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Nos últimos anos, o equino atleta vem sendo cada vez mais requerido. Dessa forma, as exigências por alto desempenho têm fomentado o interesse pelo estudo das afecções relacionadas com a fisiopatologia de diversas enfermidades dos equinos. A relação entre o íon magnésio e o exercício físico tem recebido atenção significativa visto que este íon está intimamente relacionado ao tecido muscular estriado esquelético. Além disso, dentre as principais estratégias para a detecção e acompanhamento clínico de lesões musculares, destacam-se a avaliação das atividades das enzimas creatino quinase (CK), lactato desidrogenase (LDH) e aspartato aminotransferase (AST). A busca pelo estabelecimento de parâmetros que se relacionam entre si é um fator determinante na compreensão de alterações fisiológicas encontradas diante do esforço em equinos atletas. Desta forma, o presente trabalho teve como objetivo determinar como as concentrações sanguíneas do íon magnésio e as atividades enzimáticas das enzimas CK, LDH e AST comportaram-se em equinos Puro Sangue Árabe finalistas de provas de enduro de 90km e relacionar as possíveis alterações com o tipo de esforço físico desempenhado pelos animais. Foram avaliadas a atividade enzimática das enzimas CK, LDH, AST e a concentração do íon magnésio no exercício em relação ao repouso de 14 equinos clinicamente hígidos da raça Puro Sangue Árabe, sendo 9 machos e 5 fêmeas, com idades variando entre 6 a 12 anos, submetidos a treinamento para enduro e participantes de provas de 90 km. Pode-se observar que as variáveis acima mencionadas sofreram aumento com diferença estatística em relação ao repouso. O exercício físico de enduro determinou a ocorrência de alterações nas atividades enzimáticas das enzimas CK (p≤0,001), LDH (p=0,0001), AST (p=0,0007) e na concentração do íon magnésio (p=0,0004), no exercício em relação ao repouso (p≤0,05). Fato que determinou alteração de permeabilidade das células musculares estriadas esqueléticas, sugerindo o estabelecimento de um processo inflamatório agudo. Devido à expressão da atividade enzimática da CK (p≤0,001), por sua especificidade em relação à ocorrência de danos na musculatura estriada esquelética, juntamente com o íon magnésio (p=0,0004) que participa de várias reações celulares. Houve alterações na concentração de proteína plasmática total (p=0,0009) e hematócrito (p=0,0001), entre os momentos avaliados. Portanto estes resultados servem como valores de referência de equinos finalistas de provas de enduro de 90 km, auxiliando na prevenção da ocorrência de possíveis danos musculares e processos inflamatórios severos.In recent years, due to rising competitive demands, the equine athlete is being increasingly required. Thus, the demands for high performance have fostered interest in the study of pathophysiology of various horse diseases. The relationship between magnesium and exercise has received significant attention because this ion is closely related with the skeletal muscle tissue. Moreover, among the main strategies for the detection and monitoring of clinical muscle damage, features the evaluation of the activity of the enzymes creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST). The search for the establishment of parameters that relate to each other is a determining factor in understanding the physiological changes found on athletic horses in effort. Thus, this study aimed to determine how the blood concentrations of magnesium ion and the enzymatic activities of the enzymes CK, LDH and AST behave in Arabian finalist horses in endurance races of 90km and to relate possible changes to the type of physical effort played by animals. It was evaluated the enzymatic activities of the enzymes CK, LDH, AST e the concentration of the ion magnesium in exercise in relation to the rest state of 14 clinically healthy Arabian horses, 9 males and 5 females, with ages ranging from 6 to 12 years, undergoing endurance training and participants in 90 km distance rides. All variables evaluated had an increase with statistical differences in relation to rest. The physical endurance exercise determined the occurrence of changes in enzyme activities of CK (p≤0.001), LDH (p=0.0001), AST (p=0.0007) and in the concentration of magnesium ion (p=0.0004), in exercise in relation to rest (p≤0.05). Fact that determined changes in permeability of striated skeletal muscle cells, suggesting the establishment of an acute inflammatory process. Mainly due to the expression of enzymatic activity of CK (p≤0.001), for its specificity in relation to the damage to skeletal striated muscles, along with the magnesium ion (p=0.0004) that actively acts in various cellular reactions. There were changes in total plasma protein concentrations (p=0.0009) and hematocrit (p=0.0001), between the evaluated moments. Therefore, these results serve as a reference of support equine finalists in an endurance race of 90 km, aiding in the prevention of the occurrence muscle damage and severe inflammatory processes.

Foi avaliado o comportamento da osmolaridade, do ânion gap, do pH e dos íons plasmáticos mensuráveis de 14 equinos, 9 machos e 5 fêmeas, Puro Sangue Árabe finalistas em provas de enduro de 90 km. Para tanto, foram colhidas em dois momentos (repouso e após o exercício prolongado) amostras de sangue venoso para a mensuração dessas variáveis. Pode-se verificar, a partir do repouso, aumento significativo dos valores do Hct, das PPT e do AG, sugerindo perda de fluidos e discreto grau de desidratação. O pH e o íon H+ quase não se alteraram, indicando ausência de distúrbios metabólicos. Reduções com diferenças significativas foram observadas para os íons Cl-, HCO3-, K+, Ca++, assim como do EB. Pode-se então, sugerir que o tipo de exercício a que os animais foram submetidos foi compatível com a capacidade atlética e ainda que a suplementação durante a competição contribuísse para minimizar tais perdas.

