovery, vol. 2, no. 1, pp. 11–12, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. I. Palomo, C. Toro, and M. Alarcón, “The role of platelets in the pathophysiology of atherosclerosis (Review),” Molecular Medicine Reports, vol. 1, no. 2, pp. 179–184, 2008. View at Scopus
  17. N. E. Barrett, L. Holbrook, S. Jones et al., “Future innovations in anti-platelet therapies,” British Journal of Pharmacology, vol. 154, no. 5, pp. 918–939, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. N. C. Raju and J. W. Eikelboom, “The aspirin controversy in primary prevention,” Current Opinion in Cardiology, vol. 27, pp. 499–507, 2012.
  19. G. Vilahur and L. Badimon, “Antiplatelet properties of natural products,” Vascular Pharmacology, 2013.
  20. R. Estruch, E. Ros, J. Salas-Salvado, et al., “Primary prevention of cardiovascular disease with a Mediterranean diet,” New England Journal of Medicine, vol. 368, pp. 1279–1290, 2013.
  21. M. De Lorgeril, S. Renaud, N. Mamelle et al., “Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease,” The Lancet, vol. 343, no. 8911, pp. 1454–1459, 1994. View at Publisher · View at Google Scholar · View at Scopus
  22. L. Das, E. Bhaumik, U. Raychaudhuri, and R. Chakraborty, “Role of nutraceuticals in human health,” Journal of Food Science and Technology, vol. 49, pp. 173–183, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. T.-S. Voa and K. Se-Kwon, “Fucoidans as a natural bioactive ingredient for functional foods,” Journal of Functional Foods, vol. 5, pp. 16–27, 2013.
  24. J. C. Griffiths, D. R. Abernethy, S. Schuber, and R. L. Williams, “Functional food ingredient quality: opportunities to improve public health by compendial standardization,” Journal of Functional Foods, vol. 1, no. 1, pp. 128–130, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. E. Fuentes, O. Forero-Doria, G. Carrasco, et al., “Effect of tomato industrial processing on phenolic profile and antiplatelet activity,” Molecules, vol. 18, pp. 11526–11536, 2013.
  26. L. M. Ostertag, N. O'Kennedy, G. W. Horgan, P. A. Kroon, G. G. Duthie, and B. de Roos, “In vitro anti-platelet effects of simple plant-derived phenolic compounds are only found at high, non-physiological concentrations,” Molecular Nutrition and Food Research, vol. 55, no. 11, pp. 1624–1636, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. L. A. Moraes, L. Piqueras, and D. Bishop-Bailey, “Peroxisome proliferator-activated receptors and inflammation,” Pharmacology and Therapeutics, vol. 110, no. 3, pp. 371–385, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. W. Ahmed, O. Ziouzenkova, J. Brown et al., “PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?” Journal of Internal Medicine, vol. 262, no. 2, pp. 184–198, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. E. Fuentes, F. Fuentes, G. Vilahur, L. Badimon, and I. Palomo, “Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome,” Mediators of Inflammation, vol. 2013, Article ID 136584, 11 pages, 2013. View at Publisher · View at Google Scholar
  30. C. Duval, G. Chinetti, F. Trottein, J.-C. Fruchart, and B. Staels, “The role of PPARs in atherosclerosis,” Trends in Molecular Medicine, vol. 8, no. 9, pp. 422–430, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. G. D. Barish, A. R. Atkins, M. Downes et al., “PPARδ regulates multiple proinflammatory pathways to suppress atherosclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 11, pp. 4271–4276, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Tanaka, J. Yamamoto, S. Iwasaki et al., “Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15924–15929, 2003. View at Publisher · View at Google Scholar · View at Scopus
  33. H. Duez, J.-C. Fruchart, and B. Staels, “PPARs in inflammation, atherosclerosis and thrombosis,” Journal of Cardiovascular Risk, vol. 8, no. 4, pp. 187–194, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Kersten, B. Desvergne, and W. Wahli, “Roles of PPARS in health and disease,” Nature, vol. 405, no. 6785, pp. 421–424, 2000. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Inoue, X.