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Background: Intensive Care Unit (ICU) patients are known to lose muscle mass and function during ICU stay. Ultrasonography (US) application for the assessment of the skeletal muscle is a promising tool and might help detecting muscle changes and thus several dysfunctions during early stages of ICU stay. MUSiShock is a research project aiming to investigate structure and function of diaphragm and peripheral muscles using ultrasound techniques in septic shock patients, and to assess their relevance in several clinical outcomes such as the weaning process. Methods and design: This is a research protocol from an observational prospective cohort study. We plan to assess eighty-four septic shock patients during their ICU stay at the following time-points: at 24 hours of ICU admission, then daily until day 5, then weekly, at extubation time and at ICU discharge. At each time-point, we will measure the quadriceps rectus femoris and diaphragm muscles, using innovative US muscle markers such as Shear-Wave Elastography (SWE). In parallel, the Medical Research Council (MRC) sum score for muscle testing and the Airway occlusion pressure (P0.1) will also be collected. We will describe the association between SWE assessment and other US markers for each muscle. The association between the changes in both diaphragm and rectus femoris US markers over time will be explored as well; finally, the analysis of a combined model of one diaphragm US marker and one limb muscle US marker to predict weaning success/failure will be tested. Discussion: By using muscle ultrasound at both diaphragm and limb levels, MUSiShock aims to improve knowledge in the early detection of muscle dysfunction and weakness, and their relationship with muscle strength and MV weaning, in critically ill patients. A better anticipation of these short-term muscle structure and function outcomes may allow clinicians to rapidly implement measures to counteract it. Trial registration: ClinicalTrials.gov, NCT04550143. Registered on 16 September 2020. [ABSTRACT FROM AUTHOR]

Study Design: Systematic review. Background: Existing systematic reviews and meta-analyses do not support a specific physical therapy treatment for lateral elbow tendinopathy (LET). The results of these studies, however, may not accurately represent the current state of evidence. This may be due, in part, to methodological limitations in these studies, specifically the lack of utilization of standardized and disease-specific outcome measures. Objectives: To determine the effectiveness of physical therapy interventions in treating chronic lateral elbow tendinopathy as assessed in randomized controlled trials (RCTs) using pain-free grip strength and/or patient-rated tennis elbow evaluation questionnaire as outcome measures. Methods: A search of PubMed, Physiotherapy Evidence Database (PEDro), Scopus database, Google Scholar and bibliography was conducted from inception to November 2018. The methodological quality of the identified RCTs were assessed using the PEDro scale and the modified Sackett scale was used to appraise findings based on the level of evidence. Results: A total of two thousand nine hundred and six citations were identified, however, only twenty-two RCTs matched the eligibility criteria and were included in the review. The identified studies varied in design, investigated diverse physical therapy modalities that were applied for dissimilar periods, assessed outcome measures at unalike periods, and showed inconsistent results. Conclusion: A rigorous review of literature showed insufficient evidence to support or refute the effectiveness of many of the current physical therapy interventions for chronic LET. Nevertheless, the results might suggest immediate efficacy of mobilization with movement of the elbow joint and short-term efficacy of myofascial release technique. Level of evidence: Therapy, level 1a- [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18–20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1β, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring. [ABSTRACT FROM AUTHOR]

