• Korean Journal of Pharmacognosy
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• v.52 no.3
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• pp.127-133
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• 2021

Platelet activation plays a major role in cardiovascular disorders (CVDs). Thus, disrupting platelet activation represents an attractive therapeutic target on CVDs. Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and CVDs. In other report, the effect of esculetin has been examined in human platelet activation and experimental mouse models, and esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619, and its mechanism is not also clearly known. This study investigated the effect of esculetin on collagen-induced human platelet aggregation, and we clarified the mechanism. Esuletin has effects on the down regulation of PI3K/Akt and MAPK, phosphoproteins that act in the signaling process in platelet aggregation. The effects of esculetin reduced of TXA₂ production and phospholipase A₂ activation, and intracellular granule secretion including ATP and serotonin, leading to inhibit platelet aggregation. These results clearly clarified the effect of esculetin in inhibiting platelet activity and thrombus formation in humans.

• Biomedical Science Letters
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• v.12 no.4
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• pp.337-341
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• 2006

Platelets clearly play an important role in inflammatory responses. In this study, we aimed to evaluate the relationship between aging and platelet activation. A total number of 799 persons (383 males and 416 females), who were apparently healthy and aged more than 20 years were recruited by a health promotion center in a community-based hospital in Seoul, Korea. We collected material data about their medical history and health behavior. Platelet parameters including mean platelet component (MPC), mean platelet volume (MPV), and platelet component distribution width (PCDW) were determined within 1 hour after blood collection using the ADVIA 120 automated hematology analyzer. The MPC of the women ($27.2{\pm}1.2$) was significantly love. than that of the men ($27.5{\pm}1.3$). The MPC of all participants was found to decrease with increasing age (P<0.01). Study participants in their twenties had the highest MPC ($27.7{\pm}1.1$), followed by those in their thirties ($27.6{\pm}1.1$), forties ($27.4{\pm}1.3$), fifties ($27.2{\pm}1.3$), sixties ($27.2{\pm}1.2$) and seventies ($27.1{\pm}1.2$). Multiple regression analysis showed that aging and gender were related with MPC after adjusting for confounding factors, including age, gender, smoking habit, hypertension, diabetes, body mass index and total cholesterol level. The this study shows that aging is related to platelet activation. Future research will need to determine the implications of increased platelet activation with aging, especially regarding the increased incidence of cardiovascular diseases and related mortalities that occur in older age groups.

• Biomedical Science Letters
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• v.13 no.1
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• pp.11-15
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• 2007

We examined the effects of pregnancy and pregnancy-induced hypertension (PIH) on platelet activation. Thirty-six women with PIH (blood pressure > 140/90 mm Hg after two consecutive measurements after the $24^{th}$ weeks of gestation) without proteinuria, fifty-six normotensive pregnant women, and fifty non-pregnant women were studied. WBC, RBC, platelet related variables, including mean platelet component (MPC), mean platelet volume (MPV) and platelet component distribution width (PCDW) were determined for this study. MPC levels were significantly lower in women with PIH compared with normotensive pregnant women and non-pregnant women (P<0.05). MPC levels were inversely con-elated with PIH (r=-0.49, P<0.001), systolic BP (r=-0.22, P<0.01), diastolic BP (r=-0.17, P<0.005), WBC (r=-0.30, P<0.001), MPV (r=-0.41, P<0.001), and PCDW (r=-0.68, P<0.001), and positively con-elated with RBC (r=0.32, P<0.001), platelet count (r=0.21, P<0.05), and mean platelet mass (MPM) (r=0.18, P<0.05). MPC levels were found to be an independent factor associated with PIH and PCDW (P<0.01) after adjustments were made for potential confounding factors such as gestational age, systolic blood pressure, diastolic blood pressure, WBC, RBC, Platelet count, and PCDW. In conclusion, MPC levels were significantly lower in women with PIH, and MPC levels were found to be an independent factor associated with PIH and PCDW. Therefore, platelet activation is suggested as a useful predictor for patients with PIH.