-F. Jiang, T. Katayama, S. Osada, K. Umesono, and S. Namura, “Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor α in mice,” Neuroscience Letters, vol. 352, no. 3, pp. 203–206, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. W. Verreth, D. De Keyzer, M. Pelat et al., “Weight loss-associated induction of peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice,” Circulation, vol. 110, no. 20, pp. 3259–3269, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. F. Akbiyik, D. M. Ray, K. F. Gettings, N. Blumberg, C. W. Francis, and R. P. Phipps, “Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes,” Blood, vol. 104, no. 5, pp. 1361–1368, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. D. M. Ray, S. L. Spinelli, J. J. O'Brien, N. Blumberg, and R. P. Phipps, “Platelets as a novel target for PPARγ ligands: implications for inflammation, diabetes, and cardiovascular disease,” BioDrugs, vol. 20, no. 4, pp. 231–241, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. F. Y. Ali, P. C. J. Armstrong, A.-R. A. Dhanji et al., “Antiplatelet actions of statins and fibrates are mediated by PPARs,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 5, pp. 706–711, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. L. Levesque and S. T. Crooke, “Depletion of protein kinase C-α by antisense oligonucleotides alters beta-adrenergic function and reverses the phorbol ester-induced reduction of isoproterenol-induced adenosine 3′-5′-cyclic monophosphate accumulation in murine Swiss 3T3 fibroblasts,” Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 1, pp. 425–434, 1998. View at Scopus
  41. F. Y. Ali, M. G. Hall, B. Desvergne, T. D. Warner, and J. A. Mitchell, “PPARβ/δ agonists modulate platelet function via a mechanism involving PPAR receptors and specific association/repression of PKCα—brief report,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 11, pp. 1871–1873, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. D. Libersan, G. Rousseau, and Y. Merhi, “Differential regulation of P-selectin expression by protein kinase A and protein kinase G in thrombin-stimulated human platelets,” Thrombosis and Haemostasis, vol. 89, no. 2, pp. 310–317, 2003. View at Scopus
  43. U. R. Schwarz, A. L. Kobsar, M. Koksch, U. Walter, and M. Eigenthaler, “Inhibition of agonist-induced p42 and p38 mitogen-activated protein kinase phosphorylation and CD40 ligand/P-selectin expression by cyclic nucleotide-regulated pathways in human platelets,” Biochemical Pharmacology, vol. 60, no. 9, pp. 1399–1407, 2000. View at Publisher · View at Google Scholar · View at Scopus
  44. J. A. Rosado, T. Porras, M. Conde, and S. O. Sage, “Cyclic nucleotides modulate store-mediated calcium entry through the activation of protein-tyrosine phosphatases and altered actin polymerization in human platelets,” Journal of Biological Chemistry, vol. 276, no. 19, pp. 15666–15675, 2001. View at Publisher · View at Google Scholar · View at Scopus
  45. B. O. Jensen, F. Selheim, S. O. Døskeland, A. R. L. Gear, and H. Holmsen, “Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide,” Blood, vol. 104, no. 9, pp. 2775–2782, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. W. Zhang and R. W. Colman, “Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A,” Blood, vol. 110, no. 5, pp. 1475–1482, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. M. A. H. Feijge, K. Ansink, K. Vanschoonbeek, and J. W. M. Heemskerk, “Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3,” Biochemical Pharmacology, vol. 67, no. 8, pp. 1559–1567, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. R. F. Storey, H. M. Judge, R. G. Wilcox, and S. Heptinstall, “Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin,” Thrombosis and Haemostasis, vol. 88, no. 3, pp. 488–494, 2002. View at Scopus
  49. Y. Ozeki, H. Ito, Y. Nagamura, F. Unemi, and T. Igawa, “12(S)-HETE plays a role as a mediator of expression of platelet CD62 (P-selectin),” Platelets, vol. 9, no. 5, pp. 297–302, 1998. View at Publisher · View at Google Scholar · View at Scopus
  50. P. Bogaty, J. M. Brophy, M. Noel et al., “Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study,” Circulation, vol. 110, no. 8, pp. 934–939, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Srinivasan, F. Mir, J.-S. Huang, F. T. Khasawneh, S. C.-T. Lam, and G. C. Le Breton, “The P2Y12 antagonists, 2-methylthioadenosine 5′-monophosphate triethylammonium salt and cangrelor (ARC69931MX), can inhibit human platelet aggregation through a Gi-independent increase in cAMP levels,” Journal of Biological Chemistry, vol. 284, no. 24, pp. 16108–16117, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Suryadevara, M. Ueno, A. Tello-Montoliu, et al., “Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus,” Thrombosis and Haemostasis, vol. 108, pp. 930–936, 2012.