Exertional rhabdomyolysis is a complex and poorly understood entity. The inflammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker representing muscle damage. Considerable variation exists in CK response between different subjects. Genetic elements may act as predisposition factors for exertional rhabdomyolysis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A promoter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow flexor muscles. IL6 G-174C and TNFA G-308A genotypes were analyzed for possible relationship with changes in serum CK activity. IL6 G-174C genotype was associated with CK activity in a dose-dependent fashion. Subjects with one or more of the -174C allele had a greater increase and higher peak CK values than subjects homozygous for the G allele (mean +/- SE U/L: GG, 2,604 +/- 821; GC, 7,592 +/- 1,111; CC, 8,403 +/- 3,849, ANOVA P = 0.0003 for GG + GC genotypes versus CC genotype, P = 0.0005 for linear trend). IL6-174CC genotype was associated with a greater than threefold increased risk of massive CK response (adjusted odds ratio 3.29, 95% confidence interval 1.27-7.85, P = 0.009). A milder association (P = 0.06) was noted between TNFA G-308A genotype and CK activity. In conclusion, we found a strong association of the IL6 G-174C genotype with systemic CK response to strenuous exercise. Data suggest that homozygosity for the IL6-174C allele is a clinically important risk factor for exercise-induced muscle injury, further supporting the central role of cytokines in the reactive inflammatory process of muscle damage and repair. [ABSTRACT FROM AUTHOR]

Age is a known susceptibility factor for the cardiotoxicity of several anticancer drugs, including mitoxantrone (MTX). The impact of anticancer drugs in young patients is underestimated, thus we aimed to evaluate the cardiotoxicity of MTX in juvenile and adult animals. Juvenile (3 week-old) and adult (8–10 week-old) male CD-1 mice were used. Each group was treated with a 9.0 mg/kg cumulative dose of MTX or saline; they were maintained in a drug-free period for 3-weeks after the last administration to allow the development of late toxicity (protocol 1), or sacrificed 24 h after the last MTX administration to evaluate early cardiotoxicity (protocol 2). In protocol 1, no adult mice survived, while 2 of the juveniles reached the end of the protocol. High plasma aspartate aminotransferase/alanine aminotransferase ratio and a high cardiac reduced/oxidized glutathione ratio were found in the surviving MTX-treated juvenile mice. In protocol 2, a significant decrease in plasma creatine-kinase MB in juveniles was found 24 h after the last MTX-administration. Cardiac histology showed that both MTX-treated populations had significant damage, although higher in adults. However, MTX-treated juveniles had a significant increase in fibrotic tissue. The MTX-treated adults had higher values of cardiac GSSG and protein carbonylation, but lower cardiac noradrenaline levels. For the first time, mature adult animals were shown to be more susceptible to MTX as evidenced by several biomarkers, while young animals appear to better adjust to the MTX-induced cardiac injury. Even so, the higher level of fibrotic tissue and the histological damage showed that MTX also causes cardiac damage in the juvenile population. [ABSTRACT FROM AUTHOR]

The present review was conducted to determine the efficacy of high‐voltage monophasic pulsed current (HVMPC) in treating diabetic ulcers, assess its effect on skin lesions with each of the pathophysiologic factors potentially contributing to diabetic ulcers, evaluate its safety, and identify treatment parameters. Electronic search of PubMed, Scopus, PEDro and Google Scholar databases was conducted. The revised tool for assessing risk of bias in randomised trials (RoB 2), the risk of bias in non‐randomised studies‐of interventions (ROBINS‐I) and the Joanna Briggs Institute (JBI) critical appraisal tool were used to assess risk of bias and methodological quality. Overall quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles. Thirty‐two studies matched the eligibility criteria, and included 1061 patients with 1103 skin lesions of selected aetiologies; 12 randomised controlled trials were included in quantitative synthesis. HVMPC plus standard wound care (SWC) likely increased the probability of complete wound healing of pressure ulcers (PrUs) compared with sham/no stimulation plus SWC; relative risk (RR) 2.08; 95% CI: [1.42, 3.04], p = 0.0002; I2 = 0%, p = 0.61; eight studies, 358 ulcers. Although conclusive evidence regarding the effect of HVMPC on diabetic ulcers was not found, collateral evidence might suggest a potential benefit. Direct evidence, with moderate certainty, may support its efficacy in treating PrUs, albeit few adverse reactions were reported. Other observations, moreover, might indicate that this efficacy may not be limited to PrUs. Nonetheless, several aspects remain to be clarified for safe and effective application of electrical stimulation for wound healing. [ABSTRACT FROM AUTHOR]

