Assessing mitochondria-targeted acyl hydroquinones on the mitochondrial platelet function and cytotoxic activity: Role of the linker length.

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.

The Use of Triphenyl Phosphonium Cation Enhances the Mitochondrial Antiplatelet Effect of the Compound Magnolol.

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.

Frailty in Aging and the Search for the Optimal Biomarker: A Review.

In the context of accelerated aging of the population worldwide, frailty has emerged as one of the main risk factors that can lead to loss of self-sufficiency in older people. This syndrome is defined as a reduced state of physiological reserve and functional capacity. The main diagnostic tools for frailty are based on scales that show deficits compared to their clinical application, such as the Fried frailty phenotype, among others. In this context, it is important to have one or more biomarkers with clinical applicability that can objectively and precisely determine the degree or risk of frailty in older people. The objective of this review was to analyze the biomarkers associated with frailty, classified according to the pathophysiological components of this syndrome (inflammation, coagulation, antioxidants, and liver function, among others). The evidence demonstrates that biomarkers associated with inflammation, oxidative stress, skeletal/cardiac muscle function, and platelet function represent the most promising markers of frailty due to their pathophysiological association with this syndrome. To a lesser extent but with the possibility of greater innovation, biomarkers associated with growth factors, vitamins, amino acids, and miRNAs represent alternatives as markers of this geriatric syndrome. Likewise, the incorporation of artificial intelligence represents an interesting approach to strengthening the diagnosis of frailty by biomarkers.

Characterization by Gender of Frailty Syndrome in Elderly People according to Frail Trait Scale and Fried Frailty Phenotype.

Background: Frailty has emerged as one of the main geriatric syndromes to be prevented in order to improve quality of health and life in the elderly. In this sense, the characterization of this syndrome through reliable and feasible diagnostic tools for clinical use, such as the Frail Trait Scale 5 (FTS-5) and Frail Trait Scale 3 (FTS-3), represents the basis for this objective. Objectives: To characterize the frailty syndrome in a population of older adults using FTS-5, FTS-3, and Fried phenotype (FP) as frailty diagnostic tools. Design: Cross-sectional study. Participants: 300 adults ≥65 years recruited from different Family Health Centers and community groups of older people in Talca, Chile. Methods: The diagnosis of frailty was made according to FP, FTS-5, and FTS-3 tools. Data about sociodemographic characteristics and anthropometric measurements were collected by a clinical interview by a previously trained health professional. Results: A total prevalence of frailty according to the FP of 19.7% was observed; while in the group of women and men it was 21.4% and 15.0%, respectively. Concerning the FTS-5 tool, the total prevalence of frailty was 18%, while in the group of women and men was 18.0% and 17.5%, respectively. The FTS-3 tool shows a total prevalence of frailty of 23.3%, while in the group of women and men a prevalence of 22.7% and 25.0%, respectively. A significant difference is observed with respect to the presence of the Fried criteria of "weakness" (women: 21.4%, men: 38.8%) and "weight loss" (women: 16.8%, men: 7.5%; p < 0.05). A significant difference is observed concerning the average score of "Handgrip" criteria, "walking time", and "Physical Activity Scale for the Elderly" (PASE) between the group of women and men. Frailty, diagnosed by FTS-3, is significantly associated with the risk factors of overweight (body mass index ≥ 25) (OR: 10.225, 95% CI: 1.297−80.617) and advanced age (age ≥ 75 years) (OR: 1.839, 95% CI: 1.040−3.250). Conclusion: The prevalence of frailty observed with the FTS-5 (18%) and FTS-3 (23.3%) tools are similar to the prevalence observed through the FP (19.7%) and those reported in other observational studies. Considering the similar prevalence of frailty diagnosed with the three tools, FTS-3 should be a valuable tool for the screening of frailty in the community.

Comparando fuerza tensil en incisiones cerradas con nylon 5-0 y 2-octylcianoacrilato / Tensile strength of sutures closed with nylon or octylcyanoacrylate in rabbits

Objetivo: Comparar la fuerza tensil de heridas cerradas mediante una sutura monofilamento no reabsorbible (nylon 5-0) y un polímero adhesivo (2-octylcianoacrilato). Material y Método: Estudio experimental. En incisiones de piel, utilizando conejos de la misma raza, se han realizado dos grupos de diez conejos, con dos incisiones cada uno, cerradas con 2-octycianoacrilato y con nylon 5-0 como control. Se ha valorado la fuerza tensil mediante un tensiómetro, en 2 tiempos: al 7° día (grupo I) y al 10° día (grupo II) post cirugía, y se ha tomado una muestra para análisis histológico. Los cálculos estadísticos se hicieron a través de prueba T-Student, y un p < 0,05 se tomó como significación estadística. Resultados: El valor medio de la fuerza tensil en el grupo I fue de 9,65 + 2,72 Newtons para las incisiones cerradas con 2-octylcianoacrilato y 9,28 + 3,28 Newtons para las cerradas con nylon 5-0, no existiendo diferencia estadísticamente significativa (P = 0,801). En el grupo II el valor medio de la fuerza tensil fue 10,98 +4,80 Newtons para las incisiones cerradas con 2-octylcianoacrilato, y 9,08 + 3,58 Newtons para las cerradas con nylon 5-0, no existiendo diferencia estadísticamente significativa (p = 0,357). El estudio histológico mostró mayor inflamación, celularidad, fibrosis y proliferación vascular en incisiones cerradas con nylon 5-0. Conclusiones: La sutura de piel realizada con el polímero adhesivo 2-octylcianoacrilato es tan resistente a la tracción como la realizada con la sutura monofilamento no reabsorbible nylon 5-0 y presenta menor reacción inflamatoria local al estudio histológico.

Background: Cyanoacrylate can be used for incision closure with better esthetical results, less pain and lower incidence of infections. However, it could have a lower resistance to tension. Aim: To compare tensile strength of wounds closed with a non reabsorbable monofilament suture and octylcyanoacrylate. Material and Methods: Two skin incisions were done in the dorsal area of 20 rabbits. One incision was closed with nylon 5-0 with stitches every 0.5 cm and the other was closed with 2 layers of octylcyanoacrylate. Groups of nine rabbits were killed at seven and ten days after the procedure. A skin rectangle of the wound area was removed and the tensile force of the suture was measured with a specially devised instrument. A histological study of the incision was also done. Results: At seven days, tensile strength of sutures closed with cyanoacrylate and nylon were 9.65 + 2.72 and 9.28 + 2.38 Newtons, respectively, p=NS. At ten days, the figures were 10.98 + 4.8 and 9.08 + 3.58 Newtons respectively, p=NS. The histological study showed more inflammation, cellularity, fibrosis and vascular proliferation in sutures closed with nylon. Conclusions: No differences in tensile strength of sutures closed with cyanoacrylate or nylon were observed in this animal model. Sutures closed with nylon had a higher inflammatory reaction.