This study aimed to evaluate the cardiorespiratory and hemogasometric effects of epidural ketamine and its associations with morphine and xylazine in ewes submitted to transcervical cervix transposition with a hegar dilator. Ten Santa Inês breed ewes were studied in a cross over model study where three epidural protocols (GK = ketamine 2.0 mg kg-1; GKM = ketamine 2.0 mg kg-1 + morphine 0.1 mg kg-1; GKX = ketamine 2.0 mg kg-1 + xylazine 0.05 mg kg-1) were compared among each other and with a control treatment (GS= saline 1 mL/7.5 kg). The assessed variables were heart rate, respiratory frequency, ear temperature, non-invasive blood pressure and hemogasometric analysis. All parameters were assessed at baseline and then ewes were sedated with an association of acepromazine (0.1 mg kg -1) and diazepam (0.2 mg kg -1). Ten minutes after sedation all parameters were reassessed and afterwards the epidural injections were performed. Hemogasometry was repeated at 15 and 30 minutes after epidural and the other parameters assessed at 05, 15, 30, 45 and 60 minutes after epidural. GKX showed a slight respiratory depression with lower levels of PO2 and a compensatory increase in respiratory frequency. GKM presented the lower temperature mean. All protocols showed few cardiorespiratory effects when compared with control. Epidural with 2.0 mg kg-1 ketamine isolated was considered the best option for short procedures as obstetric manipulations in sheep due to its cardiorespiratory stability when compared with the protocols using associations.

Foram estabelecidos os parâmetros eletrocardiográficos de 20 equinos Puro Sangue Árabe em repouso e após exercício prolongado de enduro. A frequência cardíaca média foi de 35,85bpm em repouso, com predominância do ritmo sinusal, e de 53,78bpm, com taquicardia sinusal após o exercício. Como variação fisiológica, observou-se marcapasso migratório, e como não fisiológica, complexo ventricular prematuro. No pós-exercício, ocorreu aumento da amplitude das ondas P, R, S e T, com onda P tendendo a se tornar única em 35% dos animais e bífida positiva em 65%, e a onda T monofásica positiva. Houve redução da duração das ondas, dos intervalos e dos segmentos, e alongamento do QTc; porém, o complexo QRS quase não se alterou. O eixo elétrico, no plano frontal, apresentou desvios à direita e à esquerda em repouso sugestivo de aumento de câmara e hipertrofia secundárias ao treinamento, ao passo que, após o exercício, demonstrou desvio extremo para a direita, indicando alterações eletrolíticas. O escore cardíaco médio foi de 128,45ms, o que caracteriza os animais como atletas, sendo reduzido a 118,60ms após o exercício.Electrocardiographic parameters of 20 Thoroughbred Arabian horses were established at rest and after prolonged endurance exercise. The mean heart rate was 35.85bpm at rest with predominant sinus rhythm, and 53.78bpm with sinus tachycardia after exercise. As physiological variation, wandering pacemaker was observed, and as non physiological, premature ventricular complex was noted. At post-exercise there was an increase of the amplitude of waves P, R, S and T, with P wave tending to become single in 35% of the animals and bifid positive in 65%, and with monophase positive T wave. There was a reduction in the duration of the waves, intervals and segments, and elongation of QTc, but the QRS complex hardly changed. The electrical axis in the frontal plane showed deviations to the right and to the left at rest, suggesting chamber enlargement and hypertrophy secondary to training, while after the exercise it showed extreme deviation to the right, indicating electrolyte imbalances. The average heart score was 128.45ms, which features the animals as athletes, being reduced to 118.60ms after exercise.

O maleato de timolol 0,5% é um fármaco recomendado para tratamento de glaucoma em cães. Após instilação, e absorvido para a circulação sistêmica e por ser um antagonista beta-adrenérgico pode promover efeitos colaterais sistêmicos importantes sobre a condução elétrica cardíaca. No presente estudo, foi avaliada a alteração causada pelo timolol 0,5% oftálmico no eletrocardiograma. Foram selecionados seis cães hígidos para participar de dois tratamentos oftálmicos diferentes: no primeiro foi instilado placebo (hipromelose 0,5%) e no segundo utilizou-se timolol 0,5%. O colírio foi instilado a cada 12 horas por 14 dias. Os parâmetros eletrocardiográficos foram mensurados nos tempos: zero, 10, 60, 120, 240, 360 e 720 minutos após instilação da solução ocular nos dias primeiro, sétimo e décimo quarto de cada tratamento. As alterações eletrocardiográficas foram mais evidentes entre 120 e 240 minutos pós-instilação de timolol 0,5% quando comparado com o tratamento placebo. O ritmo foi irregular, com momentos de arritmia sinusal e bradicardia sinusal. Os intervalos RR e PR prolongaram significativamente (p < 0,05) desde o primeiro dia de instilação de timolol, sendo o prolongamento mais expressivo no décimo quarto dia de tratamento. O intervalo QT demonstrou pouca variação, apenas prolongando significativamente (p < 0,05) no décimo quarto dia de aplicação de timolol. O intervalo QTc não demonstrou alteração significativa (p > 0,05). Apesar das alterações encontradas, não foram observadas manifestações clínicas relacionadas ao timolol nos animais estudados. Deve-se considerar, porém, que os animais em questão eram hígidos e, portanto, as alterações decorrentes do uso do timolol em animais com cardiopatias preexistentes poderiam promover sinais clínicos, sendo recomendada a avaliação cardíaca de pacientes previamente à prescrição do timolol oftálmico.