The muscle cells, or myofibers, are one of the three multinucleated cell types, along with osteoclasts and cytotrophoblasts. This aspect of skeletal muscle has led to the concept of myonuclear domain, which is defined as the theoretical amount of cytoplasm within a muscle fiber controlled by a single myonucleus. Considering the huge plasticity of skeletal muscle fibers, the myonuclear domain has become one aspect of major interest under situations leading to muscle atrophy (spinal cord isolation and transaction, microgravity, hindlimb suspension and chronic denervation) hypertrophy (synergist ablation and bouts of exercise) and day-to-day wear and tear (age, body size, muscle function and fiber type-related differences). This concept is supported by several studies reporting that changes in muscle fibers' cross-sectional area (CSA) are paralleled by an alteration in the number of myonuclei, maintaining constant the relationship between them. This implies a fairly strict regulation of the myonuclear number that is governed by two opposing mechanisms: the gain of myonuclei by the fusion of muscle stem cells into hypertrophying muscle fibers and the loss of myonuclei by apoptosis/necrosis in atrophying muscle fibers. The aim of this review is to scrutinize the changes in the myonuclear domain in skeletal muscle fibers considering the atrophic and hypertrophic processes, emphasizing the differences between the various methods utilized to achieve these morphological alterations, and the differences between muscle responses according to their phenotype (different function and fiber type composition) and animal age (relevance to sarcopenia). [ABSTRACT FROM AUTHOR]

Objective: The effects of hindlimb unweighting by tail suspension on mice's soleus muscle cross-sectional area (CSA) and myonuclei content were studied. Design: Five groups of male Charles River CD 1 mice (n=10 per group) were assigned to varying hindlimb suspension (HS) periods: control (cont), 1 (1HS), 2 (2HS), 3 (3HS) and 8 (8HS) days. Immediately after the suspension period, the soleus muscles were removed in order to assess morphometry data. The CSA and number of myonuclei were determined in a total of 5011 fibers (1098, 793, 1363, 1281, 1276 fibers for the cont, 1HS, 2HS, 3HS, 8HS groups, respectively) from different areas in the mid-portion region of the soleus muscle, and the CSA per myonucleus ratio was calculated. Results: The results showed that the removing of weight bearing had a negative impact on muscle fiber CSA (1686 ± 516 μm2, 1506 ± 470 μm2, 1235 ± 340 μm2, 1277 ± 412 μm2 and 1075 ± 356 μm2 in the cont, 1HS, 2HS, 3HS and 8HS groups, respectively) and myonuclei number per fiber (1.91 ± 1.17, 1.94 ± 1.30, 1.55 ± 1.01, 1.48 ± 1.00 and 0.83 ± 0.76 in the cont, 1HS, 2HS, 3HS and 8HS groups, respectively). The CSA per myonucleus ratio was 993 ± 522 μm2, 854 ± 443 μm2, 815 ± 374 μm2, 881 ± 442 μm2 and 957 ± 367 μm2 in the cont, 1HS, 2HS, 3HS and 8HS groups, respectively. Thus, there were no significant differences between the control and 8HS groups. Conclusion: The morphological data is consistent with the hypothesis that, despite the muscle fiber atrophy induced by HS, the CSA per myonucleus ratio is apparently maintained, reinforcing the concept of myonuclear domain. [ABSTRACT FROM AUTHOR]

