## 4 Discussion  
PTE is a naturally occurring dimethylether and an analog of resveratrol; it has stronger metabolic activity than resveratrol due to single hydroxyl group attachment, but resveratrol has three hydroxyl groups. Resveratrol, a polyphenol compound, was reported to aid the prevention of atherosclerosis and heart diseases [26]. However, resveratrol possesses low bioavailability with rapid first-pass metabolism [26]. PTE has been recommended because its chemical structure leads to increased lipophilicity and membrane permeability, ensuing in better pharmacokinetics than those of resveratrol [27]. Therefore, PTE's plasma concentration and bioavailability are much better than those of resveratrol under equimolar doses, unrelated to the dose and route of administration. The pharmacokinetics of PTE in rats have been reported; under the daily oral dosage of 56 mg/kg for 14 days, the rats' blood concentration was approximately 2550 ng/mL (~10 \(\upmu\)M) [28], indicating that the concentration used in the antiplatelet was reasonable after dietary intake. Even if regular PTE obtained from natural sources would be insufficient for achieving the plasma concentration required to inhibit in vivo platelet activation, long-term intake of a sufficient quantity of PTE is ideally suited for preventing CVDs. Thus, PTE is a potentially innovative candidate for treating arterial thrombosis-related diseases for humans. The function of NF-\(\kappa\)B is well studied in nucleated cells. Stimulation by cytokines, ultraviolet radiation, free radicals, or viral infection can trigger NF-\(\kappa\)B activation, resulting in inflammation and impairing cell survival, differentiation, and proliferation [24]. Hence, the inhibition of NF-\(\kappa\)B would be an ideal target for the treatment of inflammatory diseases or cancers. In the present study, PTE had good inhibitory potency in collagen-stimulated NF-\(\kappa\)B activation (IKK, \(\mathrm{I}\)\(\mathrm{R}\)\(\mathrm{\SI}\)\(\mathrm{\SI}\)\(\mathrm{\SI}\)\(\mathrm{\SI}\), and p65 phosphorylation, as well as \(\mathrm{I}\)\(\mathrm{k}\  
Studying the function of Akt in platelets is predominantly achieved by using mice models and deleting individual Akt isoforms. Among the generated genetically modified mice, only Akt1-deficient mice have exhibited a significant defect in response to collagen. Specifically, Akt1 deficiency reduced platelet aggregation and prolonged tail bleeding duration, suggesting that Akt1 is the major isoform preferentially activated during collagen-mediated platelet activation and contributes more directly to hemostasis [32,33]. By contrast, deletion of Akt2 results in a normal response to collagen stimulation [32]. Furthermore, Akt3-deficient mice respond normally to collagen stimulation and exhibit a decreased response to thrombin and TXA2 [34]. However, the role of Akt3 in platelet activation is controversial, as [PERSON] et al. [35] reported that although Akt3 is expressed in platelets, the researchers were unable to detect activation of Akt3 after agonist stimulation. Pharmacological inhibitors for each isoform have not yet been developed; however, the role of Akt has also been studied using the pan Akt inhibitor MK-2206, which significantly inhibited human platelet activation induced by various agonists [35]. In the present study, MK-2206 clearly reduced NF-\(\kappa\)B activation, and BAY11-7082 also markedly diminished Akt phosphorylation, suggesting that the signals of NF-\(\kappa\)B and Akt are mutually activated after collagen stimulation in human platelets and that those signals participate critically in the antiplatelet effects of PTE. However, we have not ruled out the possibility that other unknown signals are involved in the PTE-mediated inhibition of platelet activation. Experimental animal models are key in understanding the therapeutic significance of candidate drugs against arterial thrombosis.