• Korean Journal of Pharmacognosy
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• v.52 no.1
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• pp.26-33
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• 2021

During blood vessel damage, an essential step in the hemostatic process is platelet activation. However, it is important to properly control platelet activation, as various cardiovascular diseases, such as stroke, atherosclerosis, and myocardial infarction, are also caused by excessive platelet activation. Found primarily in the roots of plants of the genus Artemisia or Scopolia, isoscopoletin has been studied to demonstrate its potential pharmacological effects against Alzheimer's disease and anticancer, but the mechanisms and roles involved in thrombus formation and platelet aggregation are insufficient. This study investigated the effect of isoscopoletin on U46619-induced human platelet activation. As a result, isoscopoletin significantly increased the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) dose-dependently. In addition, isoscopoletin significantly phosphorylated inositol 1, 4, 5-triphosphate receptor (IP3R) and vasodilator-stimulated phosphprotein (VASP), which are known substrates for cAMP-dependent kinases and cGMP-dependent kinases. Phosphorylated IP3R by isoscopoletin inhibited Ca2+ mobilization from the dense tubular system Ca2+ channels to cytosol, and phosphorylated VASP was involved in the inhibition of fibrinogen binding through αIIb/β3 inactivation in the platelet membrane. Isoscopoletin finally reduced thrombin-induced fibrin clotting production. Therefore, this study suggests that isoscopoletin has a potent antiplatelet effect and may be helpful for platelet-related thrombotic diseases.

• Biomedical Science Letters
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• v.29 no.3
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• pp.184-189
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• 2023

Normal activation of platelets and their aggregation are crucial during hemostasis process. It appears excessive or abnormal aggregation of platelets may bring about cardiovascular diseases like stroke, atherosclerosis, and thrombosis. For this reason, finding a substance that can regulate platelet aggregation or suppress aggregation will aid in the prevention and treatment of cardiovascular diseases. Artemisinin, a compound derived from Artemisia or Scopolia plants, has shown potential in various areas such as anticancer and Alzheimer's disease research. However, the specific role and mechanisms by which artemisinin influences platelet activation and thrombus formation are not yet fully understood. This study investigated the effects of artemisinin on platelet activation and thrombus formation. This study examined the effect of artemisinin on regulation of U46619-induced platelet aggregation, granule secretion. In addition, the effects of artemisinin on phosphorylation of PI3K/Akt and MAPK pathway involved in platelet aggregation was studied. As a result, artemisinin significantly downregulated of PI3K/Akt and MAPK pathway. In addition, artemisinin significantly reduced granule secretion, and platelet aggregation was inhibited by artemisinin. Therefore, we suggest that artemisinin is an anti-platelet substance that regulates PI3K/Akt and MAPK pathway and is valuable as a therapeutic and preventive agent for platelet-derived cardiovascular disease.

• Journal of Food Hygiene and Safety
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• v.13 no.4
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• pp.355-359
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• 1998

Platelet activation is originated by the intracellular or/and extracellular $Ca^{2+}$. Agonist-induced $Ca^{2+}$ entry through a plasma-membrane pathway has been reported repeatedly, but the mechanisms has proven harder to elucidate. Recently, a number of natural products have been isolated from medicinal plants and marine organisms and have proved to be useful chemical tools for resolving the mechanism of cellular functions. In an attempt to understand the mechanism of platelet activation in Bupleuri Radix, we have studied some aspects of the isolation of active components and their dependence of external $Ca^{2+}$> on platelet activation. Acetone extract of Bupleuri Radix has the most activity on platelet activation and it's active components were identified as saikosaponin a and d. Their optimal concentration was respectively $20\;\mu\textrm{g}/ml$ and $5\;\mu\textrm{g}/ml$ and their platelet activation was not dependent on external $Ca^{2+}$>, whereas optimal concentration of each agonist was arachidonic acid ($10\;\mu\textrm{M}$), collagen ($10\;\mu\textrm{M}/ml$), thrombin (0.1 unit/mi), PAF (5 nM), PMA ($5\;\mu\textrm{M}$), ionophore A23187 ($2\;\mu\textrm{g}$) and their dependence of external $Ca^{2+}$> on platelet activation appeared to thrombin > collagen $\geq$ PAF > PMA > arachdonic acid> ionophore A23187. These results suggest that saikosaponin is different from each agonists in the dependence of external $Ca^{2+}$ on platelet activation.

