3,5,2′,4′-Tetramethoxystilbene, a fully methylated resveratrol analog, prevents platelet aggregation and thrombus formation by targeting the protease-activated receptor 4 pathway

Chiang, Yi-Chun; Wu, Yu-Shan; Wang, Hui‐Chun; Tsai, Meng-Chun; Wu, Chueh-Hung

doi:10.1016/j.cbi.2022.109889

Cited by 7 publications

(5 citation statements)

References 51 publications

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“…To our knowledge, no similar data exists to compare our results. However, a recent study reported that the 3,5,2′,4′-tetramethoxystilbene selectively inhibits PAR4-mediated human platelet aggregation, ATP secretion, integrin αIIbβ3 activation, and signaling pathways [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Platelets are crucial in primary hemostasis and thrombus formation, but recent evidence suggests their involvement in diseases such as atherosclerosis, cancer, diabetes, and neurodegeneration [ 25 ]. We have previously shown that resveratrol acetylated derivatives could inhibit platelet aggregation against PAF [ 26 ]; however, there is only one recent study that found that the 3,5,2′,4′-tetramethoxy derivative of resveratrol inhibits thrombin-induced platelet aggregation [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Fragopoulou,

Gkotsi,

Petsini

et al. 2023

Molecules

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Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives’ ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives’ anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4′-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4′-methyl group of 4′-methoxy derivative is oriented similarly to the fluorophenyl–pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4′-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Fragopoulou,

Gkotsi,

Petsini

et al. 2023

Molecules

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“…And lastly, 3,5,2′,4′-tetramethoxystilbene (TMS) is a fully methylated analog of resveratrol, a phenol found in red wine. TMS binds PAR4 and has been shown to reduce thrombus formation in vitro ( 45 ). P2Y1 targeting: Platelets express P2Y1 and P2Y12 ADP-receptors ( 15 , 46 ).…”

Section: The Present and Future Of Antiplatelet Therapeuticsmentioning

confidence: 99%

“…BMS-986120 and BMS-986141 are specific, small molecule inhibitors of PAR4, which show antithrombotic efficacy with very low bleeding effect in nonhuman primates and in healthy individuals, and the latter is showing promise in an ongoing clinical trial (42,43). P4pal-i1 is a PAR4 pepducin inhibitor currently being investigated for antithrombotic properties, and has been shown to significantly decrease arterial occlusion in guinea pigs (44). And lastly, 3,5,2′,4′-tetramethoxystilbene (TMS) is a fully methylated analog of resveratrol, a phenol found in red wine.…”

Section: New Antiplatelet Therapy Directed Against Proposed Target Pa...mentioning

confidence: 99%

Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis

Sim,

Shiferawe,

Wood

2023

Front. Cardiovasc. Med.

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Antithrombotic therapy is a delicate balance between the benefits of preventing a thrombotic event and the risks of inducing a major bleed. Traditional approaches have included antiplatelet and anticoagulant medications, require careful dosing and monitoring, and all carry some risk of bleeding. In recent years, several new targets have been identified, both in the platelet and coagulation systems, which may mitigate this bleeding risk. In this review, we briefly describe the current state of antithrombotic therapy, and then present a detailed discussion of the new generation of drugs that are being developed to target more safely existing or newly identified pathways, alongside the strategies to reverse direct oral anticoagulants, showcasing the breadth of approaches. Combined, these exciting advances in antithrombotic therapy bring us closer than we have ever been to the “holy grail” of the field, a treatment that separates the hemostatic and thrombotic systems, preventing clots without any concurrent bleeding risk.

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“…The effects of resveratrol on mitigating CVD risk factors have been attributed to its antioxidant [ 106 ], anti-inflammatory [ 161 ], antiplatelet [ 162 ], and lipid-lowering properties in preclinical studies [ 163 , 164 ]. Regarding the effect in humans, the first clinical trial of resveratrol with CVD patients was reported by Brasnyó et al [ 36 ] , in which, type 2 diabetic patients showed improvements in insulin sensitivity and oxidative stress after taking 10 mg of resveratrol daily for one month.…”

Section: What Is Known About Their Effect On Cardiac Aging and Cvd?mentioning

confidence: 99%

Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences

et al. 2022

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The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease (CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction (CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas: (1) mechanisms underlying age-related cardiac remodeling; (2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women; (3) we select a few polyphenol or polyamine rich compounds as the CR-mimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

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3,5,2′,4′-Tetramethoxystilbene, a fully methylated resveratrol analog, prevents platelet aggregation and thrombus formation by targeting the protease-activated receptor 4 pathway

Cited by 7 publications

References 51 publications

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis

Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences

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