[Trauma Injuries Associated with Rope Bullfights in the Azores: A Cross-Sectional Study]. / Trauma Associado às Touradas à Corda nos Açores: Um Estudo Transversal.

INTRODUCTION: The aim of the study was to describe trauma injuries associated with rope bullfights in the Azores, Portugal, regarding the cause of the incident, trauma mechanism, most affected anatomical areas, and injury severity. METHODS: Two-year cross-sectional study in the local hospital with prospective data collection. Patients who were consecutively admitted to the local hospital's emergency department with trauma injuries from the bull's direct impact or from falls either during the bull's escape or when handling the rope, were included. Data on general demographics, lesion characteristics, treatments, need for hospitalization and mortality were collected. RESULTS: Fifty-six incidents and 80 trauma injuries were identified. The main cause of trauma was the bull's direct impact (37; 66.07%) and the mechanism of injury was blunt trauma in all patients (100%; 56). Head and neck injuries (27; 33.75%) were the most common. The median Injury Severity Score at the emergency department admission was 4. Major trauma was noted in five patients (8.92%). Ten patients (17.85%) needed hospitalization with a median hospital stay of seven days. Three of the 10 hospitalized patients (30%) were previously admitted to the intensive care unit. Surgery was performed in six patients (10.71%). CONCLUSION: The main cause of trauma was the bull's direct impact, and the mechanism of injury was blunt trauma. The most affected anatomical areas were the head and neck. These findings are a wake-up call to the impact of these events regarding the economic costs they entail, the costs for the health of the local population, the safety measures currently implemented and the availability of the necessary means to treat these patients.

Introdução: O objetivo deste estudo foi caracterizar as lesões traumáticas tauromáquicas ocorridas nas touradas à corda nos Açores no que diz respeito à causa do incidente, mecanismo de trauma, área anatómica mais afetada e gravidade das lesões. Métodos: Estudo unicêntrico, transversal, com a colheita prospetiva de dados realizada durante dois anos. Foram incluídos os doentes que consecutivamente recorreram ao serviço de urgência do hospital local por lesões traumáticas ocorridas por trauma direto com o animal ou quedas aquando da fuga ou manuseio da corda. Foram colhidos dados demográficos gerais, características da lesão, tratamentos efetuados, necessidade de internamento hospitalar e mortalidade. Foi realizada uma análise estatística descritiva com recurso ao software estatístico SPSS. Resultados: Registaram-se 56 admissões hospitalares e 80 lesões traumáticas. A principal causa de traumatismo foi o trauma direto com o animal (37; 66,07%) e o mecanismo de lesão foi o trauma fechado (56; 100%). As áreas anatómicas mais afetadas foram a cabeça e pescoço (27; 33,75%). A mediana de Injury Severity Score foi de 4 à admissão hospitalar. Cinco doentes (8,92%) apresentaram trauma major. Dez doentes (17,85%) necessitaram de internamento hospitalar com uma mediana de dias de internamento de sete (IIQ 4,5 dias). Três (30%) dos doentes internados necessitaram de internamento em unidade de cuidados intensivos. Seis doentes (10,71%) foram submetidos a cirurgia. Conclusão: A principal causa de traumatismo foi o trauma direto com o animal e o mecanismo de lesão foi o trauma fechado. As áreas anatómicas mais afetadas foram a cabeça e pescoço. Estes dados constituem um alerta para o impacto destes eventos no que diz respeito aos custos económicos que acarretam, aos custos para a saúde da população local, às medidas de segurança atualmente implementadas e à disponibilidade dos meios necessários para tratar estes doentes.

Best Practices for Data Management and Sharing in Experimental Biomedical Research.

Effective data management is crucial for scientific integrity and reproducibility, a cornerstone of scientific progress. Well-organized and well-documented data enable validation and building upon results. Data management encompasses activities including organization, documentation, storage, sharing, and preservation. Robust data management establishes credibility, fostering trust within the scientific community and benefiting researchers' careers. In experimental biomedicine, comprehensive data management is vital due to the typically intricate protocols, extensive metadata, and large datasets. Low-throughput experiments, in particular, require careful management to address variations and errors in protocols and raw data quality. Transparent and accountable research practices rely on accurate documentation of procedures, data collection, and analysis methods. Proper data management ensures long-term preservation and accessibility of valuable datasets. Well-managed data can be revisited, contributing to cumulative knowledge and potential new discoveries. Publicly funded research has an added responsibility for transparency, resource allocation, and avoiding redundancy. Meeting funding agency expectations increasingly requires rigorous methodologies, adherence to standards, comprehensive documentation, and widespread sharing of data, code, and other auxiliary resources. This review provides critical insights into raw and processed data, metadata, high-throughput versus low-throughput datasets, a common language for documentation, experimental and reporting guidelines, efficient data management systems, sharing practices, and relevant repositories. We systematically present available resources and optimal practices for wide use by experimental biomedical researchers.

Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.

Characterizing Early Cardiac Metabolic Programming via 30% Maternal Nutrient Reduction during Fetal Development in a Non-Human Primate Model.

Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.

Idosos Domiciliados: Saúde Geral x Higiene Bucal / Elderly People Living at Home: General Health x Oral Hygiene

O Serviço Integrado da Assistência Domiciliar (SIAD) foi criado a fim de prestar atendimento integral domiciliar a idosos que apresentam incapacidade de se locomover para as unidades de atendimento de saúde da Marinha do Brasil (MB). Com a finalidade de avaliar o perfil de saúde geral e de higiene dental desses pacientes, foi realizado um estudo transversal, quantitativo e descritivo, no qual foram incluídos idosos com 60 anos ou mais, assistidos entre fevereiro de 2017 a dezembro de 2022. Pode-se observar que a maioria dos idosos eram longevos, com média de idade de 82,52 anos (±8,66), mulheres (63,52%) e possuíam dependência total para realizar atividades básicas de vida diária (88,9%). Conclui-se que a síndrome demencial foi o diagnóstico principal mais encontrado (44,3%), a maioria possuía comorbidade associada (71,9%), sendo a Hipertensão Arterial Sistêmica (59,2%) e o Diabetes Mellitus (28,9%) as mais recorrentes. Foi encontrada uma elevada prevalência de idosos domiciliados com higiene bucal insatisfatória (34,7%) ou irregular (57,2%). No entanto, não houve associação entre higiene dental, comorbidades e grau de dependência. Assim sendo, é imprescindível que os idosos domiciliados recebam orientações e sejam submetidos a um acompanhamento rigoroso e constante, juntamente com seus cuidadores, a fim de promover a melhoria da higiene oral desses pacientes.

The Integrated Home Assistance Service (IHAS) was created to provide integral home care for elderly people who are unable to go to the health care units of the Brazilian Navy. A cross-sectional, quantitative, and descriptive study was carried out to evaluate the general health and dental hygiene profile of these patients. The study included elderly people aged 60 years or older who were assisted between February 2017 and December 2022. Most of them were long-lived, with a mean age of 82.52 (±8.66) years, women (63.52%) and totally dependent on performing basic activities of daily living (88.9%). The most common diagnosis among them was dementia syndrome, accounting for 44.3% of cases. Additionally, a large portion of the elderly had associated comorbidities (71.9%), with Systemic Arterial Hypertension (59.2%) and Diabetes Mellitus (28.9%) as the most recurrent conditions. The study found a high prevalence of elderly with unsatisfactory (34.7%) or irregular (57.2%) oral hygiene. Nevertheless, there was no significant association between dental hygiene and comorbidities or the degree of dependence. Therefore, it is imperative that elderly people living at home receive guidance and undergo meticulous and ongoing monitoring, in conjunction with their caregivers to promote improvements in the oral hygiene of these patients.

Influence of the maxillary dimensions and anterior teeth anatomy on the buccal impaction of upper permanent canines: A three-dimensional case-control study.

OBJECTIVE: The diagnosis of impacted upper permanent canines (IUPC) is a relatively common clinical finding. The aim of this study was to investigate the association of the buccal impaction of upper permanent canines with their dimensions and the maxilla bone base. MATERIAL AND METHODS: Cone beam computed tomography files of 66 patients were allocated into: impaction group (ICG/n=33/mean age 15.7±3.9 years), with 44 impacted canines by the buccal side; control group (CG/n=33/mean age 15.66±3.99 years), matched for age and sex, with 66 canines normally erupted. The following measurements were obtained from ICG and CG groups: linear and volumetric canine dimensions, linear measurements of upper permanent central and lateral incisors, measurements of the anterior perimeter and transverse segments of the maxilla. Independent Student's t-test was used for intergroup analysis with correction of Bonferroni (α=0,005). RESULTS: Higher values were found in the means of the variables regarding to the anterior teeth crowns in the ICG group, however, without a significant difference (P<0,005). The upper arch anterior perimeter of the individuals with canine impaction through buccal area was reduced compared to CG (P=0.001). CONCLUSIONS: It can be concluded that individuals with upper buccal impacted permanent canine showed a significantly smaller anterior perimeter of the maxillary arch when compared to the control group. Although greater canine mesiodistal diameter was found in this group, there is no statistical association with the occurrence of this condition.

