Undiagnosed type 2 diabetes is common - intensified screening of established risk groups is imperative in Sweden: the SDPP cohort.

BACKGROUND: Undiagnosed type 2 diabetes (T2D) is a global problem. Current strategies for diagnosis in Sweden include screening individuals within primary healthcare who are of high risk, such as those with hypertension, obesity, prediabetes, family history of diabetes, or those who smoke daily. In this study, we aimed to estimate the proportion of individuals with undiagnosed T2D in Stockholm County and factors associated with T2D being diagnosed by healthcare. This information could improve strategies for detection. METHODS: We used data from the Stockholm Diabetes Prevention Programme (SDPP) cohort together with information from national and regional registers. Individuals without T2D aged 35-56 years at baseline were followed up after two ten-year periods. The proportion of diagnosed T2D was based on register information for 7664 individuals during period 1 and for 5148 during period 2. Undiagnosed T2D was assessed by oral glucose tolerance tests at the end of each period. With logistic regression, we analysed factors associated with being diagnosed among individuals with T2D. RESULTS: At the end of the first period, the proportion of individuals with T2D who had been diagnosed with T2D or not was similar (54.0% undiagnosed). At the end of the second period, the proportion of individuals with T2D was generally higher, but they were less likely to be undiagnosed (43.5%). The likelihood of being diagnosed was in adjusted analyses associated with overweight (OR=1.85; 95% CI 1.22-2.80), obesity (OR=2.73; 95% CI 1.76-4.23), higher fasting blood glucose (OR=2.11; 95% CI 1.67-2.66), and self-estimated poor general health (OR=2.42; 95% CI 1.07-5.45). Socioeconomic factors were not associated with being diagnosed among individuals with T2D. Most individuals (>71%) who developed T2D belonged to risk groups defined by having at least two of the prominent risk factors obesity, hypertension, daily smoking, prediabetes, or family history of T2D, including individuals with T2D who had not been diagnosed by healthcare. CONCLUSIONS: Nearly half of individuals who develop T2D during 10 years in Stockholm County are undiagnosed, emphasizing a need for intensified screening of T2D within primary healthcare. Screening can be targeted to individuals who have at least two prominent risk factors.

Early substance use disorders and subsequent NEET-not in education, employment or training-a national cohort study.

BACKGROUND: Substance use problems have been associated with poor labour market outcomes. This study investigated whether substance use disorders (SUD) in emerging adulthood increase the likelihood of later being not in employment, education or training (NEET). METHODS: A national cohort study of 23 5295 males and 227 792 females born between 1981 and 1987. SUD was assessed between ages 17 and 24 years. Logistic regression models were used to estimate the odds ratios (ORs) of NEET, between ages 25-34. Sibling-comparison analysis was performed to account for potential shared genetic and environmental factors. RESULTS: Having been diagnosed with a SUD was associated with the likelihood of being NEET among males [OR = 1.37, 95% confidence interval (CI), 1.25-1.49] and females (1.19, 1.13-1.27) after adjusting for domicile, origin, psychiatric diagnosis and parental psychiatric diagnosis. Early SUD was also associated with a gradual increase in the ORs of accumulation of years being NEET. This was more evident among females. In the sibling-comparison analysis, we found a higher OR of NEET among same-sex sibling males 1.39 (1.06-1.82) and females 1.28 (0.99-1.66) with SUD. These risks were fully attenuated when another psychiatric diagnosis was adjusted for. CONCLUSION: Early SUD was associated with an increased likelihood of being NEET in both males and females. Neither origin, domicile, psychiatric diagnoses nor parental psychiatric diagnoses did fully explain the association. The combination of unmeasured familial factors and having other psychiatric disorders largely explained these associations.

A TinyML Deep Learning Approach for Indoor Tracking of Assets.

Positioning systems have gained paramount importance for many different productive sector; however, traditional systems such as Global Positioning System (GPS) have failed to offer accurate and scalable solutions for indoor positioning requirements. Nowadays, alternative solutions such as fingerprinting allow the recognition of the characteristic signature of a location based on RF signal acquisition. In this work, a machine learning (ML) approach has been considered in order to classify the RSSI information acquired by multiple scanning stations from TAG broadcasting messages. TinyML has been considered for this project, as it is a rapidly growing technological paradigm that aims to assist the design and implementation of ML mechanisms in resource-constrained embedded devices. Hence, this paper presents the design, implementation, and deployment of embedded devices capable of communicating and sending information to a central system that determines the location of objects in a defined environment. A neural network (deep learning) is trained and deployed on the edge, allowing the multiple external error factors that affect the accuracy of traditional position estimation algorithms to be considered. Edge Impulse is selected as the main platform for data standardization, pre-processing, model training, evaluation, and deployment. The final deployed system is capable of classifying real data from the installed TAGs, achieving a classification accuracy of 88%, which can be increased to 94% when a post-processing stage is implemented.