  53. K. Andersen, M. Hurlen, H. Arnesen, and I. Seljeflot, “Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease,” Thrombosis Research, vol. 108, no. 1, pp. 37–42, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. S. C. Fox, J. A. May, A. Shah, U. Neubert, and S. Heptinstall, “Measurement of platelet P-selectin for remote testing of platelet function during treatment with clopidogrel and/or aspirin,” Platelets, vol. 20, no. 4, pp. 250–259, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. K. Nishijima, J. Kiryu, A. Tsujikawa et al., “Platelets adhering to the vascular wall mediate postischemic leukocyte-endothelial cell interactions in retinal microcirculation,” Investigative Ophthalmology and Visual Science, vol. 45, no. 3, pp. 977–984, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. S. P. Jackson, W. S. Nesbitt, and E. Westein, “Dynamics of platelet thrombus formation,” Journal of Thrombosis and Haemostasis, vol. 7, no. 1, pp. 17–20, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Zoungas, B. P. McGrath, P. Branley et al., “Cardiovascular Morbidity and Mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial,” Journal of the American College of Cardiology, vol. 47, no. 6, pp. 1108–1116, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. F. B. Hu, “Plant-based foods and prevention of cardiovascular disease: an overview,” American Journal of Clinical Nutrition, vol. 78, pp. 544S–551S, 2003.
  59. E. J. Fuentes, L. A. Astudillo, M. I. Gutiérrez et al., “Fractions of aqueous and methanolic extracts from tomato (Solanum lycopersicum L.) present platelet antiaggregant activity,” Blood Coagulation and Fibrinolysis, vol. 23, no. 2, pp. 109–117, 2012. View at Publisher · View at Google Scholar · View at Scopus
  60. M. R. Adams, D. L. Golden, H. Chen, T. C. Register, and E. T. Guggery, “A diet rich in green and yellow vegetables inhibits atherosclerosis in mice,” Journal of Nutrition, vol. 136, no. 7, pp. 1886–1889, 2006. View at Scopus
  61. S. Pierre, L. Crosbie, and A. K. Duttaroy, “Inhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro,” Platelets, vol. 16, no. 8, pp. 469–473, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. C. Torres-Urrutia, L. Guzmán, G. Schmeda-Hirschmann et al., “Antiplatelet, anticoagulant, and fibrinolytic activity in vitro of extracts from selected fruits and vegetables,” Blood Coagulation and Fibrinolysis, vol. 22, no. 3, pp. 197–205, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. A. K. Duttaroy and A. Jørgensen, “Effects of kiwi fruit consumption on platelet aggregation and plasma lipids in healthy human volunteers,” Platelets, vol. 15, no. 5, pp. 287–292, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Naemura, T. Mitani, Y. Ijiri et al., “Anti-thrombotic effect of strawberries,” Blood Coagulation and Fibrinolysis, vol. 16, no. 7, pp. 501–509, 2005. View at Scopus
  65. A. Naemura, H. Ohira, M. Ikeda, K. Koshikawa, H. Ishii, and J. Yamamoto, “An experimentally antithrombotic strawberry variety is also effective in humans,” Pathophysiology of Haemostasis and Thrombosis, vol. 35, no. 5, pp. 398–404, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. K. S. Osmont, C. R. Arnt, and I. L. Goldman, “Temporal aspects of onion-induced antiplatelet activity,” Plant Foods for Human Nutrition, vol. 58, no. 1, pp. 27–40, 2003. View at Publisher · View at Google Scholar · View at Scopus
  67. H. Fukao, H. Yoshida, Y.-I. Tazawa, and T. Hada, “Antithrombotic effects of odorless garlic powder both in vitro and in vivo,” Bioscience, Biotechnology and Biochemistry, vol. 71, no. 1, pp. 84–90, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. P. F. Cavagnaro, A. Camargo, C. R. Galmarini, and P. W. Simon, “Effect of cooking on garlic (Allium sativum L.) antiplatelet activity and thiosulfinates content,” Journal of Agricultural and Food Chemistry, vol. 55, no. 4, pp. 1280–1288, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. D. Sabha, B. Hiyasat, K. Grötzinger et al., “Allium ursinum L.: bioassay-guided isolation and identification of a galactolipid and a phytosterol exerting antiaggregatory effects,” Pharmacology, vol. 89, no. 5-6, pp. 260–269, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. S. S. Chang, V. S. Lee, and Y. L. Tseng, “Gallic acid attenuates platelet activation and platelet-leukocyte aggregation: involving pathways of Akt and GSK3beta,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 683872, 8 pages, 2012. View at Publisher · View at Google Scholar
  71. J. A. Guerrero, M. L. Lozano, J. Castillo, O. Benavente-García, V. Vicente, and J. Rivera, “Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor,” Journal of Thrombosis and Haemostasis, vol. 3, no. 2, pp. 369–376, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. E. Fuentes, M. Alarcon, L. Astudillo, et al., “Protective mechanisms of guanosine from Solanum lycopersicum on agonist-induced platelet activation: role of sCD40L,” Molecules, vol. 18, pp. 8120–8135, 2013.
