ABSTRACT
Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.
Subject(s)
Blood Platelets , Hydroquinones , Membrane Potential, Mitochondrial , Mitochondria , Organophosphorus Compounds , Platelet Aggregation Inhibitors , Reactive Oxygen Species , Mitochondria/metabolism , Mitochondria/drug effects , Humans , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/chemistry , Hydroquinones/pharmacology , Hydroquinones/chemistry , Blood Platelets/metabolism , Blood Platelets/drug effects , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/chemistry , Membrane Potential, Mitochondrial/drug effects , Reactive Oxygen Species/metabolism , Platelet Aggregation/drug effects , Platelet Activation/drug effects , Oxidative Phosphorylation/drug effectsABSTRACT
Although platelets are anucleated cells, they have fully functional mitochondria, and currently, it is known that several processes that occur in the platelet require the action of mitochondria. There are plenty of mitochondrial-targeted compounds described in the literature related to cancer, however, only a small number of studies have approached their interaction with platelet mitochondria and/or their effects on platelet activity. Recent studies have shown that magnolia extract and mitochondria-targeted magnolol can inhibit mitochondrial respiration and cell proliferation in melanoma and oral cancer cells, respectively, and they can also induce ROS and mitophagy. In this study, the effect of triphenylphosphonium cation, linked by alkyl chains of different lengths, to the organic compound magnolol on human-washed platelets was evaluated. We demonstrated that the addition of triphenylphosphonium by a four-carbon linker to magnolol (MGN4) considerably enhanced the Magnolol antiplatelet effect by a 3-fold decrease in the IC50. Additionally, platelets exposed to MGN4 5 µM showed several differences from the control including increased basal respiration, collagen-induced respiration, ATP-independent respiration, and reduced ATP-dependent respiration and non-mitochondrial respiration.
ABSTRACT
Phaseolus vulgaris L. has beneficial effects on several chronic non-communicable diseases (e.g., cardiovascular diseases) related to oxidative stress. This redox state may influence platelet activation and aggregation; which is crucial in thrombus formation. In this work, the antiplatelet and antioxidant potential of aqueous extracts obtained by green processes, microwave-assisted extraction and ultrasound-assisted extraction, from 25 landraces of common beans were investigated. Phenol content and antioxidant potential were determined using the Folin-Ciocalteu method, total monomeric anthocyanin and ORAC assay, respectively. The antiplatelet potential of the extracts was explored by turbidimetry. Microwave extraction showed higher phenol content and antioxidant activity in most extracts. Soja landrace extract obtained by microwave-assisted extraction showed higher phenol content and antioxidant activity (893.45 ± 87.30 mg GAE/g and 35,642.85 ± 2588.88 ORAC µmolTE/g, respectively). Although most of the extracts obtained by microwave-assisted extraction showed antiplatelet activity, the extract of Hallado Aleman landrace obtained by ultrasound-assisted extraction (IC50 = 0.152 ± 0.018 mg/mL) had the highest antiplatelet potential. The extraction method, MAE and UAE, influences the biological potential of the beans, specifically the antiplatelet activity and antioxidant activity. The functional value of this legume for direct consumption by the population was evidenced, as well as its inclusion in food formulations.