Characterization of Rice Yield Based on Biomass and SPAD-Based Leaf Nitrogen for Large Genotype Plots.

The use of Unmanned Aerial Vehicle (UAV) images for biomass and nitrogen estimation offers multiple opportunities for improving rice yields. UAV images provide detailed, high-resolution visual information about vegetation properties, enabling the identification of phenotypic characteristics for selecting the best varieties, improving yield predictions, and supporting ecosystem monitoring and conservation efforts. In this study, an analysis of biomass and nitrogen is conducted on 59 rice plots selected at random from a more extensive trial comprising 400 rice genotypes. A UAV acquires multispectral reflectance channels across a rice field of subplots containing different genotypes. Based on the ground-truth data, yields are characterized for the 59 plots and correlated with the Vegetation Indices (VIs) calculated from the photogrammetric mapping. The VIs are weighted by the segmentation of the plants from the soil and used as a feature matrix to estimate, via machine learning models, the biomass and nitrogen of the selected rice genotypes. The genotype IR 93346 presented the highest yield with a biomass gain of 10,252.78 kg/ha and an average daily biomass gain above 49.92 g/day. The VIs with the highest correlations with the ground-truth variables were NDVI and SAVI for wet biomass, GNDVI and NDVI for dry biomass, GNDVI and SAVI for height, and NDVI and ARVI for nitrogen. The machine learning model that performed best in estimating the variables of the 59 plots was the Gaussian Process Regression (GPR) model with a correlation factor of 0.98 for wet biomass, 0.99 for dry biomass, and 1 for nitrogen. The results presented demonstrate that it is possible to characterize the yields of rice plots containing different genotypes through ground-truth data and VIs.

Injury Surveillance and Training Load Methods Used by Health Professionals in Tennis: An Online Multinational Survey.

CONTEXT: Injury surveillance and training load monitoring are both essential for the development of preventative strategies for gradual-onset musculoskeletal injuries in elite sport. Our aim was to survey health professionals working with elite tennis players on whether and how they monitor injuries and training load. DESIGN: A cross-sectional multinational online open-survey. METHODS: The survey was developed and advertised in English, Spanish, and Portuguese languages on social media channels, a tennis academic journal, professional tennis associations, and clinical networks of the research team, from December 2020 to April 2021. RESULTS: 72 health professionals from 27 different countries working with elite tennis players responded to the survey. Injury surveillance is performed by 94% (68/72) of the survey respondents, with only 10% (7/68) using the consensus-recommended Oslo Sports Trauma Research Center questionnaire. Most common barriers identified by health professionals to injury surveillance are time constraints (66%), lack of knowledge (43%), and technology (31%). Training load monitoring is performed by 50% (36/72) of the health professionals working with elite tennis players. Main metrics monitored are weekly differences in training load (72%) and acute:chronic workload ratio (58%). Most common reasons for training load monitoring are injury prevention (94%), training planning (81%), and player feedback (53%). CONCLUSIONS: Despite a high percentage of health professionals implementing injury surveillance metrics, most of them do not use any validated method. Only half of health professionals working with elite tennis players monitor training load. Lack of knowledge and technology were the main barriers reported for adequately monitoring injuries.

Characterization of data-driven clusters in diabetes-free adults and their utility for risk stratification of type 2 diabetes.

BACKGROUND: The prevention of type 2 diabetes is challenging due to the variable effects of risk factors at an individual level. Data-driven methods could be useful to detect more homogeneous groups based on risk factor variability. The aim of this study was to derive characteristic phenotypes using cluster analysis of common risk factors and to assess their utility to stratify the risk of type 2 diabetes. METHODS: Data on 7317 diabetes-free adults from Sweden were used in the main analysis and on 2332 diabetes-free adults from Mexico for external validation. Clusters were based on sex, family history of diabetes, educational attainment, fasting blood glucose and insulin levels, estimated insulin resistance and ß-cell function, systolic and diastolic blood pressure, and BMI. The risk of type 2 diabetes was assessed using Cox proportional hazards models. The predictive accuracy and long-term stability of the clusters were then compared to different definitions of prediabetes. RESULTS: Six risk phenotypes were identified independently in both cohorts: very low-risk (VLR), low-risk low ß-cell function (LRLB), low-risk high ß-cell function (LRHB), high-risk high blood pressure (HRHBP), high-risk ß-cell failure (HRBF), and high-risk insulin-resistant (HRIR). Compared to the LRHB cluster, the VLR and LRLB clusters showed a lower risk, while the HRHBP, HRBF, and HRIR clusters showed a higher risk of developing type 2 diabetes. The high-risk clusters, as a group, had a better predictive accuracy than prediabetes and adequate stability after 20 years. CONCLUSIONS: Phenotypes derived using cluster analysis were useful in stratifying the risk of type 2 diabetes among diabetes-free adults in two independent cohorts. These results could be used to develop more precise public health interventions.

