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 anti-inflammatory 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 adaptation.

JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression.

Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject's life. Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20-treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells-microglia and astrocytes-from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1ß). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.

Guanosine protects against behavioural and mitochondrial bioenergetic alterations after mild traumatic brain injury.

Traumatic brain injury (TBI) constitutes a heterogeneous cerebral insult induced by traumatic biomechanical forces. Mitochondria play a critical role in brain bioenergetics, and TBI induces several consequences related with oxidative stress and excitotoxicity clearly demonstrated in different experimental model involving TBI. Mitochondrial bioenergetics alterations can present several targets for therapeutics which could help reduce secondary brain lesions such as neuropsychiatric problems, including memory loss and motor impairment. Guanosine (GUO), an endogenous neuroprotective nucleoside, affords the long-term benefits of controlling brain neurodegeneration, mainly due to its capacity to activate the antioxidant defense system and maintenance of the redox system. However, little is known about the exact protective mechanism exerted by GUO on mitochondrial bioenergetics disruption induced by TBI. Thus, the aim of this study was to investigate the effects of GUO in brain cortical and hippocampal mitochondrial bioenergetics in the mild TBI model. Additionally, we aimed to assess whether mitochondrial damage induced by TBI may be related to behavioral alterations in rats. Our findings showed that 24 h post-TBI, GUO treatment promotes an adaptive response of mitochondrial respiratory chain increasing oxygen flux which it was able to protect against the uncoupling of oxidative phosphorylation (OXPHOS) induced by TBI, restored the respiratory electron transfer system (ETS) established with an uncoupler. Guanosine treatment also increased respiratory control ratio (RCR), an indicator of the state of mitochondrial coupling, which is related to the mitochondrial functionality. In addition, mitochondrial bioenergetics failure was closely related with locomotor, exploratory and memory impairments. The present study suggests GUO treatment post mild TBI could increase GDP endogenous levels and consequently increasing ATP levels promotes an increase of RCR increasing OXPHOS and in substantial improve mitochondrial respiration in different brain regions, which, in turn, could promote an improvement in behavioral parameters associated to the mild TBI. These findings may contribute to the development of future therapies with a target on failure energetic metabolism induced by TBI.

Guanosine protects against Ca2+-induced mitochondrial dysfunction in rats.

Mitochondria play an important role in cell life and in the regulation of cell death. In addition, mitochondrial dysfunction contributes to a wide range of neuropathologies. The nucleoside Guanosine (GUO) is an endogenous molecule, presenting antioxidant properties, possibly due to its direct scavenging ability and/or from its capacity to activate the antioxidant defense system. GUO demonstrate a neuroprotective effect due to the modulation of the glutamatergic system and maintenance of the redox system. Thus, considering the few studies focused on the direct effects of GUO on mitochondrial bioenergetics, we designed a study to evaluate the in vitro effects of GUO on rat mitochondrial function, as well as against Ca2+-induced impairment. Our results indicate that GUO prevented mitochondrial dysfunction induced by Ca2+ misbalance, once GUO was able to reduce mitochondrial swelling in the presence of Ca2+, as well as ROS production and hydrogen peroxide levels, and to increase manganese superoxide dismutase activity, oxidative phosphorylation and tricarboxylic acid cycle activities. Our study indicates for the first time that GUO could direct prevent the mitochondrial damage induced by Ca2+ and that these effects were not related to its scavenging properties. Our data indicates that GUO could be included as a new pharmacological strategy for diseases linked to mitochondrial dysfunction.

High-intensity interval training improves inflammatory and adipokine profiles in postmenopausal women with metabolic syndrome.

This study investigate the effects of high-intensity interval training (HIIT) on systemic levels of inflammatory and hormonal markers in postmenopausal women with metabolic syndrome (MS). Fifteen postmenopausal women with MS completed the training on treadmills. Functional, body composition parameters, maximal oxygen uptake (VO2max), and lipid profile were assessed before and after HIIT. Serum or plasma levels of cytokines and hormonal markers were measured along the intervention. The analysis of messenger RNA (mRNA) expression of these cytokines was performed in peripheral blood mononuclear cells (PBMC). VO2max and some anthropometric parameters were improved after HIIT, while decreased levels of proinflammatory markers and increased levels of interleukin-10 (IL-10) were also found. Adipokines were also modulated after 12 weeks or training. The mRNA expression of the studied genes was unchanged after HIIT. In conclusion, HIIT benefits inflammatory and hormonal axis on serum or plasma samples, without changes on PBMC of postmenopausal MS patients.

Antioxidant protection by ß-selenoamines against thioacetamide-induced oxidative stress and hepatotoxicity in mice.

Thioacetamide (TAA) is a hepatotoxin that rapidly triggers the necrotic process and oxidative stress in the liver. Nevertheless, organic selenium compounds, such as ß-selenoamines, can be used as pharmacological agents to diminish the oxidative damage. Thus, the aim of this study was to investigate the protective effect of the antioxidant ß-selenoamines on TAA-induced oxidative stress in mice. Here, we observed that a single intraperitoneal injection of TAA (200 mg/kg) dramatically elevated some parameters of oxidative stress, such as lipid peroxidation and reactive oxygen species (ROS) production, as well as depleted cellular antioxidant defenses. In addition, TAA-induced edema and morphological changes in the liver, which correlate with high serum aspartate and alanine aminotransferase enzyme activities, and a decrease in cell viability. Conversely, a significant reduction in liver lipid peroxidation, ROS production, and edema was observed in animals that received an intraperitoneal injection of ß-selenoamines (15.6 mg/kg) 1 h after TAA administration.

Protective Effects of Aqueous Extract of Luehea divaricata against Behavioral and Oxidative Changes Induced by 3-Nitropropionic Acid in Rats.

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.

Positive effects of resistance training on inflammatory parameters in men with metabolic syndrome risk factors / Efectos positivos del entrenamiento de resistencia en los parámetros inflamatorios de hombres con factores de riesgo de síndrome metabólico

Background: evidences have shown a strongly association between metabolic syndrome (MS), cardiovascular diseases and chronic low-grade inflammation, being this last, related with the occurrence of sarcopenia and atherosclerosis. Despite several benefits, the effects of resistance training (RT) on inflammatory profile are controversial. Thereby, this study aims to investigate the effects of a RT on the inflammatory profile of men with MS risk factors. Methods: fifteen sedentary men (57.53±7.07 years old) with 2 or more MS components underwent a RT for 14 weeks (3 times per week), with intensity ranging between 40 and 70% of one repetition maximum. The dual-energy X-ray absorptiometry was used to body composition assessment and serum was collected to evaluate biochemical and inflammatory parameters before and after the RT. Results: despite the absence of changes in body weight, total muscular content and biochemical parameters, the individuals demonstrated a reduction on body fat content (p < 0.05), in higher levels of intelerukin-10 (p< 0.05) and in the stabilization of interleukin-1 beta and interferon-gamma concentrations. It was concluded that a moderate RT benefits inflammatory profile, contributing to a lower risk of cardiovascular diseases (AU)

Introducción: la evidencia muestra la relación entre síndrome metabólico (SM), enfermedades cardiovasculares e inflamación crónica de bajo grado, que está relacionada con la aparición de sarcopenia y aterosclerosis. A pesar de muchos beneficios, los efectos del entrenamiento de resistencia (ER) sobre la inflamación son controvertidos. Este estudio tiene como objetivo investigar los efectos de 14 semanas de ER en el perfil inflamatorio de hombres con factores de riesgo para SM. Métodos: quince varones sedentarios (57,53±7,07 años) con 2 o más componentes del SM fueron sometidos a un ER moderado durante 14 semanas (tres veces a la semana), con una intensidad que oscila entre 40 y 70% de una repetición máxima. La absorciometría dual de rayos X se utilizó para la evaluación de la composición corporal y el suero se recogió para evaluar los parámetros bioquímicos e inflamatorios antes y después de la ER. Resultados: a pesar del mantenimiento de la masa corporal, la masa muscular total y los parámetros bioquímicos, hubo una reducción en la grasa corporal (p < 0,05). Además, el ER disminuyó los niveles de factor de necrosis tumoral alfa e interleucina-6 circulante (p< 0,05), aumentó la concentración de interleucina-10 (p< 0,05) y mantuvo la interleucina-1 y el interferón-gamma. Se concluyó que 14 semanas de ER moderado provocan beneficios sobre el perfil inflamatorio, contribuyendo a la reducción del riesgo cardiovascular (AU)

An active lifestyle induces positive antioxidant enzyme modulation in peripheral blood mononuclear cells of overweight/obese postmenopausal women.

AIMS: The aim of this study was to investigate the effects of an active lifestyle on mitochondrial functioning, viability, bioenergetics, and redox status markers in peripheral blood mononuclear cells (PBMC) of overweight/ obese postmenopausal women. MATERIALS AND METHODS: We performed a cross-sectional study with postmenopausal women aged 45­64 years and body mass index N 25 kg/m2, divided into physically active (n = 23) and sedentary (n = 12) groups. Mitochondria functioning and viability, bioenergetics and redox status parameters were assessed in PBMC with spectrophotometric and fluorometric assays. KEY FINDINGS: No differences were found in the enzyme activity of complexes I and II of the electron transport chain (ETC), mitochondrial superoxide dismutase (MnSOD) activity, methyl-tetrazolium reduction levels and reduced glutathione and oxidized glutathione levels between the groups. However, the physically active group presented higher levels of reactive oxygen species (ROS) (P= 0.04) and increased catalase (CAT) (P= 0.029), total (P= 0.011) and cytosolic SOD (CuZnSOD) (P= 0.009) activities. SIGNIFICANCE: An active lifestyle that includes aerobic exercise for at least 30 min, three times per week may improve antioxidant enzyme activities in PBMC in overweight/obese postmenopausal women, without changes in the activity of the ETC enzymes. However, this low intensity physical activity is not able to induce relevant mitochondrial adaptations.