• Journal of Applied Biological Chemistry
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• v.64 no.3
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• pp.317-322
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• 2021

Among the different cardiovascular disorders (CVDs), the activation of platelets is a necessary step. Based on this knowledge, therapeutic treatments for CVDs that target the disruption of platelet activation are proving to be worthwhile. One such substance, a bioactive 6,7-dihydroxy derived from coumarin, is 6,7-Dihydroxy-2H-1-benzopyran-2-one (esculetin). This compound has demonstrated several pharmacological effects on CVDS as well as various other disorders including diabetes, obesity, and renal failure. In various reports, esculetin and its effect has been explored in experimental mouse models, human platelet activation, esculetin-inhibited collagen, and washed human platelets exhibiting aggregation via arachidonic acid. Yet, esculetin affected aggregation with agonists like U46619 or thrombin in no way. This study investigated esculetin and how it affected human platelet aggregation activated through U46619. Ultimately, we confirmed that esculetin had an effect on the aggregation of human platelets when induced from U46619 and clarified the mechanism. Esculetin interacts with the downregulation of both phosphoinositide 3-kinase/Akt and mitogen-activated protein kinases, important phosphoproteins that are involved in activating platelets and their signaling process. The effects of esculetin reduced TXA₂ production, phospholipase A₂ activation, and platelet secretion of intracellular granules (ATP/serotonin), ultimately causing inhibition of overall platelet aggregation. These results clearly define the effect of esculetin in inhibiting platelet activity and thrombus formation in humans.

• International Journal of Internet, Broadcasting and Communication
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• v.11 no.4
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• pp.1-10
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• 2019

This Dietary cholesterol augments lipid profile and primes production and activation of platelets, leading to development of atherosclerosis which produce several detrimental effects on cardiovascular health. Ethnomedicine and Mediterranean diet are natural sources and cost effective modes against several ailments including cardiovascular diseases while fermented foods have gained interest due to their increased nutrient profile, enhanced bioavailability and efficacy. Garlic has been known to reduce cholesterol and inhibit platelet activation. We examined whether fermented garlic ameliorates effects of hypercholesterolemia and platelet functions in rats. Methodology: Male SD rats were fed with hypercholesterolemia diet and treated with spirulina, fermented and non-fermented preparations of garlic for one month. Platelet aggregation and granule secretion were assessed to evaluate platelet activation. Liver and kidney weights, lipid and enzymatic profile of serum and whole blood analysis was performed. Expressions of SREBP, ACAT-2 and HMG-CoA were assessed using RT-PCR while liver and adipose tissues were analyzed for histological changes. Both fermented and non-fermented garlic inhibited platelet aggregation and granule secretion while fermented garlic showed greater inhibitor tendency. Fermented garlic significantly reduced liver weight and triglycerides concentrations than non-fermented garlic. Similarly, fermented garlic greatly abrogated the detrimental effects of steatosis on liver and adipose tissues. Fermented garlic significantly improved lipid profile and modulated platelet functions, thereby inhibiting atherosclerosis and platelet related cardiovascular disorders.