Breast cancer (BC) continues to significantly impact women worldwide. Numerous studies show that physical activity (PA) significantly enhances the quality of life, aids recovery, and improves survival rates in BC patients. PA's influence extends to altering DNA methylation patterns on both a global and gene-specific scale, potentially reverting abnormal DNA methylation, associated with carcinogenesis and various pathologies. This review consolidates the findings of the current literature, highlighting PA's impact on DNA methylation in BC patients. Our systematic analysis indicates that PA may elevate global DNA methylation within tumour tissues. Furthermore, it appears to modify gene-specific promoter methylation across a wide spectrum of genes in various tissues. Through bioinformatic analysis, to investigate the functional enrichment of these affected genes, we identified a predominant enrichment in metabolic pathways, cell cycle regulation, cell cycle checkpoints, mitosis, cellular stress responses, and molecular functions governing diverse binding processes. The Human Protein Atlas corroborates this enrichment, indicating gene functionality across 266 tissues, notably within various breast tissues. This systematic review unveils PA's capacity to systematically alter DNA methylation patterns across multiple tissues, particularly in BC patients. Emphasising its influence on crucial biological processes and functions, this alteration holds potential for restoring normal cellular functionality and the cell cycle. This reversal of cancer-associated patterns could potentially enhance recovery and improve survival outcomes.

Moringa oleifera is widely grown throughout the tropics and increasingly used for its therapeutic and nutraceutical properties. These properties are attributed to potent antioxidant and metabolism regulators, including glucosinolates/isothiocyanates as well as flavonoids, polyphenols, and phenolic acids. Research to date largely consists of geographically limited studies that only examine material available locally. These practices make it unclear as to whether moringa samples from one area are superior to another, which would require identifying superior variants and distributing them globally. Alternatively, the finding that globally cultivated moringa material is essentially functionally equivalent means that users can easily sample material available locally. We brought together accessions of Moringa oleifera from four continents and nine countries and grew them together in a common garden. We performed a metabolomic analysis of leaf extracts (MOLE) using an LC-MSMS ZenoTOF 7600 mass spectrometry system. The antioxidant capacity of leaf samples evaluated using the Total Antioxidant Capacity assay did not show any significant difference between extracts. MOLE samples were then tested for their antioxidant activity on C2C12 myotubes challenged with an oxidative insult. Hydrogen peroxide (H 2 O 2 ) was added to the myotubes after pretreatment with different extracts. H 2 O 2 exposure caused an increase in cell death that was diminished in all samples pretreated with moringa extracts. Our results show that Moringa oleifera leaf extract is effective in reducing the damaging effect of H 2 O 2 in C2C12 myotubes irrespective of geographical origin. These results are encouraging because they suggest that the use of moringa for its therapeutic benefits can proceed without the need for the lengthy and complex global exchange of materials between regions.

Purpose: Studies indicate that the rated perceived exertion (RPE) during physical exercise can be lower in field environments than indoors. The environmental conditions of those studies are explored. Furthermore, we study if the same phenomenon is valid when cycling indoors versus in cycle commuting environments with high levels of stimuli from both traffic and suburban-urban elements., Methods: Twenty commuter cyclists underwent measurements of heart rate (HR) and oxygen uptake ([Formula: see text]O2) and RPE assessments for breathing and legs, respectively, while cycling in both laboratory and field conditions. A validated mobile metabolic system was used in the field to measure [Formula: see text]O2. Three submaximal cycle ergometer workloads in the laboratory were used to establish linear regression equations between RPE and % of HR reserve (%HRR) and %[Formula: see text]O2max, separately. Based on these equations, RPE from the laboratory was predicted and compared with RPE levels at the participants' individual cycle commutes at equal intensities. The same approach was used to predict field intensities and for comparisons with corresponding measured intensities at equal RPE levels., Results: The predicted RPE levels based on the laboratory cycling were significantly higher than the RPE levels in cycle commuting at equal intensities (67% of HRR; 65% of [Formula: see text]O2max). For breathing, the mean RPE levels were; 14.0-14.2 in the laboratory and 12.6 in the field. The corresponding levels for legs were; 14.0-14.2 and 11.5. The range of predicted field intensities in terms of %HRR and %[Formula: see text]O2max was 46-56%, which corresponded to median differences of 19-30% compared to the measured intensities in field at equal RPE., Conclusion: The cycle commuters perceived a lower exertion during their cycle commutes compared to ergometer cycling in a laboratory at equal exercise intensities. This may be due to a higher degree of external stimuli in field, although influences from other possible causes cannot be ruled out., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Olsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most anticancer treatments act on oxidative-stress pathways by producing reactive oxygen species (ROS) to kill cancer cells, commonly resulting in consequential drug-induced systemic cytotoxicity. Physical activity (PA) has arisen as an integrative cancer therapy, having positive health effects, including in redox-homeostasis. Here, we investigated the impact of an online supervised PA program on promoter-specific DNA methylation, and corresponding gene expression/activity, in 3 antioxidants- (SOD1, SOD2, and CAT) and 3 breast cancer (BC)-related genes (BRCA1, L3MBTL1 and RASSF1A) in a population-based sample of women diagnosed with primary BC, undergoing medical treatment. We further examined mechanisms involved in methylating and demethylating pathways, predicted biological pathways and interactions of exercise-modulated molecules, and the functional relevance of modulated antioxidant markers on parameters related to aerobic capacity/endurance, physical fatigue and quality of life (QoL). PA maintained levels of SOD activity in blood plasma, and at the cellular level significantly increased SOD2 mRNA (≈+77 %), contrary to their depletion due to medical treatment. This change was inversely correlated with DNA methylation in SOD2 promoter (≈-20 %). Similarly, we found a significant effect of PA only on L3MBTL1 promoter methylation (≈-25 %), which was inversely correlated with its mRNA (≈+43 %). Finally, PA increased TET1 mRNA levels (≈+15 %) and decreased expression of DNMT3B mRNA (≈-28 %). Our results suggest that PA-modulated DNA methylation affects several signalling pathways/biological activities involved in the cellular oxidative stress response, chromatin organization/regulation, antioxidant activity and DNA/protein binding. These changes may positively impact clinical outcomes and improve the response to cancer treatment in post-surgery BC patients., 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.)

