GuestSeminars
Zoom session
Add to Calendar 2024-11-12 14:00:00 2024-11-12 15:00:00 GuestSeminars@UCIBIO | Přemysl Mladěnka Antiplatelet effect of 4-methylcatechol, a flavonoid colonic metabolite Přemysl Mladěnka, Faculty of Pharmacy, Charles University, Czechia   Hosts: Fernando Remião, UCIBIO-FFUP ZOOM link: https://ucibio.pt/l/GuestSeminars   Abstract: Flavonoid can decrease the risk of ischemic stroke at least according to epidemiological studies. They have, however, very low bioavailability, and hence rather their metabolites can be responsible for the observed effect. Aims: a) To test if colonic metabolites of flavonoids possess the antiplatelet effect, b) to investigate the mechanism of action of the most potent of them Methods: Series of colonic metabolites of flavonoids were incubated with whole human blood ex vivo in presence of arachidonic acid, an inducer of platelet aggregation. Platelet activity was further tested by different methods (standard turbidimetry, impedance aggregometry, ELISA) to determine the mechanism of action. Generally healthy persons as well as patients suffering from hypercholesterolemia and diabetes mellitus were also included in the investigation. Results: Only 4 out of 29 metabolites appeared to have a clinically relevant effect with 4-methylcatechol (4MC) being the most active by far. It inhibited platelet aggregation with an IC50 of approximately 3 µM, which is about one order of magnitude lower than that of the standard antiplatelet drug acetylsalicylic acid (aspirin, ASA). These results were confirmed in groups of generally healthy persons as well as in patients. Future mechanistic investigation revealed that 4MC did not block cyclooxygenase 1 or thromboxane synthase at achievable concentrations but affected coupling of these enzymatic reactions. Structure analysis uncovered that catechol ring is not needed for a strong antiplatelet effect. Conclusion: 4MC, a common metabolite of many polyphenolic compounds, is a potent antiplatelet substance with higher potency than ASA and can be employed as a template for novel antiplatelet drugs. Acknowledgement: This work was supported by the Czech Research Health Council (NU21-02-00135).   Short Bio: Prof. Přemysl Mladěnka, Pharm.D., Ph.D., born 1980, is an experimental pharmacologist working at the Faculty of Pharmacy, Charles University, Czech Republic. He was appointed full professor of human and veterinary pharmacology in 2020. His research is mostly dedicated to the cardiovascular system with emphasis on investigation of the effects of natural compounds, their metabolites or close derivatives on the heart and vascular function, and blood platelets at different levels (in vitro, ex vivo and in vivo). He is also investigating novel chelators of different pathophysiologically relevant metals (e.g. iron, copper, cobalt, zinc, calcium, magnesium). He served as an editor in Nutrients (2019-2024), from 2021 nowadays he has been an academic editor in Oxidative Medicine and Cellular Longevity. At present, he is an author of 118 peer-reviewed papers, which were cited more than 2700 times. His H-index without self-citations is 26 (Scopus, 5.11.2024). More information is available at https://portal.faf.cuni.cz/Profile/Mladenka-Premysl/?lang=en-gb   Zoom session UCIBIO info@simbiose.com Europe/Lisbon public
mladenka

Antiplatelet effect of 4-methylcatechol, a flavonoid colonic metabolite

Přemysl Mladěnka, Faculty of Pharmacy, Charles University, Czechia

 

Hosts: Fernando Remião, UCIBIO-FFUP


ZOOM link: https://ucibio.pt/l/GuestSeminars

 

Abstract:

Flavonoid can decrease the risk of ischemic stroke at least according to epidemiological studies. They have, however, very low bioavailability, and hence rather their metabolites can be responsible for the observed effect.


Aims: a) To test if colonic metabolites of flavonoids possess the antiplatelet effect, b) to investigate the mechanism of action of the most potent of them


Methods: Series of colonic metabolites of flavonoids were incubated with whole human blood ex vivo in presence of arachidonic acid, an inducer of platelet aggregation. Platelet activity was further tested by different methods (standard turbidimetry, impedance aggregometry, ELISA) to determine the mechanism of action. Generally healthy persons as well as patients suffering from hypercholesterolemia and diabetes mellitus were also included in the investigation.


Results: Only 4 out of 29 metabolites appeared to have a clinically relevant effect with 4-methylcatechol (4MC) being the most active by far. It inhibited platelet aggregation with an IC50 of approximately 3 µM, which is about one order of magnitude lower than that of the standard antiplatelet drug acetylsalicylic acid (aspirin, ASA). These results were confirmed in groups of generally healthy persons as well as in patients. Future mechanistic investigation revealed that 4MC did not block cyclooxygenase 1 or thromboxane synthase at achievable concentrations but affected coupling of these enzymatic reactions. Structure analysis uncovered that catechol ring is not needed for a strong antiplatelet effect.


Conclusion: 4MC, a common metabolite of many polyphenolic compounds, is a potent antiplatelet substance with higher potency than ASA and can be employed as a template for novel antiplatelet drugs.


Acknowledgement: This work was supported by the Czech Research Health Council (NU21-02-00135).

 

Short Bio:

Prof. Přemysl Mladěnka, Pharm.D., Ph.D., born 1980, is an experimental pharmacologist working at the Faculty of Pharmacy, Charles University, Czech Republic. He was appointed full professor of human and veterinary pharmacology in 2020. His research is mostly dedicated to the cardiovascular system with emphasis on investigation of the effects of natural compounds, their metabolites or close derivatives on the heart and vascular function, and blood platelets at different levels (in vitro, ex vivo and in vivo). He is also investigating novel chelators of different pathophysiologically relevant metals (e.g. iron, copper, cobalt, zinc, calcium, magnesium). He served as an editor in Nutrients (2019-2024), from 2021 nowadays he has been an academic editor in Oxidative Medicine and Cellular Longevity. At present, he is an author of 118 peer-reviewed papers, which were cited more than 2700 times. His H-index without self-citations is 26 (Scopus, 5.11.2024). More information is available at https://portal.faf.cuni.cz/Profile/Mladenka-Premysl/?lang=en-gb  

GuestSeminars@UCIBIO | Přemysl Mladěnka