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is an amphetamine derivative drug with entactogenic, empathogenic and hallucinogenic properties, commonly consumed at rave parties in a polydrug abuse pattern, especially with cannabis, tobacco and ethanol. Since both MDMA and ethanol may cause deleterious effects to the liver, the evaluation of their putative hepatotoxic interaction is of great interest, especially considering that most of the MDMA users are regular ethanol consumers. Thus, the aim of the present study was to evaluate, in vivo, the acute hepatotoxic effects of MDMA (10mg/kg i.p.) in CD-1 mice previously exposed to 12% ethanol as drinking fluid (for 8 weeks). Body temperature was continuously measured for 12h after MDMA administration and, after 24h, hepatic damage was evaluated. The administration of MDMA to non pre-treated mice resulted in sustained hyperthermia, which was significantly increased in ethanol pre-exposed mice. A correspondent higher increase of hepatic heat shock transcription factor (HSF-1) activation was also observed in the latter group. Furthermore, MDMA administration resulted in liver damage as confirmed by histological analysis, slight decrease in liver weight and increased plasma transaminases levels. These hepatotoxic effects were also exacerbated when mice were pre-treated with ethanol. The activities of some antioxidant enzymes (such as SOD, GPx and Catalase) were modified by ethanol, MDMA and their joint action. The hepatotoxicity resulting from the simultaneous exposure to MDMA and ethanol was associated with a higher activation of NF-κB, indicating a pro-inflammatory effect in this organ. In conclusion, the obtained results strongly suggest that the consumption of ethanol increases the hyperthermic and hepatotoxic effects associated with MDMA abuse. [Copyright &y& Elsevier]

Doxorubicin (DOX) is a topoisomerase II inhibitor used in cancer therapy. Despite its efficacy, DOX causes serious adverse effects, such as short- and long-term cardiotoxicity. This work aimed to assess the short- and long-term cardiotoxicity of DOX and the role of inflammation and antioxidant defenses on that cardiotoxicity in a mice model. Adult CD-1 male mice received a cumulative dose of 9.0 mg/kg of DOX (2 biweekly intraperitoneal injections (ip), for 3 weeks). One week (1W) or 5 months (5M) after the last DOX administration, the heart was collected. One week after DOX, a significant increase in p62, tumor necrosis factor receptor (TNFR) 2, glutathione peroxidase 1, catalase, inducible nitric oxide synthase (iNOS) cardiac expression, and a trend towards an increase in interleukin (IL)-6, TNFR1, and B-cell lymphoma 2 associated X (Bax) expression was observed. Moreover, DOX induced a decrease on nuclear factor erythroid-2 related factor 2 (Nrf2) cardiac expression. In both 1W and 5M, DOX led to a high density of infiltrating M1 macrophages, but only the 1W-DOX group had a significantly higher number of nuclear factor κB (NF-κB) p65 immunopositive cells. As late effects (5M), an increase in Nrf2, myeloperoxidase, IL-33, tumor necrosis factor-α (TNF-α), superoxide dismutase 2 (SOD2) expression, and a trend towards increased catalase expression were observed. Moreover, B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and carbonylated proteins expression decreased, and a trend towards decreased p38 mitogen-activated protein kinase (MAPK) expression were seen. Our study demonstrated that DOX induces adverse outcome pathways related to inflammation and oxidative stress, although activating different time-dependent response mechanisms. [ABSTRACT FROM AUTHOR]

The salivary glands play a central role in the secretion of saliva, whose composition and volume affect oral and overall health. A lesser-explored dimension encompasses the possible changes in salivary gland proteomes in response to fluctuations in sex hormone levels. This study aimed to examine the effects of chronic exposure to testosterone on salivary gland remodeling, particularly focusing on proteomic adaptations. Therefore, male Wistar rats were implanted with subcutaneous testosterone-releasing devices at 14 weeks of age. Their submandibular glands were histologically and molecularly analyzed 47 weeks later. The results underscored a significant increase in gland mass after testosterone exposure, further supported by histologic evidence of granular duct enlargement. Despite increased circulating sex hormones, there was no detectable shift in the tissue levels of estrogen alpha and androgen receptors. GeLC-MS/MS and subsequent bioinformatics identified 308 proteins in the submandibular glands, 12 of which were modulated by testosterone. Of note was the pronounced upregulation of Klk3 and the downregulation of Klk6 and Klk7 after testosterone exposure. Protein–protein interaction analysis with the androgen receptor suggests that Klk3 is a potential target of androgenic signaling, paralleling previous findings in the prostate. This exploratory analysis sheds light on the response of salivary glands to testosterone exposure, providing proteome-level insights into the associated weight and histological changes. [ABSTRACT FROM AUTHOR]

The article offers information on the changes to the editorial team of the periodical International Journal of Sports Medicine including retirement of the editor-in chief professor Appell Coriolano and the appointment of Hans-Joachim Appell Coriolano as assistant editor.