Influence of the maxillary dimensions and lateral incisor anatomy on the palatal impaction of maxillary permanent canines: A three-dimensional case-control study.

OBJECTIVE: The diagnosis of impacted upper permanent canines (IUPC) is a relatively common clinical finding. The aim of this study was to investigate associations between the upper permanent canines palatal impaction, lateral incisors morphology and the maxilla bone base. MATERIAL AND METHODS: Cone-beam tomography files from 62 subjects were divided into 2 groups: impaction group (ICG/n=31; mean age 14.3±2.4) with 45 canines impacted on the palatal side and age- and sex-matched control group (CG/n=31; mean age 14.3±2.3), with 62 normally erupted canines. Linear and volumetric measurements of the lateral incisors, linear transversal measures and the maxillary anterior perimeter were taken. Independent Student's t-test was used for intergroup analysis with correction of Bonferroni. RESULTS: Significant differences were found for crown length and root diameter (buccal-palatal) (P<0.005). The maxillary anterior perimeter in the ICG was reduced in relation to the GC but not significantly (P=0.008). The transverse skeletal variables of the maxilla were equivalent in the intergroup comparison (P>0.005). CONCLUSION: Smaller dimensions in the crown length and in the upper permanent lateral incisors root buccal-palatal diameter were associated with the impaction of upper permanent canines on the palatal side. The maxillary transverse morphology did not show any association with the occurrence of this condition.

Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.

Maternal obesity (MO) is rising worldwide, affecting half of all gestations, constituting a possible risk-factor for some pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress (OS) and mitochondrial dysfunction. Maternal hepatic disease increases maternal and fetal morbidity and mortality. Understanding the role of MO on liver function and pathophysiology could be crucial for better understanding the altered pathways leading to PALD and liver disease, possibly paving the way to prevention and adequate management of disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes (fed 150% of recommended nutrition starting 60 days before conception). Maternal hepatic redox state, mitochondrial respiratory chain (MRC), and OS markers were investigated. MO decreased MRC complex-II activity and its subunits SDHA and SDHB protein expression, increased complex-I and complex-IV activities despite reduced complex-IV subunit mtCO1 protein expression, and increased ATP synthase ATP5A subunit. Hepatic MO-metabolic remodeling was characterized by decreased adenine nucleotide translocator 1 and 2 (ANT-1/2) and voltage-dependent anion channel (VDAC) protein expression and protein kinase A (PKA) activity (P<0.01), and augmented NAD+/NADH ratio due to reduced NADH levels (P<0.01). MO showed an altered redox state with increased OS, increased lipid peroxidation (P<0.01), decreased GSH/GSSG ratio (P=0.005), increased superoxide dismutase (P=0.03) and decreased catalase (P=0.03) antioxidant enzymatic activities, lower catalase, glutathione peroxidase (GPX)-4 and glutathione reductase protein expression (P<0.05), and increased GPX-1 abundance (P=0.03). MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.

Treatment of intracardiac thrombi using ultra-slow low-dose thrombolytic therapy: A case report.

A 57-year-old male with previously known severe primary mitral regurgitation was admitted to the intensive care unit (ICU) due to massive venous thromboembolism, associated with right ventricular dysfunction and two large mobile right atrial thrombi. Due to deterioration in his clinical condition despite standard treatment with unfractionated heparin, it was decided to use an ultra-slow low-dose thrombolysis protocol, which consisted of a 24-hour infusion of 24 mg of alteplase at a rate of 1 mg per hour, without initial bolus. The treatment was continued for 48 consecutive hours, with clinical improvement and resolution of the intracardiac thrombi and no complications. One month after ICU admission, successful mitral valve repair surgery was conducted. This case demonstrates that ultra-slow low-dose thrombolysis is a valid bailout treatment option in patients with large intracardiac thrombi refractory to the standard approach.

Metabolic Priming as a Tool in Redox and Mitochondrial Theragnostics.

Theragnostics is a promising approach that integrates diagnostics and therapeutics into a single personalized strategy. To conduct effective theragnostic studies, it is essential to create an in vitro environment that accurately reflects the in vivo conditions. In this review, we discuss the importance of redox homeostasis and mitochondrial function in the context of personalized theragnostic approaches. Cells have several ways to respond to metabolic stress, including changes in protein localization, density, and degradation, which can promote cell survival. However, disruption of redox homeostasis can lead to oxidative stress and cellular damage, which are implicated in various diseases. Models of oxidative stress and mitochondrial dysfunction should be developed in metabolically conditioned cells to explore the underlying mechanisms of diseases and develop new therapies. By choosing an appropriate cellular model, adjusting cell culture conditions and validating the cellular model, it is possible to identify the most promising therapeutic options and tailor treatments to individual patients. Overall, we highlight the importance of precise and individualized approaches in theragnostics and the need to develop accurate in vitro models that reflect the in vivo conditions.

Family Satisfaction With Critical Care: Before and After the COVID-19 Outbreak.

Introduction Family satisfaction with intensive care units (ICU) is recognized as a key component of the quality of care. As a result, family members are now more involved in the care process, and their needs are recognized throughout the ICU stay. The coronavirus disease 2019 (COVID-19) changed healthcare worldwide, due to the several restrictions imposed; the communication patterns changed drastically, and institutions were forced to adapt to create a balance between security and the needs of relatives. The aim of this study was to assess family members' satisfaction with the ICU and determine if the COVID-19 restructuring affected family satisfaction. Methods A prospective observational study was performed among the designated family members (DFM) of ICU patients over two time periods, a pre-pandemic period from December 2019 to February 2020 and a pandemic period from May 2020 to February 2021. The Family Satisfaction in the Intensive Care Unit 24 (FS-ICU 24) questionnaire, which was given to the DFM, was the instrument used to determine family satisfaction. Results The study involved 290 DFM, 175 during the pre-pandemic phase and 115 during the pandemic period. The overall and domain-specific family satisfaction scores were high (score > 80) in both the pre-pandemic and pandemic periods. The greatest satisfaction levels were related with symptom management and how nurses and doctors cared for the patient. No statistical differences were found between the two time periods. Lastly, a positive association between the two domains explored by FS-ICU 24, satisfaction with care and satisfaction with decision-making process, was verified in both time frames. Conclusion The data obtained revealed very good outcomes on the different FS-ICU 24 domains, in line with other studies in literature. No significant differences were found between the pre-pandemic and pandemic periods, suggesting that the measures implemented during the COVID-19 were successful. The importance of involving families in the decision-making process, providing them with accurate information, and active listening, as well as using better communication skills, is emphasized throughout all these results. The relevance of measuring family satisfaction should be brought to the attention of family members and healthcare professionals so that additional research may be conducted.

Predicting kill sites of an apex predator from GPS data in different multiprey systems.

Kill rates are a central parameter to assess the impact of predation on prey species. An accurate estimation of kill rates requires a correct identification of kill sites, often achieved by field-checking GPS location clusters (GLCs). However, there are potential sources of error included in kill-site identification, such as failing to detect GLCs that are kill sites, and misclassifying the generated GLCs (e.g., kill for nonkill) that were not field checked. Here, we address these two sources of error using a large GPS dataset of collared Eurasian lynx (Lynx lynx), an apex predator of conservation concern in Europe, in three multiprey systems, with different combinations of wild, semidomestic, and domestic prey. We first used a subsampling approach to investigate how different GPS-fix schedules affected the detection of GLC-indicated kill sites. Then, we evaluated the potential of the random forest algorithm to classify GLCs as nonkills, small prey kills, and ungulate kills. We show that the number of fixes can be reduced from seven to three fixes per night without missing more than 5% of the ungulate kills, in a system composed of wild prey. Reducing the number of fixes per 24 h decreased the probability of detecting GLCs connected with kill sites, particularly those of semidomestic or domestic prey, and small prey. Random forest successfully predicted between 73%-90% of ungulate kills, but failed to classify most small prey in all systems, with sensitivity (true positive rate) lower than 65%. Additionally, removing domestic prey improved the algorithm's overall accuracy. We provide a set of recommendations for studies focusing on kill-site detection that can be considered for other large carnivore species in addition to the Eurasian lynx. We recommend caution when working in systems including domestic prey, as the odds of underestimating kill rates are higher.

Workplace isolation, loneliness and wellbeing at work: The mediating role of task interdependence and supportive behaviours.

