Diclofenac Administration after Physical Training Blunts Adaptations of Peripheral Systems and Leads to Losses in Exercise Performance: In Vivo and In Silico Analyses

Recovery in athletes is hampered by soreness and fatigue. Consequently, nonsteroidal antiinflammatory drugs are used as an effective strategy to maintain high performance. However, impact of these drugs on adaptations induced by training remains unknown. This study assessed the effects of diclofenac administration (10 mg/kg/day) on rats subjected to an exhaustive test, after six weeks of swimming training. Over the course of 10 days, three repeated swimming bouts were performed, and diclofenac or saline were administered once a day. Trained animals exhibited higher muscle citrate synthase and lower plasma creatinine kinase activities as compared to sedentary animals, wherein diclofenac had no impact. Training increased time to exhaustion, however, diclofenac blunted this effect. It also impaired the increase in plasma and liver interleukin-6 levels. The trained group exhibited augmented catalase, glutathione peroxidase, and glutathione reductase activities, and a higher ratio of reduced-to-oxidized glutathione in the liver. However, diclofenac treatment blunted all these effects. Systems biology analysis revealed a close relationship between diclofenac and liver catalase. These results confirmed that regular exercise induces inflammation and oxidative stress, which are crucial for tissue adaptations. Altogether, diclofenac treatment might be helpful in preventing pain and inflammation, but its use severely affects performance and tissue adaptatio

Protective Effects of Aqueous Extract of Luehea divaricata

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. Accordingly, 3-nitropropionic acid (3-NP) has been found to effectively produce HD-like symptoms. Luehea divaricata (L. divaricata), popularly known in Brazil as “açoita-cavalo,” may act as a neuroprotective agent in vitro and in vivo. We evaluated the hypothesis that the aqueous extract of L. divaricata could prevent behavioral and oxidative alterations induced by 3-NP in rats. 25 adult Wistar male rats were divided into 5 groups: (1) control, (2) L. divaricata (1000 mg/kg), (3) 3-NP, (4) L. divaricata (500 mg/kg) + 3-NP, and (5) L. divaricata (1000 mg/kg) + 3-NP. Groups 2, 4, and 5 received L. divaricata via intragastric gavage daily for 10 days. Animals in groups 3, 4, and 5 received 20 mg/kg 3-NP daily from days 8–10. At day 10, parameters of locomotor activity and biochemical evaluations were performed. Indeed, rats treated with 3-NP showed decreased locomotor activity compared to controls. Additionally, 3-NP increased levels of reactive oxygen species and lipid peroxidation and decreased ratio of GSH/GSSG and acetylcholinesterase activity in cortex and/or striatum. Our results suggest that rats pretreated with L. divaricata prior to 3-NP treatment showed neuroprotective effects when compared to 3-NP treated controls, which may be due to its antioxidant properties

N-acetylcysteine+nimesulide : an association strategy aiming to prevent nimesulide-induced hepatotoxicity