Knowing the therapeutic effects of regular physical exercise on kidney toxicity induced by a single dose of doxorubicin (DOX) in animal models, the aim of this study is to verify the effectiveness of regular voluntary running on kidney histology after a prolonged DOX administration, mimicking a chemotherapy protocol. Thirty-four male Wistar rats were randomly divided into two clusters: DOX (n = 17) and SSS (sterile saline solution, n = 17), receiving a weekly intraperitoneal injection of DOX (2 mg/kg) or vehicle for 7 weeks, respectively. Two weeks after the last injection, five animals from each cluster (SSSG, n = 5; DOXG, n = 5) were euthanized, while the remaining ones were divided into sedentary (DOXsed, n = 6; SSSsed, n = 6) and active subgroups (DOXact, n = 6; SSSact, n = 6). Active animals were placed individually in cages with a running wheel for regular voluntary activity. After 2 months, the animals were euthanized and kidneys were histologically examined. Compared to SSSG, kidneys from DOXG revealed higher levels of damage, more collagen content and thickening of Bowman’s capsule (p < .05). The levels of damage and thickness of Bowman’s capsule increased in DOXsed as compared to DOXG (p < .05). Compared to DOXsed, the DOXact presented an overall improvement in kidney structure (p < .05), with a decrease in collagen content and of the thickness of Bowman’s capsule. The results allow concluding that regular voluntary running attenuate the long-term harmful effects on kidney structure induced by a prolonged DOX treatment. These results, supporting the potential benefit of physical activity in patients under DOX treatment, need to be tested in humans. [ABSTRACT FROM AUTHOR]

Context: Deep friction massage (DFM) is often used in the treatment of tendinopathies; however, the pressure applied may vary and interfere with the obtained results. Objective: To assess whether the immediate effects of DFM on pain (pain intensity and time to onset of analgesia) and muscle strength are dependent on the pressure applied during the DFM application in athletes with patellar tendinopathy. Design: Randomized, controlled, cross-over trial. Setting: University research laboratory (institutional). Participants: Ten athletes with diagnosis of unilateral patellar tendinopathy (age 27.90 [5.24] y). Interventions: All participants attended 4 sessions, 3 treatment sessions with DFM applied with different pressures (the mean pressure--previously determined for each participant--and the mean pressure ± 25%) and a control session, each of which was separated by 48 hours. Main Outcome Measures: Pain (intensity upon palpation and time to onset of analgesia), and muscle strength of knee extensors were assessed before and immediately after each session. Results: Pain intensity changed significantly over time (F1,9 = 52.364; P < .001; ηp² = .853) and among sessions (F3,27 = 82.588; P < .001; ηp² = .902), with a significant interaction for group x time (F3,27 = 19.841; P < .001; ηp² = .688). The knee extensors strength did not change significantly over time (F1,9 = 2.240; P = .17; ηp² = .199), nor a significant interaction for session x time was observed (F3,27 = 3.276; P = 07; ηp² = .267). Regardless of the pressure applied, the time to onset of analgesia was not significantly different (F2,18 = 1.026; P > .05; = ηp²). Conclusion: It was shown that DFM induces an immediate reduction in pain intensity upon palpation, regardless of the pressure performed. Notwithstanding, the reader should take into account the small sample size and the caution needed in the results' interpretation. [ABSTRACT FROM AUTHOR]