  73. J. B. Park, “5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets,” Journal of Nutritional Biochemistry, vol. 20, no. 10, pp. 800–805, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. E. Fuentes, R. Castro, and L. Astudillo, “Bioassay-guided isolation and HPLC determination of bioactive compound that relate to the antiplatelet activity (adhesion, secretion, and aggregation) from Solanum lycopersicum,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 147031, 10 pages, 2012. View at Publisher · View at Google Scholar
  75. J. Wang, Z.-G. Huang, H. Cao et al., “Screening of anti-platelet aggregation agents from Panax notoginseng using human platelet extraction and HPLC-DAD-ESI-MS/MS,” Journal of Separation Science, vol. 31, no. 6-7, pp. 1173–1180, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Anfossi, I. Russo, P. Massucco et al., “Adenosine increases human platelet levels of cGMP through nitric oxide—possible role in its antiaggregating effect,” Thrombosis Research, vol. 105, no. 1, pp. 71–78, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. T. Minamino, M. Kitakaze, H. Asanuma et al., “Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs,” Journal of Clinical Investigation, vol. 101, no. 8, pp. 1643–1653, 1998. View at Scopus
  78. J. B. Park, “Caffedymine from cocoa has COX inhibitory activity suppressing the expression of a platelet activation marker, P-selectin,” Journal of Agricultural and Food Chemistry, vol. 55, no. 6, pp. 2171–2175, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. J. B. Park, “N-coumaroyldopamine and N-caffeoyldopamine increase cAMP via beta 2-adrenoceptors in myelocytic U937 cells,” FASEB Journal, vol. 19, no. 6, pp. 497–502, 2005. View at Publisher · View at Google Scholar · View at Scopus
  80. J. B. Park and N. Schoene, “Clovamide-type phenylpropenoic acid amides, N-coumaroyldopamine and N-caffeoyldopamine, inhibit platelet-leukocyte interactions via suppressing P-selectin expression,” Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 2, pp. 813–819, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. T. Takahashi and M. Miyazawa, “N-Caffeoyl serotonin as selective COX-2 inhibitor,” Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 7, pp. 2494–2496, 2012.
  82. H.-J. Cho, J. Y. Cho, M. H. Rhee, and H.-J. Park, “Cordycepin (3′-deoxyadenosine) inhibits human platelet aggregation in a cyclic AMP- and cyclic GMP-dependent manner,” European Journal of Pharmacology, vol. 558, no. 1–3, pp. 43–51, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. H. J. Cho, J. Y. Cho, M. H. Rhee, C. R. Lim, and H. J. Park, “Cordycepin (3′-deoxyadenosine) inhibits human platelet aggregation induced by U46619, a TXA2 analogue,” Journal of Pharmacy and Pharmacology, vol. 58, no. 12, pp. 1677–1682, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. B. H. Shah, Z. Nawaz, S. A. Pertani et al., “Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling,” Biochemical Pharmacology, vol. 58, no. 7, pp. 1167–1172, 1999. View at Publisher · View at Google Scholar · View at Scopus
  85. K. C. Srivastava, A. Bordia, and S. K. Verma, “Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 52, no. 4, pp. 223–227, 1995. View at Publisher · View at Google Scholar · View at Scopus
  86. L. Zhang, Z.-L. Gu, Z.-H. Qin, and Z.-Q. Liang, “Effect of curcumin on the adhesion of platelets to brain microvascular endothelial cells in vitro,” Acta Pharmacologica Sinica, vol. 29, no. 7, pp. 800–807, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. A. M. Siddiqui, X. Cui, R. Wu et al., “The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-γ,” Critical Care Medicine, vol. 34, no. 7, pp. 1874–1882, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. H.-F. Chiu, S.-P. Yang, Y.-L. Kuo, Y.-S. Lai, and T.-C. Chou, “Mechanisms involved in the antiplatelet effect of C-phycocyanin,” British Journal of Nutrition, vol. 95, no. 2, pp. 435–440, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. G. Hsiao, P. O.-H. Chou, M.-Y. Shen, D.-S. Chou, C.-H. Lin, and J.-R. Sheu, “C-phycocyanin, a very potent and novel platelet aggregation inhibitor from Spirulina platensis,” Journal of Agricultural and Food Chemistry, vol. 53, no. 20, pp. 7734–7740, 2005. View at Publisher · View at Google Scholar · View at Scopus