Breast cancer (BC) is one of the most commonly diagnosed types of cancer in women. Oxidative stress may contribute to cancer etiology through several mechanisms. A large body of evidence indicates that physical activity (PA) has positive effects on different aspects of BC evolution, including mitigation of negative effects induced by medical treatment. With the aim to verify the capacity of PA to counteract negative effects of BC treatment on systemic redox homeostasis in postsurgery female BC patients, we have examined the modulation of circulating levels of oxidative stress and inflammation markers. Moreover, we evaluated the impacts on physical fitness and mental well-being by measuring functional parameters, body mass index, body composition, health-related quality of life (QoL), and fatigue. Our investigation revealed that PA was effective in maintaining plasma levels of superoxide dismutase (SOD) activity and tGSH, as well as peripheral blood mononuclear cells' (PBMCs) mRNA levels of SOD1 and heat-shock protein 27. Moreover, we found a significant decrease in plasma interleukin-6 (≈0.57 ± 0.23-fold change, p < 0.05) and increases in both interleukin-10 (≈1.15 ± 0.35-fold change, p < 0.05) and PBMCs' mRNA level of SOD2 (≈1.87 ± 0.36-fold change, p < 0.05). Finally, PA improves functional parameters (6 min walking test, ≈+6.50%, p < 0.01; Borg, ≈-58.18%, p < 0.01; sit-and-reach, ≈+250.00%, p < 0.01; scratch right, ≈-24.12%, and left, ≈-18.81%, p < 0.01) and body composition (free fat mass, ≈+2.80%, p < 0.05; fat mass, ≈-6.93%, p < 0.05) as well as the QoL (physical function, ≈+5.78%, p < 0.05) and fatigue (cognitive fatigue, ≈-60%, p < 0.05) parameters. These results suggest that a specific PA program not only is effective in improving functional and anthropometric parameters but may also activate cellular responses through a multitude of actions in postsurgery BC patients undergoing adjuvant therapy. These may include modulation of gene expression and protein activity and impacting several signaling pathways/biological activities involved in tumor-cell growth; metastasis; and inflammation, as well as moderating distress symptoms known to negatively affect QoL., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of this study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Persistent organic pollutants are widespread in the marine environment. They can bioaccumulate and biomagnify in marine organisms through the food web with a potentially toxic effect on living organisms. The sea turtle Caretta caretta is a carnivorous animal with opportunistic feeding behavior. These turtles tend to bioaccumulate pollutants through food, and hence they can be considered an indicator of chemical pollutants in the marine ecosystem. In this study, 44 loggerhead sea turtles were considered, and liver and fat tissue were sampled from each of them to investigate the levels of dioxins (PCDD/Fs) and polychlorinated biphenyls (PCBs) in sea turtles and their potential correlation with sex and size in terms of curved carapace length (CCL). Results suggested that these contaminants were easily bioaccumulated, and PCBs were predominant compared to dioxins in both liver and fat tissue. The congener patterns were similar to those found in sea fish. Moreover, there were no differences in the contamination levels between females and males, nor was there a correlation with the size. There is a need to harmonize the methodological approaches to better evaluate the results and trends over time and to monitor the species and indirectly the health status of the marine environment.

A central feature of the skeletal muscle is its ability to regenerate through the activation, by environmental signals, of satellite cells. Once activated, these cells proliferate as myoblasts, and defects in this process profoundly affect the subsequent process of regeneration. High levels of reactive oxygen species such as hydrogen peroxide (H 2 O 2 ) with the consequent formation of oxidized macromolecules increase myoblasts' cell death and strongly contribute to the loss of myoblast function. Recently, particular interest has turned towards the beneficial effects on muscle of the naturally occurring polyamine spermidine (Spd). In this work, we tested the hypothesis that Spd, upon oxidative challenge, would restore the compromised myoblasts' viability and redox status. The effects of Spd in combination with aminoguanidine (Spd-AG), an inhibitor of bovine serum amine oxidase, on murine C2C12 myoblasts treated with a mild dose of H 2 O 2 were evaluated by analyzing: (i) myoblast viability and recovery from wound scratch; (ii) redox status and (iii) polyamine (PAs) metabolism. The treatment of C2C12 myoblasts with Spd-AG increased cell number and accelerated scratch wound closure, while H 2 O 2 exposure caused redox status imbalance and cell death. The combined treatment with Spd-AG showed an antioxidant effect on C2C12 myoblasts, partially restoring cellular total antioxidant capacity, reducing the oxidized glutathione (GSH/GSSG) ratio and increasing cell viability through a reduction in cell death. Moreover, Spd-AG administration counteracted the induction of polyamine catabolic genes and PA content decreased due to H 2 O 2 challenges. In conclusion, our data suggest that Spd treatment has a protective role in skeletal muscle cells by restoring redox balance and promoting recovery from wound scratches, thus making myoblasts able to better cope with an oxidative insult.