Long-Term Exposure to Source-Specific Fine Particles and Mortality─A Pooled Analysis of 14 European Cohorts within the ELAPSE Project.

We assessed mortality risks associated with source-specific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5 identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5 components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 µg/m3 increase) across five identified sources. On a 1 µg/m3 basis, the residual oil-related PM2.5 had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5 mass, suggesting that past estimates using the generic PM2.5 exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.

Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels.

Platelet activation plays a key role in cardiovascular diseases. The generation of mitochondrial reactive oxygen species (ROS) has been described as a critical step required for platelet activation. For this reason, it is necessary to find new molecules with antiplatelet activity and identify their mechanisms of action. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces mitochondrial overproduction of ROS. In this work, the antiplatelet effect of MitoQ through platelet adhesion and spreading, secretion, and aggregation was evaluated. Thus MitoQ, in a non-toxic effect, decreased platelet adhesion and spreading on collagen surface, and expression of P-selectin and CD63, and inhibited platelet aggregation induced by collagen, convulxin, thrombin receptor activator peptide-6 (TRAP-6), and phorbol 12-myristate 13-acetate (PMA). As an antiplatelet mechanism, we showed that MitoQ produced mitochondrial depolarization and decreased ATP secretion. Additionally, in platelets stimulated with antimycin A and collagen MitoQ significantly decreased ROS production. Our findings showed, for the first time, an antiplatelet effect of MitoQ that is probably associated with its mitochondrial antioxidant effect.

Platelet Activation Is Triggered by Factors Secreted by Senescent Endothelial HMEC-1 Cells In Vitro.

Aging is one of the main risk factors for the development of chronic diseases, with both the vascular endothelium and platelets becoming functionally altered. Cellular senescence is a form of permanent cell cycle arrest initially described in primary cells propagated in vitro, although it can also be induced by anticancer drugs and other stressful stimuli. Attesting for the complexity of the senescent phenotype, senescent cells synthesize and secrete a wide variety of bioactive molecules. This "senescence-associated secretory phenotype" (SASP) endows senescent cells with the ability to modify the tissue microenvironment in ways that may be relevant to the development of various physiological and pathological processes. So far, however, the direct role of factors secreted by senescent endothelial cells on platelet function remains unknown. In the present work, we explore the effects of SASP factors derived from senescent endothelial cells on platelet function. To this end, we took advantage of a model in which immortalized endothelial cells (HMEC-1) were induced to senesce following exposure to doxorubicin, a chemotherapeutic drug widely used in the clinic. Our results indicate that (1) low concentrations of doxorubicin induce senescence in HMEC-1 cells; (2) senescent HMEC-1 cells upregulate the expression of selected components of the SASP and (3) the media conditioned by senescent endothelial cells are capable of inducing platelet activation and aggregation. These results suggest that factors secreted by senescent endothelial cells in vivo could have a relevant role in the platelet activation observed in the elderly or in patients undergoing therapeutic stress.

In Vitro Assay of Quinoa (Chenopodium quinoa Willd.) and Lupin (Lupinus spp.) Extracts on Human Platelet Aggregation.

Cardiovascular disease (CVD) is the leading cause of death throughout the world. A major risk factor for CVD is platelet aggregation. Various plant extracts exhibit anti-aggregatory action in vitro. The dietary intake of traditional plant crops such as quinoa (Chenopodium quinoa Willd) and lupin (Lupinus spp., Fabaceae family), highly recognized for their high nutritional value, is increasing worldwide. The aim of the study was to assay possible antiplatelet effects of quinoa and lupin bean extracts in vitro. The proximate chemical composition of quinoa grains and the three most widely known lupin cultivars: blue (L. angustifolius), yellow (L. luteus or mutabilis) and white (L. albus) grown in Chile were analyzed. The anti-aggregation activity of the ethanol extracts of the crops was assayed using flow cytometry in ADP-stimulated human platelets, and their inhibition of the maximal platelet aggregation was measured. All the lupin extracts exhibited a significant anti-aggregatory effect (p < 0.0001), while quinoa extracts did not exert this effect compared to control platelets. In conclusion, lupin beans extracts exhibited an anti-aggregatory effect on activated human platelets.