Introduction: Nimesulide is a potent anti-inflammatory with rapid and long-lasting effects, but also with a high risk of hepatotoxicity. Objective: This work aimed to prevent nimesulide-induced hepatotoxicity through the association of nimesulide with a hepatoprotective agent. Materials and Methods: First, we tested three hepatoprotective agents: N-acetylcysteine, L-carnitine, and Gingko biloba extract in an in vitro hepatic cell model. Both N-acetylcysteine and G. biloba showed promisor results. We selected N-acetylcysteine to continue the studies in an animal model. In vivo study was performed using male Wistar rats divided in 4 groups: control, nimesulide (100mg/kg/day), nimesulide (100mg/kg/day) + N-acetylcysteine (100mg/kg/day) and N-acetylcysteine alone (100mg/kg/day). Treatments were given by gavage, daily, for 15 days. Results: Animals receiving nimesulide alone showed lower body weight gain compared to control. Body weight gain in the nimesulide + N-acetylcysteine group was higher than nimesulide alone, evidencing lower toxicity. However, the body weight gain of the nimesulide + N-acetylcysteine group was still lower than the control animals. Animals treated with nimesulide alone presented an increased relative mass of heart, liver, and spleen and significant hepatic damage seen in microscopy when compared to other groups. N-acetylcysteine co-administered with nimesulide prevented the increased heart mass, but the same was not true with liver and spleen. Conclusions: This work evidence partial protection elicited by the association of N-acetylcysteine and nimesulide against nimesulide-induced hepatotoxicity.Introdução: A nimesulida é um potente anti-inflamatório com efeitos rápidos e duradouros, mas também com alto risco de hepatotoxicidade. Objetivo: Este trabalho teve como objetivo prevenir a hepatotoxicidade induzida pela nimesulida por meio da associação de nimesulida a um hepatoprotetor. Materiais e Métodos: Primeiro, testamos três possíveis hepatoprotetores: N-acetilcisteína, L-carnitina e extrato de Gingko biloba em um modelo de células hepáticas in vitro. N-acetilcisteína e G. biloba apresentaram bom potencial hepatoprotetor. Selecionamos a N-acetilcisteína para continuar os estudos em um modelo animal. O estudo in vivo foi realizado com ratos Wistar machos divididos em 4 grupos: controle, nimesulida (100 mg/kg/dia), nimesulida (100 mg/kg/dia) + N-acetilcisteína (100 mg/kg/dia) e N-acetilcisteína isolada (100 mg/kg/dia). Os tratamentos foram realizados por gavagem, diariamente, por 15 dias. Resultados: Os animais que receberam nimesulida isoladamente apresentaram menor ganho de peso corporal em comparação ao controle. O ganho de peso corporal no grupo nimesulida + N-acetilcisteína foi maior que o nimesulida isolado, evidenciando menor toxicidade. No entanto, o ganho de peso corporal do grupo nimesulida + N-acetilcisteína ainda era menor do que os animais controle. Os animais tratados com nimesulida isoladamente apresentaram aumento da massa relativa do coração, fígado e baço e dano hepático significativo observado na microscopia quando comparados a outros grupos. A N-acetilcisteína co-administrada com nimesulida impediu o aumento da massa cardíaca, mas tal fato não ocorreu com o fígado e o baço. Conclusões: Este trabalho evidencia proteção parcial provocada pela associação de N-acetilcisteína e nimesulida contra hepatotoxicidade induzida por nimesulida.Introducción: La nimesulida es un potente antiinflamatorio con efectos rápidos y duraderos, pero también con un alto riesgo de hepatotoxicidad. Objetivo: Este estudio tuvo como objetivo prevenir la hepatotoxicidad inducida por nimesulida combinando nimesulida con un medicamento hepatoprotector. Materiales y métodos: Primero, probamos tres candidatos: N-acetilcisteína, L-carnitina y extracto de Gingko biloba en un modelo de células hepáticas in vitro. N-acetilcisteína y G. biloba mostraron buen potencial. A continuación, seleccionamos N-acetilcisteína para continuar los estudios en un modelo animal. El estudio in vivo se realizó con ratas Wistar machos divididas en 4 grupos: control,nimesulida (100 mg/kg/día), nimesulida (100 mg/kg/día) + N-acetilcisteína (100 mg/kg/día) y N-acetilcisteína aislada (100 mg/kg/día). Los tratamientos se realizaron por sonda, diariamente, durante 15 días. Resultados: Los animales que recibieron nimesulida sola mostraron menos aumento de peso corporal en comparación con el control. El aumento de peso corporal en el grupo de nimesulida + N-acetilcisteína fue mayor que el de nimesulida sola, mostrando menos toxicidad. Sin embargo, el aumento de peso corporal del grupo nimesulida + N-acetilcisteína fue aún menor que el de los animales de control. Los animales tratados con nimesulida sola mostraron un aumento en la masa relativa del corazón, el hígado y el bazo y un daño hepático significativo observado al microscopio en comparación con otros grupos. La N-acetilcisteína administrada conjuntamente con nimesulida evitó el aumento de la masa cardíaca, pero no sucedió lo mismo con el hígado y el bazo. Conclusiones: Este trabajo muestra una protección parcial causada por la asociación de N-acetilcisteína y nimesulida contra la hepatotoxicidad inducida por la nimesulida

Caffeine Intake May Modulate Inflammation Markers in Trained Rats

Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments

Functional and biochemical adaptations of elite level futsal players from Brazil along a training season

Background and objective: Although hard training is mandatory in elite level futsal training, few studies have proposed a biochemical follow up in futsal players during a whole season. Therefore, the aim of this study was to compare functional and biochemical markers in Brazilian elite level futsal players throughout a competition season.Materials and methods: Eight players aged 25.5 ± 5.4 years were evaluated at three time points: preseason (T1), immediately before the FIFA®-Intercontinental-Futsal-Cup (T2), and at the end of the season (T3), with a tapering period of 1 week before T2. Functional parameters (weight, height, body fat, VO2max, heart rate, and distance ran) and blood sampling for cell count and lipid profile (cholesterol, HDL-C, LDL-C, triglycerides) were assessed at each time point. After, a Yo-Yo R2 test was carried out in each time point (T1, T2 and T3) and blood samples to assess skeletal muscle damage (creatine kinase [CK], lactate dehydrogenase [LDH]), inflammation (C-reactive protein [CRP]) and oxidative stress markers (ischemia modified albumin [IMA], and advanced oxidation protein products [AOPP]) were obtained before and after the tests.Results: Although functional parameters did not change throughout the season, greater total number of erythrocytes (P ≤ 0.05), and hemoglobin (P ≤ 0.05) were found at T2 compared to T1. Similarly, lower LDH (P ≤ 0.05) and CK (P ≤ 0.05) levels were found at T2 compared to T1. CPR levels were also decreased at T2 in comparison to T1 both before and after Yo-Yo R2 test (P ≤ 0.05), while IMA and AOPP levels showed only a season effect (P ≤ 0.05).Conclusions: The tapering strategy was successful considering players presented lower levels of muscle damage, inflammation and oxidative stress makers before T2, which preceded the main championship of the year. These results are of great relevance, considering the team won the FIFA®-Intercontinental-Futsal-Cup, which happened at T2. Thus, it seems that routine-based biochemical markers may be useful as training control means in this population

Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico

Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N4-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na+/K+) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na+/K+) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme’s active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment