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Platelet inhibition is a fundamental objective to prevent and treat thrombus formation. Platelet activation depends on mitochondrial function. This study aims to identify a new mitochondria-targeting compound with antiplatelet activity at safe concentrations in vitro. Cytotoxicity and viability tests were performed on human platelets from volunteer donors, together with experiments on aggregation, platelet activation, mitochondrial function, mitochondrial respiration, and thioredoxin reductase 2 (TrxR2) enzymatic activity in isolated platelet mitochondria. The compound MitoCDNB, corresponding to the molecule 5-chloro-2,4-dinitrophenylamino linked with triphenylphosphonium cation (TPP+) by a butyl chain and methanesulfonate as the counterion, was evaluated. MitoCDNB demonstrates potent, high mitochondria-selective antiplatelet effects that provide a novel approach to platelet inhibition with potentially minimized systemic risks. Here, we describe the first compound that inhibits platelet activation by decreasing TrxR2 enzymatic activity and collagen-stimulated maximal mitochondrial respiration, preventing aggregation and platelet activation. These results can be used to develop new antiplatelet drugs targeting mitochondria., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study explores the physiological changes associated with aging that lead to frailty syndrome, characterized by reduced vitality and degeneration across multiple bodily systems, increasing susceptibility to various pathologies. While established scales like the Fried Phenotype and Frailty Trait Scale (FTS) are commonly used for assessing frailty, incorporating biomarkers is crucial for accurate diagnosis and prognosis. Our research examines plasma oxylipin levels in frail elderly individuals to identify novel biomarkers. Diagnostic criteria for frailty included assessments using the Fried Phenotype and FTS-5, with blood samples collected from 71 elderly participants (50 women and 21 men) with mean ages of 73.6 ± 5.9 and 76.2 ± 6.2 years, respectively. Women exhibited elevated platelet counts (p-value 0.0035). The significant differences in oxylipin concentrations associated with the Fried Phenotype were particularly noteworthy, predominantly observed in women. Specifically, in women, decreased grip strength (<15 kg) and slow gait speed (<0.8 m/s) correlated with increased levels of thromboxane B 2 (TxB 2 ) and 7-HDoHE (p-values 0.0404, 0.0300, 0.0033, and 0.0033, respectively). Additionally, elevated 7-HDoHE levels correlated with a BMI exceeding 28 kg/m 2 (p-value 0.0123) and Physical Activity Scale for the Elderly (PASE) scores surpassing 5 points (p-value 0.0134) in women. In summary, our findings emphasize that frail older individuals, particularly women, exhibit higher levels of TxB 2 and 7-HDoHE compared to their non-frail counterparts, aligning with established frailty classification and scale parameters, suggesting their potential as indicative biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Platelets are small cell fragments that play a crucial role in hemostasis, requiring fast response times and fine signaling pathway regulation. For this regulation, platelets require a balance between two pathway types: the activatory and negative signaling pathways. Activatory signaling mediators are positive responses that enhance stimuli initiated by a receptor in the platelet membrane. Negative signaling regulates and controls the responses downstream of the same receptors to roll back or even avoid spontaneous thrombotic events. Several blood-related pathologies can be observed when these processes are unregulated, such as massive bleeding in activatory signaling inhibition or thrombotic events for negative signaling inhibition. The study of each protein and metabolite in isolation does not help to understand the role of the protein or how it can be contrasted; however, understanding the balance between active and negative signaling could help develop effective therapies to prevent thrombotic events and bleeding disorders.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The use of triphenylphosphonium cation (TPP + ) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10-12 carbon) increases the mitochondrial accumulation of TPP + -linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3-9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity., Methods: Human platelets were exposed in vitro to different concentrations (2-40 μM) of every compound; cellular viability, phosphatidylserine exposition, mitochondrial membrane potential (ΔΨm), intracellular calcium release, and intracellular ROS generation were assessed by flow cytometry. An in silico energetic profile was generated with Umbrella sampling molecular dynamics (MD)., Results and Conclusions: There was an increase in cytotoxic activity directly related to the length of the acyl chain and lipophilicity, as seen by three techniques, and this was consistent with a decrease in ΔΨm. The in silico energetic profiles point out that the permeability of the mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts. This information may be relevant for the design of new TPP + -based drugs with a safe cardiovascular profile., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive oxygen species (ROS) production, calcium homeostasis, apoptosis, and cell proliferation. However, the use of this type of antitumor compound presents a risk of bleeding since the platelet activation is especially dependent on the mitochondrial function. In this study, we evaluated the in vitro effect of three triphenylphosphonium-based compounds, honokiol (HNK), lonidamine (LDN), and atovaquone (ATO), on the platelet function linked to the triphenylphosphonium cation by a lineal 10-carbon alkyl chain and also the decyltriphenylphosphonium salt (decylphos). Methods: Platelets obtained by phlebotomy from healthy donors were exposed in vitro to different concentrations (0.1-10 μM) of the three compounds; cellular viability, exposure of phosphatidylserine, the mitochondrial membrane potential (∆Ψm), intracellular calcium release, and intracellular ROS generation were measured. Platelet activation and aggregation were induced by agonists (adenosine diphosphate, thrombin receptor-activating peptide-6, convulxin, or phorbol-12-myristate-13-acetate) and were evaluated by flow cytometry and light transmission, respectively. Results: The three compounds showed a slight cytotoxic effect from 1 μM, and this was concomitant with a decrease in ∆Ψm and intracellular calcium increase. Only ATO produced a modest but significant increase in intra-platelet ROS. Also, the three compounds increased the exposure to phosphatidylserine in platelets expressed in platelets positive for annexin V. None of the compounds had an inhibitory effect on the aggregation or activation markers of platelets stimulated with three different agonists. Similar results were obtained with decylphos. Conclusion: Triphenylphosphonium derivatives showed slight platelet toxicity below 1 μM, probably associated with their effect on ∆Ψm and exposure to phosphatidylserine, but no significant effect on platelet activation and aggregation, making them an antitumoral alternative with a low risk of bleeding. However, future assays on animal models and human trials are required to evaluate if their effects with a low risk for hemostasis are replicated in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Montecino-Garrido, Méndez, Araya-Maturana, Millas-Vargas, Wehinger and Fuentes.)