Quality care in epilepsy: Women's counseling and its association with folic acid prescription or recommendation.

OBJECTIVE: This study aimed to determine if annual counseling about contraception and pregnancy in the setting of treatment for epilepsy is associated with increased recommending or prescribing of folate. METHODS: This is a retrospective cohort study with medical record abstraction. We selected records from 77 women of childbearing age who had two or more visits for epilepsy at a neurology clinic. The assessment included a review of documentation from the first three visits for epilepsy within a 24-month follow-up window. We defined perfect adherence to annual counseling about the impact of epilepsy treatment on contraception or pregnancy as defect-free care for women (DFCW). A recommendation that the patient take over-the-counter folate or a prescription for folate was independently abstracted from the chart at each visit. RESULTS: The group of patients who received DFCW (N=28, 36.36%) and the group who did not receive DFCW (N=49, 63.63%) were comparable with respect to age, disease duration, baseline history of drug-resistant epilepsy (DRE), presence of concurrent psychiatric disease, epileptologist involvement, number of antiepileptic drugs (AEDs) prescribed, seizure type, and etiology. Twenty (71.4%) patients in the DFCW group and 42 (85.7%) in the non-DFCW group were not recommended or prescribed folic acid (p=0.12). CONCLUSIONS: Even with annual documentation of counseling about how epilepsy treatment may affect contraception and pregnancy, the "action" of prescribing or recommending folic acid during the ensuing 24months is frequently omitted.

Validating the concept of top scavenger: the Andean Condor as a model species.

Vultures provide the key ecosystem service of quickly removing carrion, so they have recently been assumed to be top scavengers. To challenge the concept of top scavenger (i.e. the most influential in the scavenging community and process), between 2012 and 2019, we recorded the consumption of 45 equine carcasses available for two different avian scavenger guilds in the Tropical Andes; each guild included the Andean Condor, the alleged top scavenger. The carcasses eaten by Andean Condors were consumed, on average, 1.75 times faster than those they did not eat. Furthermore, the greater abundance of feeding condors shortened carcass consumption time more than a greater abundance of any other species by 1.65 to 5.96 times, on average. These findings support the hypothesis that the Andean Condor significantly drives scavenging dynamics and is, therefore, an unrestricted top scavenger. Additionally, we established a gradient of tolerance of avian scavengers to domestic dog disturbance at carcasses, from highest to lowest: vultures > caracaras > condors. Our study framework holds great potential for advancing in food webs' comprehension through quantifying the relative functional role of scavenging communities' members and for guiding efforts to weigh up the ecological contributions of top scavengers and foster their conservation.

Exploring the size of Andean condor foraging groups along an altitudinal and latitudinal gradient in the Tropical Andes: Ecological and conservation implications.

Patterns of variation in the size of vulture foraging groups, and their ecological causes and consequences, remain little explored despite strong links with the carrion recycling service that this key functional group provides. We documented the group size-frequency pattern of Andean condors Vultur gryphus gathered to feed on 42 equine carcasses experimentally placed in Bolivia, between 2012 and 2019, along an elevation range of 1,300-4,500 m asl. Based on the location (altitude and latitude) of the foraging groups, we examined the relationship between their size and species' population parameters (size and trend), habitat conditions, and livestock carcass availability and predictability. Condors utilized a high frequency (93%) of carcasses forming groups that ranged from 1 to 80 individuals (mean = 25, median = 18) and shaped a "lazy-J curve" typical pattern of size-frequency distribution whereby few groups (5, 12%) were large (> 55 individuals) and most (21, 50%) were relatively small (<19 individuals). Group size related to altitude in that most larger groups formed at lower sites (below c. 3,000 m asl), likely following an altitudinal gradient whereby larger groups are more likely to form around larger carcasses (i.e., cattle), which are more likely to occur at lower elevations. Regardless of population size, group size could be an adaptive response of condors via local enhancement for improving individual scavenging efficiency. Many information gaps on this topic still exist, thus we provide a set of questions to address them, especially amidst the unrestricted impacts of human activities that condition vulture survival globally.

Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function.

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.

An inexpensive paracetamol sensor based on an acid-activated carbon fiber microelectrode.