Although exercise is associated with improved health in many medical conditions, little is known about the possible influences of physical activity (PA) habits pre- and post- a diagnosis of systemic sclerosis (SSc) on disease activity and progression. This cross-sectional study assessed, for the first time, self-reported pre- and post-diagnostic PA levels with the aim to verify if changes in these levels were correlated with demographic/anthropometric data (e.g., weight, height, gender, age, BMI), disease duration, diagnostic/clinical parameters (e.g., skin involvement, pulmonary hemodynamic/echocardiographic data, disease activity) related to disease activity and progression, and quality of life in a population-based sample of patients with SSc. Adult participants ( n = 34, age 56.6 ± 13.3 years) with SSc (limited cutaneous SSc, lcSSc, n = 20; diffuse cutaneous SSc, dcSSc, n = 9; sine scleroderma SSc, n = 5) were enrolled at the Division of Rheumatology and Clinical Immunology of the Humanitas Research Hospital. All medical data were recorded during periodic clinical visits by a rheumatologist. Moreover, all subjects included in this study completed extensive questionnaires to evaluate their health-related quality of life (HRQOL), and others related to health-related physical activity performed before (PRE) and after (POST) the diagnosis of disease. The linear regression analysis has shown that either a high Sport&#95;index or Leisure&#95;index in the PRE-diagnostic period was correlated with lower disease duration in dcSSc patients. Physical load during sport activity and leisure time accounted for ~61.1% and ~52.6% of the individual variation in disease duration, respectively. In lcSSc patients, a high PRE value related to physical load during sporting activities was correlated with a low pulmonary artery systolic pressure (sPAP) and the POST value of the Work&#95;index was positively correlated with the left ventricular ejection fraction (LVEF), and negatively with creatine kinase levels (CK). Interestingly, the univariate analysis showed that Work&#95;index accounts for ~29.4% of the variance in LVEF. Our analysis clearly reinforces the concept that high levels of physical load may play a role in primary prevention-delaying the onset of the disease in those subjects with a family history of SSc-as well as in secondary prevention, improving SSc management through a positive impact on different clinical parameters of the disease. However, it remains a priority to identify a customized physical load in order to minimize the possible negative effects of PA.

The imbalance between reactive oxygen species (ROS) production and antioxidant defense systems leads to macromolecule and tissue damage as a result of cellular oxidative stress. This phenomenon is considered a key factor in fatigue and muscle damage following chronic or high-intensity physical exercise. In the present study, the antioxidant effect of Moringa oleifera leaf extract (MOLE) was evaluated in C2C12 myotubes exposed to an elevated hydrogen peroxide (H 2 O 2 ) insult. The capacity of the extract to influence the myotube redox status was evaluated through an analysis of the total antioxidant capacity (TAC), glutathione homeostasis (GSH and GSSG), total free thiols (TFT), and thioredoxin (Trx) activity, as well as the enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and transferase (GST). Moreover, the ability of MOLE to mitigate the stress-induced peroxidation of lipids and oxidative damage (TBARS and protein carbonyls) was also evaluated. Our data demonstrate that MOLE pre-treatment mitigates the highly stressful effects of H 2 O 2 in myotubes (1 mM) by restoring the redox status (TFT, Trx, and GSH/GSSG ratio) and increasing the antioxidant enzymatic system (CAT, SOD, GPx, GST), thereby significantly reducing the TBARs and PrCAR levels. Our study provides evidence that MOLE supplementation has antioxidant potential, allowing myotubes better able to cope with an oxidative insult and, therefore, could represent a useful nutritional strategy for the preservation of muscle well-being.

Skeletal muscle is a tissue that has recently been recognized for its ability to produce androgens under physiological conditions. The steroidogenesis process is known to be negatively influenced by reactive oxygen species (ROS) in reproductive Leydig and ovary cells, while their effect on muscle steroidogenesis is still an unexplored field. Muscle cells are continuously exposed to ROS, resulting from both their metabolic activity and the surrounding environment. Interestingly, the regulation of signaling pathways, induced by mild ROS levels, plays an important role in muscle fiber adaptation to exercise, in a process that also elicits a significant modulation in the hormonal response. The aim of the present study was to investigate whether ROS could influence steroidogenesis in skeletal muscle cells by evaluating the release of testosterone (T) and dihydrotestosterone (DHT), as well as the evaluation of the relative expression of the key steroidogenic enzymes 5α-reductase, 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, and aromatase. C2C12 mouse myotubes were exposed to a non-cytotoxic concentration of hydrogen peroxide (H 2 O 2 ), a condition intended to reproduce, in vitro, one of the main stimuli linked to the process of homeostasis and adaptation induced by exercise in skeletal muscle. Moreover, the influence of tadalafil (TAD), a phosphodiesterase 5 inhibitor (PDE5i) originally used to treat erectile dysfunction but often misused among athletes as a "performance-enhancing" drug, was evaluated in a single treatment or in combination with H 2 O 2 . Our data showed that a mild hydrogen peroxide exposure induced the release of DHT, but not T, and modulated the expression of the enzymes involved in steroidogenesis, while TAD treatment significantly reduced the H 2 O 2 -induced DHT release. This study adds a new piece of information about the adaptive skeletal muscle cell response to an oxidative environment, revealing that hydrogen peroxide plays an important role in activating muscle steroidogenesis.

The increase in breast cancer (BC) survival has determined a growing survivor population that seems to develop several comorbidities and, specifically, treatment-induced cardiovascular disease (CVD), especially those patients treated with anthracyclines. Indeed, it is known that these compounds act through the induction of supraphysiological production of reactive oxygen species (ROS), which appear to be central mediators of numerous direct and indirect cardiac adverse consequences. Evidence suggests that physical exercise (PE) practised before, during or after BC treatments could represent a viable non-pharmacological strategy as it increases heart tolerance against many cardiotoxic agents, and therefore improves several functional, subclinical, and clinical parameters. At molecular level, the cardioprotective effects are mainly associated with an exercise-induced increase of stress response proteins (HSP60 and HSP70) and antioxidant (SOD activity, GSH), as well as a decrease in lipid peroxidation, and pro-apoptotic proteins such as Bax, Bax-to-Bcl-2 ratio. Moreover, this protection can potentially be explained by a preservation of myosin heavy chain (MHC) isoform distribution. Despite this knowledge, it is not clear which type of exercise should be suggested in BC patient undergoing anthracycline treatment. This highlights the lack of special guidelines on how affected patients should be managed more efficiently. This review offers a general framework for the role of anthracyclines in the physio-pathological mechanisms of cardiotoxicity and the potential protective role of PE. Finally, potential exercise-based strategies are discussed on the basis of scientific findings.