• Journal of Ginseng Research
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• v.48 no.4
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• pp.428-434
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• 2024

Background: Platelet-leukocyte aggregates (PLAs) play important roles in cardiovascular disease and sepsis. Red ginseng extract (RGE) has been well-studied for its antiplatelet and anti-inflammatory activities. However, the potential inhibitory effects of RGE on PLA have not been investigated. Methods: Six-week-old ICR mice were given oral gavage of RGE for 7 days, followed by an intraperitoneal injection of 15 mg/kg of lipopolysaccharide. Mice were euthanized 24 h later, and blood samples were collected for further analysis. Flow cytometry was utilized to sort populations of PLAs and platelet-neutrophil aggregates (PNAs). By using confocal microscopy, PNAs were validated. Morphological changes in platelets and leukocytes were visualized with scanning electron microscopy. Expressions of tissue factor (TF) and platelet factor 4 (PF4) were investigated using enzyme-linked immunosorbent assay. Results: Populations of activated platelets, PLAs and PNAs, were significantly increased with LPS-induction. Treatment with 200 and 400 mg/kg of RGE decreased platelet activation. Moreover, the populations of PLAs and PNAs were reduced. PNAs were visible in the blood of septic mice, and this was attenuated by treatment with 400 mg/kg of RGE. Morphologically, sepsisinduced platelet activation and fibrin formation in the blood. This was reduced with RGE treatment. Sepsis-induced increase in the plasma levels of TF and PF4 was also reduced with RGE treatment. Conclusion: This study shows that RGE is a potential therapeutic that reduces the activation of platelets and targets PLA and PNA formation. Detailed inhibitory mechanisms of RGE should be studied.

• Biomedical Science Letters
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• v.23 no.3
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• pp.251-260
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• 2017

Platelet activation is essential at the sites of vascular injury, which leads to hemostasis through adhesion, aggregation, and secretion process. However, potent and continuous platelet activation may be an important reason of circulatory disorders. Therefore, proper regulation of platelet activation may be an effective treatment for vascular diseases. In this research, inhibitory effects of cordycepin (3'-deoxyadenosine) on platelet activation were determined. As the results, cordycepin increased cAMP and cGMP, which are intracellular $Ca^{2+}$-antagonists. In addition, cordycepin reduced collagen-elevated $[Ca^{2+}]_i$ mobilization, which was increased by a cAMP-dependent protein kinase (PKA) inhibitor (Rp-8-Br-cAMPS), but not a cGMP-protein kinase (PKG) inhibitor (Rp-8-Br-cGMPS). Furthermore, cordycepin increased $IP_3RI$ ($Ser^{1756}$) phosphorylation, indicating inhibition of $IP_3$-mediated $Ca^{2+}$ release from internal store via the $IP_3RI$, which was strongly inhibited by Rp-8-Br-cAMPS, but was not so much inhibited by Rp-8-Br-cGMPS. These results suggest that the reduction of $[Ca^{2+}]_i$ mobilization is caused by the cAMP/A-kinase-dependent $IP_3RI$ ($Ser^{1756}$) phosphorylation. In addition, cordycepin increased the phosphorylation of VASP ($Ser^{157}$) known as PKA substrate, but not VASP ($Ser^{239}$) known as PKG substrate. Cordycepin-induced VASP ($Ser^{157}$) phosphorylation was inhibited by Rp-8-Br-cAMPS, but was not inhibited by Rp-8-Br-cGMPS, and cordycepin inhibited collagen-induced fibrinogen binding to ${\alpha}IIb/{\beta}_3$, which was increased by Rp-8-Br-cAMPS, but was not inhibited by Rp-8-Br-cGMPS. These results suggest that the inhibition of ${\alpha}IIb/{\beta}_3$ activation is caused by the cAMP/A-kinase-dependent VASP ($Ser^{157}$) phosphorylation. In conclusion, these results demonstrate that inhibitory effects of cordycepin on platelet activation were due to inhibition of $[Ca^{2+}]_i$ mobilization through cAMP-dependent $IP_3RI$ ($Ser^{1756}$) phosphorylation and suppression of ${\alpha}IIb/{\beta}_3$ activation through cAMP-dependent VASP ($Ser^{157}$) phosphorylation. These results strongly indicated that cordycepin might have therapeutic or preventive potential for platelet activation-mediated disorders including thrombosis, atherosclerosis, myocardial infarction, or cardiovascular disease.