Despite the negative impact of social isolation on wellbeing, research has yet to address how organisations may mitigate the effects of workplace isolation and loneliness. The main objective of the study is to explore the mediating role of task interdependence and supportive behaviours of colleagues on the relationship between workplace isolation on workplace wellbeing. A total of 137 volunteers completed a survey assessing workplace isolation, loneliness, task interdependence, supportive behaviours of colleagues and wellbeing at work. SEM analyses supported the negative effects of company isolation on workplace wellbeing. While supportive behaviours had a mediating role, task interdependence did not mediate the relationships between company isolation and loneliness, and wellbeing. The findings show that increased opportunities for interpersonal interactions at work through greater task interdependence are not enough to reverse the negative effects of workplace isolation on wellbeing. In contrast, an investment in a supportive environment may reverse the negative effects of workplace isolation on wellbeing, highlighting the importance of a supportive culture.

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells.

The NRF2-KEAP1 system is a fundamental component of the cellular response that controls a great variety of transcriptional targets that are mainly involved in the regulation of redox homeostasis and multiple cytoprotective mechanisms that confer adaptation to the stress conditions. The pleiotropic response orchestrated by NRF2 is particularly relevant in the context of oncogenic activation, wherein this transcription factor acts as a key driver of tumor progression and cancer cells' resistance to treatment. For this reason, NRF2 has emerged as a promising therapeutic target in cancer cells, stimulating extensive research aimed at the identification of natural, as well as chemical, NRF2 inhibitors. Excitingly, the influence of NRF2 on cancer cells' biology extends far beyond its mere antioxidant function and rather encompasses a functional crosstalk with the mitochondrial network that can influence crucial aspects of mitochondrial homeostasis, including biogenesis, oxidative phosphorylation, metabolic reprogramming, and mitophagy. In the present review, we summarize the current knowledge of the reciprocal interrelation between NRF2 and mitochondria, with a focus on malignant tumors and cancer stem cells.

Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age-/sex-matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age-/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age-/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Considering the group as a target, the features that contributed to better segregation of control, undSOD1, and mutSOD1 were found to be the protein levels of Tfam and glycolytic ATP production rate. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation in experimental endpoints in lymphoblasts were found between cohorts, which may be due to the age or sex of the donor. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor, and although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints, especially protein levels of Tfam and glycolytic ATP production rate, that may have a diagnostic and therapeutic interest.

Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems.

Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP+), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN4) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN4 (100 µM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 µM, 24 h) were used for complementary studies. AntiOxCIN4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN4-induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN4 in the prevention/treatment of NAFLD.

Redox profiles of amyotrophic lateral sclerosis lymphoblasts with or without known SOD1 mutations.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease that affects motor neurons. This disease is associated with oxidative stress especially in mutant superoxide dismutase 1 (mutSOD1) patients. However, less is known for the most prevalent sporadic ALS form, due to a lack of disease models. Here, we studied oxidative stress profiles in lymphoblasts from ALS patients with mutSOD1 or unknown (undSOD1) mutations. METHODS: mutSOD1 and undSOD1 lymphoblasts, as well as sex/age-matched controls (3/group) were obtained from Coriell and divided into 46 years-old-men (C1), 46 years-old-women (C2) or 26/27 years-old-men (C3) cohorts. Growth curves were performed, and several parameters associated with redox homeostasis were evaluated, including SOD activity and expression, general oxidative stress levels, lipid peroxidation, response to oxidative stimulus, glutathione redox cycle, catalase expression, and activity, and Nrf2 transcripts. Pooled (all cohorts) and paired (intra-cohort) statistical analyses were performed, followed by clustering and principal component analyses (PCA). RESULTS: Although a high heterogeneity among lymphoblast redox profiles was found between cohorts, clustering analysis based on 7 parameters with high chi-square ranking (total SOD activity, oxidative stress levels, catalase transcripts, SOD1 protein levels, metabolic response to mM concentrations of tert-butyl hydroperoxide, glutathione reductase activity, and Nrf2 transcript levels) provided a perfect cluster segregation between samples from healthy controls and ALS (undSOD1 and mutSOD1), also visualized in the PCA. CONCLUSIONS: Our results show distinct redox signatures in lymphoblasts from mutSOD1, undSOD1 and healthy controls that can be used as therapeutic targets for ALS drug development.

Evaluation of 6-Hydroxydopamine and Rotenone In Vitro Neurotoxicity on Differentiated SH-SY5Y Cells Using Applied Computational Statistics.

With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of a disease's onset, the study and modulation of mitochondrial alterations have emerged as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplish this, data on mitochondrial parameters were acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.