Validated methodology for the simultaneous determination of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs) in foods of animal origin is presented. Method performance indicators were equivalent or better than those required for the control of EU regulated (EU, 2017/644) PCDD/F and PCB congeners in these foods, and for risk assessment through dietary intake. The method uses a high (>90%) proportion of 13 Carbon-labelled surrogates for internal standardisation combined with high resolution mass spectrometry that allow accurate quantitation, and this was confirmed by multiple successful participations in proficiency testing for PCDD/Fs, PCBs and PBDEs in food. The same validation and method performance requirements as used for PCDD/Fs were followed for PBDD/Fs. The analysis of a range of food samples (eggs, milk, fish, shellfish, pork, beef and poultry), showed the occurrence of all four classes of contaminants at varying concentration ranges. In general, PCBs were the most prominent contaminant, both, in terms of dioxin-like toxicity, as well as in the occurrence of non-dioxin-like congeners, an observation that concurs with those made in other studies on Italian foods. The levels of PCDD/F and PCB occurrence are consistent with a gradual decline in contamination as reported by some other similar studies. Although all the determined contaminants were detected in the sampled foods, there was poor correlation between the occurrences of the brominated and chlorinated contaminants, and between PBDEs and PBDD/Fs, but better associations were observed between the occurrences of the chlorinated contaminants., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Prolonged or unaccustomed eccentric exercise may cause muscle damage and depending from its extent, this event negatively affects physical performance., Objectives: The aim of the present investigation was to evaluate, in humans, the effect of the flavonoid quercetin on circulating levels of the anabolic insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 2 (IGF-II), produced during the recovery period after an eccentric-induced muscle damage (EIMD)., Methods: A randomized, double-blind, crossover study has been performed; twelve young men ingested quercetin (1 g/day) or placebo for 14 days and then underwent an eccentric-induced muscle damaging protocol. Blood samples were collected, and cell damage markers [creatine kinase (CK), lactate dehydrogenase (LDH) and myoglobin (Mb)], the inflammatory responsive interleukin 6 (IL-6), IGF-I and IGF-II levels were evaluated before the exercise and at different recovery times from 24 hours to 7 days after EIMD., Results: We found that, in placebo treatment the increase in IGF-I (72 h) preceded IGF-II increase (7 d). After Q supplementation there was a more marked increase in IGF-I levels and notably, the IGF-II peak was found earlier, compared to placebo, at the same time of IGF-I (72 h). Quercetin significantly reduced plasma markers of cell damage [CK (p<0.005), LDH (p<0.001) and Mb (p<0.05)] and the interleukin 6 level [IL-6 (p<0.05)] during recovery period following EIMD compared to placebo., Conclusions: Our data are encouraging about the use of quercetin as dietary supplementation strategy to adopt in order to mitigate and promote a faster recovery after eccentric exercise as suggested by the increase in plasma levels of the anabolic factors IGF-I and IGF-II., 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 © 2021 Sgrò, Ceci, Lista, Patrizio, Sabatini, Felici, Sacchetti, Bazzucchi, Duranti and Di Luigi.)

Background: The phosphodiesterase type 5 inhibitor (PDE5I) tadalafil, in addition to its therapeutic role, has shown antioxidant effects in different in vivo models. Supplementation with antioxidants has received interest as a suitable tool for preventing or reducing exercise-related oxidative stress, possibly leading to the improvement of sport performance in athletes. However, the use/abuse of these substances must be evaluated not only within the context of amateur sport, but especially in competitions where elite athletes are more exposed to stressful physical practice. To date, very few human studies have addressed the influence of the administration of PDE5Is on redox balance in subjects with a fitness level comparable to elite athletes; therefore, the aim of this study was to investigate for the first time whether acute ingestion of tadalafil could affect plasma markers related to cellular damage, redox homeostasis, and blood polyamines levels in healthy subjects with an elevated cardiorespiratory fitness level. Methods: Healthy male volunteers (n = 12), with a VO 2max range of 40.1-56.0 mL/(kg × min), were administered with a single dose of tadalafil (20 mg). Plasma molecules related to muscle damage and redox-homeostasis, such as creatine kinase (CK), lactate dehydrogenase (LDH), total antioxidant capacity (TAC), reduced/oxidized glutathione ratio (GSH/GSSG), free thiols (FTH), antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)), as well as thiobarbituric acid reactive substances (TBARs), protein carbonyls (PrCAR), and polyamine levels (spermine (Spm) and spermidine (Spd)) were evaluated immediately before and 2, 6 and 24 hours after the acute tadalafil administration. Results: A single tadalafil administration induced an increase in CK and LDH plasma levels 24 after consumption. No effects were observed on redox homeostasis or antioxidant enzyme activities, and neither were they observed on the oxidation target molecules or polyamines levels. Conclusion: Our results show that in subjects with an elevated fitness level, a single administration of tadalafil induced a significant increase in muscle damage target without affecting plasma antioxidant status.

Moringa oleifera is a multi-purpose herbal plant with numerous health benefits. In skeletal muscle cells, Moringa oleifera leaf extract (MOLE) acts by increasing the oxidative metabolism through the SIRT1-PPARα pathway. SIRT1, besides being a critical energy sensor, is involved in the activation related to redox homeostasis of transcription factors such as the nuclear factor erythroid 2-related factor (Nrf2). The aim of the present study was to evaluate in vitro the capacity of MOLE to influence the redox status in C2C12 myotubes through the modulation of the total antioxidant capacity (TAC), glutathione levels, Nrf2 and its target gene heme oxygenase-1 (HO-1) expression, as well as enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and transferase (GST). Moreover, the impact of MOLE supplementation on lipid peroxidation and oxidative damage (i.e., TBARS and protein carbonyls) was evaluated. Our results highlight for the first time that MOLE increased not only Nrf2 and HO-1 protein levels in a dose-dependent manner, but also improved glutathione redox homeostasis and the enzyme activities of CAT, SOD, GPx and GST. Therefore, it is intriguing to speculate that MOLE supplementation could represent a valuable nutrition for the health of skeletal muscles.

Evidence suggests that physical activity (PA) influences the human gut microbiota composition, but its role is unclear because of dietary interference. The aim of this review is to clarify this issue from this new perspective in healthy individuals. Articles analyzing intestinal microbiota from fecal samples by 16S rRNA amplicon sequencing were selected by searching the electronic databases PubMed, Scopus, and Web of Science until December 2020. For each study, methodological quality was assessed, and results about microbiota biodiversity indices, phylum and genus composition, and information on PA and diet were considered. From 997 potentially relevant articles, 10 met the inclusion criteria and were analyzed. Five studies involved athletes, three were performed on active people classified on the basis of habitual PA level, and two among sedentary subjects undergoing exercise interventions. The majority of the studies reported higher variability and prevalence of the phylum Firmicutes (genera Ruminococcaceae or Fecalibacteria ) in active compared to inactive individuals, especially in athletes. The assessment of diet as a possible confounder of PA/exercise effects was completed only in four studies. They reported a similar abundance of Lachnospiraceae , Paraprevotellaceae , Ruminococcaceae , and Veillonellaceae , which are involved in metabolic, protective, structural, and histological functions. Further studies are needed to confirm these findings.

Background: 'Idiopathic' lead macrodislodgement may be due to Twiddler's syndrome depending on active twisting of pulse generator within subcutaneous pocket. All leads are involved, at any time from implantation, and frequently damaged. In the past few years, a reel syndrome was also observed: retraction of pacemaker leads into pocket without patient manipulation, owing to lead circling the generator. In other cases, a 'ratchet' mechanism has been postulated. Reel and ratchet mechanisms require loose anchoring, occur generally briefly after implantation, with non-damaged leads. We report the first case of an active-fixation coronary sinus lead selective macrodislodgement involving such ratchet mechanism., Case Summary: A 65-year-old man underwent biventricular defibrillator device implantation, with active-fixation coronary sinus lead. Eight months later, he complained of muscle contractions over device pocket. At fluoroscopy, coronary sinus lead was found near to pocket, outside of thoracic inlet. Atrial and ventricular leads were in normal position. After opening pocket, a short tract of coronary sinus lead appeared anteriorly dislocated to generator, while greater length of lead body twisted a reel behind. The distal part of lead was found outside venous entry at careful dissection. Atrial and ventricular leads were firmly anchored., Discussion: Our case is a selective 'Idiopathic' lead macrodislodgement, possibly due to a ratchet mechanism between the lead and the suture sleeve, induced by normal arm motion; such mechanism incredibly, and for first time in literature involves a coronary sinus active-fixation lead., Conclusion: Careful attention should always be paid to secure anchoring even of active-fixation coronary sinus leads., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1 G93A and hFUS +/+ , characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy.

This study was aimed at investigating whether quercetin (Q) may improve the recovery of neuromuscular function and biochemical parameters in the 7 days following an eccentric exercise-induced muscle damage (EEIMD). Sixteen men (25.9 ± 3.3 y) ingested Q (1000 mg/day) or placebo (PLA) for 14 days following a double-blind crossover study design. A neuromuscular (NM) test was performed pre-post, 24 h, 48 h, 72 h, 96 h and 7 days after an intense eccentric exercise. The force-velocity relationship of the elbow flexor muscles and their maximal voluntary isometric contraction (MVIC) were recorded simultaneously to the electromyographic signals (EMG). Pain, joint angle, arm circumference, plasma creatine kinase (CK) and lactate-dehydrogenase (LDH) were also assessed. The results showed that Q supplementation significantly attenuated the strength loss compared to PLA. During the recovery, force-velocity relationship and mean fibers conduction velocity (MFCV) persisted significantly less when participants consumed PLA rather than Q, especially at the highest angular velocities ( p < 0.02). A greater increase in biomarkers of damage was also evident in PLA with respect to Q. Q supplementation for 14 days seems able to ameliorate the recovery of eccentric exercise-induced weakness, neuromuscular function impairment and biochemical parameters increase probably due to its strong anti-inflammatory and antioxidant action.

Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors to the disease. Indeed, different studies demonstrated how oxidative stress could contribute to the fibrotic process activation at the level of the skin and visceral organs. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), which protects different cell lines from the cell damage induced by reactive oxygen species (ROS). These data make sildenafil a good candidate for therapeutic treatment aimed to protect biological macromolecules against oxidative damage, thus preserving cell viability. The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to prevent/reduce the DNA damage due to ROS action. Additionally, we evaluated the capacity for sildenafil to influence redox homeostasis and cytotoxicity, as well as cell proliferation and cell cycle progression. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment reduced ROS-induced DNA damage, counteracted the negative effects of ROS on cell viability and proliferation, and promoted the activity of specific enzymes involved in redox homeostasis maintenance. To our knowledge, in this report, we demonstrate, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results expand the use of PDE5i as therapeutic agents in SSc by indicating a protective role in tissue damage induced by oxidative insult.