  90. S.-M. Yu, C.-C. Chen, F.-N. Ko, Y.-L. Huang, T.-F. Huang, and C.-M. Teng, “Dicentrine, a novel antiplatelet agent inhibiting thromboxane formation and increasing the cyclic AMP level of rabbit platelets,” Biochemical Pharmacology, vol. 43, no. 2, pp. 323–329, 1992. View at Publisher · View at Google Scholar · View at Scopus
  91. W.-J. Ok, H.-J. Cho, H.-H. Kim et al., “Epigallocatechin-3-gallate has an anti-platelet effect in a cyclic AMP-dependent manner,” Journal of Atherosclerosis and Thrombosis, vol. 19, no. 4, pp. 337–348, 2012. View at Publisher · View at Google Scholar · View at Scopus
  92. G. Hsiao, C.-Y. Chang, M.-Y. Shen et al., “α-Naphthoflavone, a potent antiplatelet flavonoid, is mediated through inhibition of phospholipase C activity and stimulation of cyclic GMP formation,” Journal of Agricultural and Food Chemistry, vol. 53, no. 13, pp. 5179–5186, 2005. View at Publisher · View at Google Scholar · View at Scopus
  93. F.-N. Ko, Y.-S. Lee, T.-S. Wu, and C.-M. Teng, “Inhibition of cyclooxygenase activity and increase in platelet cyclic AMP by girinimbine, isolated from Murraya euchrestifolia,” Biochemical Pharmacology, vol. 48, no. 2, pp. 353–360, 1994. View at Publisher · View at Google Scholar · View at Scopus
  94. Y.-R. Jin, X.-H. Han, Y.-H. Zhang et al., “Antiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-γ2 phosphorylation and cyclooxygenase-1 activity,” Atherosclerosis, vol. 194, no. 1, pp. 144–152, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. M. C. Chang, B. J. Uang, C. Y. Tsai et al., “Hydroxychavicol, a novel betel leaf component, inhibits platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization,” British Journal of Pharmacology, vol. 152, no. 1, pp. 73–82, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. C. Y. Shih and T. C. Chou, “The antiplatelet activity of magnolol is mediated by PPAR-beta/gamma,” Biochemical Pharmacology, vol. 84, pp. 793–803, 2012.
  97. M. C. Chang, H. H. Chang, C. P. Chan, et al., “Antiplatelet effect of phloroglucinol is related to inhibition of cyclooxygenase, reactive oxygen species, ERK/p38 signaling and thromboxane A2 production,” Toxicology and Applied Pharmacology, vol. 263, pp. 287–295, 2012.
  98. W. J. Oh, M. Endale, and S. C. Park, “Dual roles of quercetin in platelets: phosphoinositide-3-kinase and MAP kinases inhibition, and cAMP-dependent vasodilator-stimulated phosphoprotein stimulation,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 485262, 10 pages, 2012. View at Publisher · View at Google Scholar
  99. J.-H. Jeng, H.-L. Wu, B.-R. Lin et al., “Antiplatelet effect of sanguinarine is correlated to calcium mobilization, thromboxane and cAMP production,” Atherosclerosis, vol. 191, no. 2, pp. 250–258, 2007. View at Publisher · View at Google Scholar · View at Scopus
  100. C. C. Chang, W. J. Lu, C. W. Chiang et al., “Potent antiplatelet activity of sesamol in an in vitro and in vivo model: pivotal roles of cyclic AMP and p38 mitogen-activated protein kinase,” Journal of Nutritional Biochemistry, vol. 21, no. 12, pp. 1214–1221, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. C.-C. Chang, W.-J. Lu, E.-T. Ong et al., “A novel role of sesamol in inhibiting NF-B-mediated signaling in platelet activation,” Journal of Biomedical Science, vol. 18, no. 1, article 93, 2011. View at Publisher · View at Google Scholar · View at Scopus
  102. T. Jayakumar, W. F. Chen, W. J. Lu, et al., “A novel antithrombotic effect of sulforaphane via activation of platelet adenylate cyclase: ex vivo and in vivo studies,” Journal of Nutritional Biochemistry, 2012.