Paracetamol, a contaminant of emerging concern, has been detected in different bodies of water, where it can impact ecological and human health. To quantify this paracetamol, electroanalytical methods have gained support. Thus, the present study developed a simple, inexpensive, and environmentally friendly method for paracetamol quantification using a carbon fiber microelectrode based on commercial carbon fiber. To improve the carbon fiber microelectrode's paracetamol sensitivity and selectivity, it was subjected to an activation process via electrochemical oxidation in an acid medium (H2SO4 or HNO3), using 20 consecutive cycles of cyclic voltammetry. The treated (activated) carbon fiber microelectrode was characterized using scanning electron microscopy and electrochemical techniques, including chronoamperometry and electrochemical impedance spectroscopy. The H2SO4-activated carbon fiber microelectrode exhibited enhanced figures of merit, with a linear dynamic range of paracetamol detection from 0.5 to 11 µmol L-1 and a limit of detection of 0.21 µmol L-1 under optimized conditions. The method was optimized by quantifying paracetamol in commercial pharmaceutical tablets, spiked running tap water, and river water (Pita River, Quito, Ecuador, latitude -0.364955°, longitude -78.404538°); the respective recovery values were 102.89, 103.93, and 112.40%. The results demonstrated an acceptable level of accuracy and the promising applicability of this carbon fiber microelectrode as a sensor to detect paracetamol.

Chemical composition and antioxidant properties of native Ecuadorian fruits: Rubus glabratus Kunth, Vaccinium floribundum Kunth, and Opuntia soederstromiana.

The native berries of South America present promising marketing opportunities owing to their high antioxidant content, notably rich in anthocyanin and phenolic compounds. However, Ecuador's endemic fruits, primarily found in the wild, lack comprehensive data regarding their phytochemical composition and antioxidant capacity, underscoring the need for research in this area. Accordingly, this study evaluated the total phenolic, anthocyanin, flavonoid, resveratrol, ascorbic acid, citric acid, sugars, and antioxidant content of three native Ecuadorian fruits: mora de monte (Rubus glabratus Kunth), mortiño (Vaccinium floribundum Kunth), and tuna de monte (Opuntia soederstromiana). Determination of resveratrol, ascorbic acid, citric acid, and sugars was determined by HPLC analysis, and UPLC analysis was used to determine tentative metabolites with nutraceutical properties. Antioxidant capacity was assessed using cyclic voltammetry and the DPPH method; differential pulse voltammetry was used to evaluate antioxidant power. Analysis of results through UPLC-QTOF mass spectrometry indicated that R. glabratus Kunth and V. floribundum Kunth are important sources of various compounds with potential health-promoting functions in the body. The DPPH results showed the following antioxidant capacities for the three fruits: R. glabratus Kunth > O. soederstromiana > V. floribundum Kunth; this trend was consistent with the antioxidant capacity results determined using the electrochemical methods.

Time-domain transmission sensor system for on-site dielectric permittivity measurements in soil: A compact, low-cost and stand-alone solution.

Dielectric-based measurement techniques have been shown to be very effective in determining the properties of various materials. These techniques have been widely used in a variety of fields and applications. Time Domain Transmission (TDT) techniques have grown in popularity because they are practical, non-destructive, provide measurements in real time and produce accurate measurements that are independent of multiple reflections. TDT techniques, on the other hand, are mostly performed with specialized bulky laboratory equipment, such as a Vector Network Analyzer (VNA) which makes TDT measurements prohibitively costly and unpractical. In fact, few works in the literature have reported portable on-site TDT systems. The aim of this paper is to design and implement a dedicated, compact, and low-cost microwave Time Domain Transmission (TDT) sensor for measuring superficial soil dielectric properties on-site. Our sensor uses a time-delay measurement technique over a microstrip transmission line to estimate the dielectric properties of the soil under test. Measurement results show that the computed mean absolute error (MAE) is less than 1.2 when compared to a calibrated dielectric assessment kit (DAK) with soils containing less than 20 % of water ( ε ' r < 5.0 ), implying that our TDT sensor system can obtain on-site measurements in relatively dry soils with acceptable accuracy.

Progressive Rehabilitation Based on EMG Gesture Classification and an MPC-Driven Exoskeleton.

Stroke is a leading cause of disability and death worldwide, with a prevalence of 200 millions of cases worldwide. Motor disability is presented in 80% of patients. In this context, physical rehabilitation plays a fundamental role for gradually recovery of mobility. In this work, we designed a robotic hand exoskeleton to support rehabilitation of patients after a stroke episode. The system acquires electromyographic (EMG) signals in the forearm, and automatically estimates the movement intention for five gestures. Subsequently, we developed a predictive adaptive control of the exoskeleton to compensate for three different levels of muscle fatigue during the rehabilitation therapy exercises. The proposed system could be used to assist the rehabilitation therapy of the patients by providing a repetitive, intense, and adaptive assistance.

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.

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.