Background: Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). FD is still an underdiagnosed disorder worldwide. Moreover, there is delay between symptom onset and Fabry diagnosis of at least 10 years. Family screening offers an important benefit for detection of new patients. The aim of this work is to present the approach along with the results of a targeted genetic strategy for pedigree analysis for FD in Argentina., Methods: By this strategy as soon as a new index Fabry patient is diagnosed, the pedigree group contacts the physician and a meeting is arranged with the physician and the family to build the family tree., Results: Pedigree analysis was carried out for full in 31 families. In the work period, we have tested 1,462 relatives, and 501 were diagnosed FD. The proportion of positive detection was 33%., Conclusion: The targeted family screening approach is successful to detect undiagnosed Fabry patients. By this approach, the highest ratio index to pedigree ever reported for FD pedigree analysis of 1:15 was obtained., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Gaucher and Fabry diseases are the most prevalent sphingolipidoses. Chronic inflammation is activated in those disorders, which could play a role in pathogenesis. Significant degrees of amelioration occur in patients upon introduction of specific therapies; however, restoration to complete health status is not always achieved. The idea of an adjunctive therapy that targets inflammation may be a suitable option for patients. PPS is a mixture of semisynthetic sulfated polyanions that have been shown to have anti-inflammatory effects in mucopolysaccharidosis type I and II patients and animal models of type I, IIIA and VI. We hypothesized PPS could be a useful adjunctive therapy to inflammation for Gaucher and Fabry diseases. The objective of this work is to analyze the in vitro effect of PPS on inflammatory cytokines in cellular models of Gaucher and Fabry diseases, and to study its effect in Gaucher disease associated in vitro bone alterations. Cultures of peripheral blood mononuclear cells from Fabry and Gaucher patients were exposed to PPS. The secretion of proinflammatory cytokines was significantly reduced. Peripheral blood cells exposed to PPS from Gaucher patients revealed a reduced tendency to differentiate to osteoclasts. Osteoblasts and osteocytes cell lines were incubated with an inhibitor of glucocerebrosidase, and conditioned media was harvested in order to analyze if those cells secrete factors that induce osteoclastogenesis. Conditioned media from this cell cultures exposed to PPS produced lower numbers of osteoclasts. We could demonstrate PPS is an effective molecule to reduce the production of proinflammatory cytokines in in vitro models of Fabry and Gaucher diseases. Moreover, it was effective at ameliorating bone alterations of in vitro models of Gaucher disease. These results serve as preclinical supportive data to start clinical trials in human patients to analyze the effect of PPS as a potential adjunctive therapy for Fabry and Gaucher diseases., Competing Interests: PPS and the patent (see below) have been licensed from Mount Sinai to Paradigm BioPharmaceuticals (Australia) and ReqMed (Japan). Dr. Simonaro is an inventor on the patent therefore revenues from the license may be made by Mount Sinai and inventors. Anti-TNF-alpha therapy for the mucopolysaccharidoses and other lysosomal disorders. Patent number: 915578 " We confirm that "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

The aim of the present investigation was to test the hypothesis that quercetin (Q) may prevent the strength loss and neuromuscular impairment associated with eccentric exercise-induced muscle damage (EEIMD). Twelve young men (26.1 ± 3.1 years) ingested either Q (1000 mg/day) or placebo (PLA) for 14 days using a randomized, double-blind, crossover study design. Participants completed a comprehensive neuromuscular (NM) evaluation before, during and after an eccentric protocol able to induce a severe muscle damage (10 sets of 10 maximal lengthening contractions). The NM evaluation comprised maximal voluntary isometric contraction (MVIC) and force⁻velocity relationship assessments with simultaneous recording of electromyographic signals (EMG) from the elbow flexor muscles. Soreness, resting arm angle, arm circumference, plasma creatine kinase (CK) and lactate dehydrogenase (LDH) were also assessed. Q supplementation significantly increased the isometric strength recorded during MVIC compared to baseline (+4.7%, p < 0.05). Moreover, the torque and muscle fiber conduction velocity (MFCV) decay recorded during the eccentric exercise was significant lower in Q compared to PLA. Immediately after the EEIMD, isometric strength, the force⁻velocity relationship and MFCV were significantly lower when participants were given PLA rather than Q. Fourteen days of Q supplementation seems able to attenuate the severity of muscle weakness caused by eccentric-induced myofibrillar disruption and sarcolemmal action potential propagation impairment.

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy., Competing Interests: The authors declare no conflict of interest.

Objective: During muscle development or regeneration, myocytes produce nerve growth factor (NGF) as well as its tyrosine-kinase and p75-neurotrophin (p75 NTR ) receptors. It has been published that the p75 NTR receptor could represent a key regulator of NGF-mediated myoprotective effect on satellite cells, but the precise function of NGF/p75 signaling pathway on myogenic cell proliferation, survival and differentiation remains fragmented and controversial. Here, we verified the role of NGF in the growth, survival and differentiation of p75 NTR -expressing L6C5 myogenic cells, specifically inquiring for the putative involvement of the nuclear factor κB (NFκB) and the small heat shock proteins (sHSPs) αB-crystallin and Hsp27 in these processes., Results: Although NGF was not effective in modulating myogenic cell growth or survival in both standard or stress conditions, we demonstrated for the first time that, under serum deprivation, NGF sustained the activity of some key enzymes involved in energy metabolism. Moreover, we confirmed that NGF promotes myogenic fusion and expression of the structural protein myosin heavy chain while modulating NFκB activation and the content of sHSPs correlated with the differentiation process. We conclude that p75 NTR is sufficient to mediate the modulation of L6C5 myogenic differentiation by NGF in term of structural, metabolic and functional changes.

Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.