  103. W. Y. Chuang, P. H. Kung, C. Y. Kuo, and C. C. Wu, “Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway,” Thrombosis & Haemostasis, vol. 109, no. 6, pp. 1120–1130, 2013. View at Publisher · View at Google Scholar
  104. T.-C. Chou, C.-Y. Shih, and Y.-T. Chen, “Inhibitory effect of α-Lipoic acid on platelet aggregation is mediated by PPARs,” Journal of Agricultural and Food Chemistry, vol. 59, no. 7, pp. 3050–3059, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. Y.-S. Lai, C.-Y. Shih, Y.-F. Huang, and T.-C. Chou, “Antiplatelet activity of α-Lipoic acid,” Journal of Agricultural and Food Chemistry, vol. 58, no. 15, pp. 8596–8603, 2010. View at Publisher · View at Google Scholar · View at Scopus
  106. W. L. Stone, K. Krishnan, S. E. Campbell, M. Qui, S. G. Whaley, and H. Yang, “Tocopherols and the treatment of colon cancer,” Annals of the New York Academy of Sciences, vol. 1031, pp. 223–233, 2004. View at Publisher · View at Google Scholar · View at Scopus
  107. S. E. Campbell, W. L. Stone, S. G. Whaley, M. Qui, and K. Krishnan, “Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (γ) expression in SW 480 human colon cancer cell lines,” BMC Cancer, vol. 3, article 25, 2003. View at Publisher · View at Google Scholar · View at Scopus
  108. J. E. Freedman, J. H. Farhat, J. Loscalzo, and J. F. Keaney Jr., “α-Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism,” Circulation, vol. 94, no. 10, pp. 2434–2440, 1996. View at Scopus
  109. T. Murohara, H. Ikeda, Y. Otsuka et al., “Inhibition of platelet adherence to mononuclear cells by α-tocopherol: role of P-selectin,” Circulation, vol. 110, no. 2, pp. 141–148, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. N. Gitlin, N. L. Julie, C. L. Spurr, K. N. Lim, and H. M. Juarbe, “Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone,” Annals of Internal Medicine, vol. 129, no. 1, pp. 36–38, 1998. View at Scopus
  111. I. Palomo, E. Leiva, and M. Vásquez, Dieta Mediterranea: Prevención de las Enfermeda des Cardiovasculares, Universidad de Talca Press, Talca, Chile, 2007.
  112. N. K. Salam, T. H.-W. Huang, B. P. Kota, M. S. Kim, Y. Li, and D. E. Hibbs, “Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study,” Chemical Biology and Drug Design, vol. 71, no. 1, pp. 57–70, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. N. Takahashi, T. Kawada, T. Goto et al., “Dual action of isoprenols from herbal medicines on both PPARγ and PPARα in 3T3-L1 adipocytes and HepG2 hepatocytes,” FEBS Letters, vol. 514, no. 2-3, pp. 315–322, 2002. View at Publisher · View at Google Scholar · View at Scopus
  114. A. Pawar and D. B. Jump, “Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor α activity in rat primary hepatoctes,” Journal of Biological Chemistry, vol. 278, no. 38, pp. 35931–35939, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. F. S. El-Feraly and Y. M. Chan, “Isolation and characterization of the sesquiterpene lactones costunolide, parthenolide, costunolide diepoxide, santamarine, and reynosin from Magnolia grandiflora L,” Journal of Pharmaceutical Sciences, vol. 67, no. 3, pp. 347–350, 1978. View at Scopus
  116. C.-C. Shen, C.-L. Ni, Y.-C. Shen et al., “Phenolic constituents from the stem bark of Magnolia officinalis,” Journal of Natural Products, vol. 72, no. 1, pp. 168–171, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. S.-S. Choi, B.-Y. Cha, Y.-S. Lee et al., “Magnolol enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells,” Life Sciences, vol. 84, no. 25-26, pp. 908–914, 2009. View at Publisher · View at Google Scholar · View at Scopus
  118. E. W. Holy, M. Forestier, E. K. Richter et al., “Dietary α-linolenic acid inhibits arterial thrombus formation, tissue factor expression, and platelet activation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 8, pp. 1772–1780, 2011. View at Publisher · View at Google Scholar · View at Scopus
  119. H. Yokoi, H. Mizukami, A. Nagatsu, H. Tanabe, and M. Inoue, “Hydroxy monounsaturated fatty acids as agonists for peroxisome proliferator-activated receptors,” Biological and Pharmaceutical Bulletin, vol. 33, no. 5, pp. 854–861, 2010. View at Publisher · View at Google Scholar · View at Scopus
  120. J. B. Park, “Isolation and characterization of N-feruloyltyramine as the p-selectin expression suppressor from garlic (Allium sativum),” Journal of Agricultural and Food Chemistry, vol. 57, no. 19, pp. 8868–8872, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. T. C. Reddy, P. Aparoy, N. K. Babu, K. A. Kumar, S. K. Kalangi, and P. Reddanna, “Kinetics and docking studies of a COX-2 inhibitor isolated from terminalia bellerica fruits,” Protein and Peptide Letters, vol. 17, no. 10, pp. 1251–1257, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. C. C. M. Appeldoorn, A. Bonnefoy, B. C. H. Lutters et al., “Gallic acid antagonizes P-selectin-mediated platelet-leukocyte interactions: implications for the French paradox,” Circulation, vol. 111, no. 1, pp. 106–112, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. N. Cook, S. R. Nahorski, C. Jagger, and D. B. Barnett, “Is the human platelet beta2 adrenoceptor coupled to adenylate cyclase?” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 337, no. 2, pp. 238–240, 1988. View at Scopus
  124. S.-H. Kim, C.-D. Jun, K. Suk et al., “Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells,” Toxicological Sciences, vol. 91, no. 1, pp. 123–131, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. H. J. Cho, H. J. Kang, Y. J. Kim, et al., “Inhibition of platelet aggregation by chlorogenic acid via cAMP and cGMP-dependent manner,” Blood Coagul Fibrinolysis, vol. 23, pp. 629–635, 2012.
  126. N. J. Kang, K. W. Lee, B. J. Shin et al., “Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression,” Carcinogenesis, vol. 30, no. 2, pp. 321–330, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. L. Yu, Y. Li, H. Fan, J. Duan, Q. Zhu, and S. Li, “Analysis of marker compounds with anti-platelet aggregation effects in mailuoning injection using platelet binding assay combined with HPLC-DAD-ESI-MS and solid-phase extraction technique,” Phytochemical Analysis, vol. 22, no. 1, pp. 87–93, 2011. View at Publisher · View at Google Scholar · View at Scopus
  128. D. C. Sloan and R. J. Haslam, “Protein kinase C-dependent and Ca2+-dependent mechanisms of secretion from streptolysin 0-permeabilized platelets: effects of leakage of cytosolic proteins,” Biochemical Journal, vol. 328, no. 1, pp. 13–21, 1997. View at Scopus
  129. M. B. Feinstein and C. Fraser, “Human platelet secretion and aggregation induced by calcium ionophores. Inhibition by PGE1 and dibutyryl cyclic AMP,” Journal of General Physiology, vol. 66, no. 5, pp. 561–581, 1975. View at Scopus
  130. P.-G. Li, L. Sun, X. Han, S. Ling, W.-T. Gan, and J.-W. Xu, “Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt-independent and PKA-dependent mechanism,” Pharmacology, vol. 89, no. 3-4, pp. 220–228, 2012. View at Publisher · View at Google Scholar · View at Scopus
  131. D. Yang, H. Chen, M. Koupenova et al., “A new role for the A2b adenosine receptor in regulating platelet function,” Journal of Thrombosis and Haemostasis, vol. 8, no. 4, pp. 817–827, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Loyau, B. Dumont, V. Ollivier et al., “Platelet glycoprotein VI dimerization, an active process inducing receptor competence, is an indicator of platelet reactivity,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 3, pp. 778–785, 2012. View at Publisher · View at Google Scholar · View at Scopus