Methylphenidate (MPH) is a first-line stimulant drug to treat attention deficit hyperactivity disorder (ADHD). Overdiagnosis of ADHD and MPH abuse lead to serious concerns about the possible long-term adverse consequences of MPH in healthy children and adolescents. We aimed to evaluate MPH effects in adolescent male Wistar rats (postnatal day 40) using an oral dose scheme (2 daily MPH doses 5 mg/kg in a 5% sucrose solution, 5 h apart, for 7 days) that mimics the therapeutic doses given to human adolescents. Twenty-four hours after the last MPH administration, rats were sacrificed and brain areas [cerebellum, prefrontal cortex (PFC), hippocampus, and striatum], peripheral organs (liver, heart, and kidneys), and blood were collected for biochemical and histological analysis. MPH treatment did not alter rats’ body temperature or weight, neither food or water intake throughout the experiment. The ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) significantly increased in the PFC and hippocampus of MPH-treated rats, meanwhile protein carbonylation remained unchanged in the brain. In the heart, the GSH/GSSG ratio and GSH levels were significantly increased, with decreased GSSG, while histology revealed significant damage, namely interstitial edema, vascular congestion, and presence of a fibrin-like material in the interstitial space. In the kidneys, MPH treatment resulted in extensive necrotic areas with cellular disorganization and cell infiltration, and immunohistochemistry analysis revealed a marked activation of nuclear factor-ĸB. This study showed that clinically relevant oral MPH doses improve the GSH redox status in the brain and heart, but evoke heart and kidney tissue damage to adolescent rats. [ABSTRACT FROM AUTHOR]

Simple Summary: This study shows the lifelong benefits of aerobic exercise in preventing early age-related consequences on mitochondrial liver function and antioxidant activity. Although exercise intensity is often cited as crucial for developing adaptive responses in the body, we demonstrated that the duration of the training protocol might be more critical for the adaptive response. Thus, physical exercise prescribers should promote the awareness of physical exercise practitioners about the importance of performing this practice regularly, as the benefits go far beyond those already known in cardiac and skeletal muscle. Most studies on the effects of physical exercise have focused on its influence on muscle tissue, forgetting its interference in liver function. Ageing leads to the progressive impairment of hepatic functions. Several biochemical and bioenergetics parameters were determined to test the impact of a lifelong aerobic training program in the hepatic age-related and the development of an adaptative response. Liver samples were collected from 28 male Wistar rats (4-week-old, 159.4 ± 11.9 g at the beginning of the protocol), randomly distributed into two groups: non-exercised or exercised and submitted to a treadmill exercise program (60 min/day, 5 days/week, at 70% of maximal running speed), for 24 (n = 9) or 54 weeks (n = 10). A maximal running speed test was performed to determine the training speed. Antioxidant enzyme activity, cellular redox status, oxidative stress, mitochondrial respiratory chain enzymes and respiratory activity were performed in liver samples. Lifelong exercise decreased the age-associated decline in mitochondrial dysfunction, increasing the respiratory rate in state 2 (mitochondrial respiration stimulated by the substrate in the absence of added ADP) (p = 0.03) and citrate synthase enzymatic activity (p = 0.007). Complex II (p < 0.0001) and IV (p < 0.001) showed a decrease in enzymatic activity. Ageing-related oxidative stress was also attenuated by physical exercise, as showed by the increase in first-line defense antioxidant enzymes (superoxide dismutase (p = 0.07) and catalase (p = 0.03)), decreased lipid peroxidation levels (p = 0.864 for total fraction, p = 0,27 for mitochondrial fraction) and higher glutathione reduced/oxidized ratio (p = 0.02). According to our results, the regular practice of exercise can prevent the liver's mitochondrial dysfunction and loss of antioxidant system efficacy that may arise from ageing, highlighting the benefit of lifelong aerobic exercise in preventing age-related hepatic impairment and associated diseases. [ABSTRACT FROM AUTHOR]

The role of antioxidant supplementation on muscle recovery after disuse is unknown. The aim was to investigate the effect of Vitamin C and E supplementation on muscle recovery after hindlimb suspension. Twenty-two Wistar rats were allocated into 4 groups: exercise with supplementation (VIT, n = 5); exercise with placebo (PLA, n = 5); hindlimb suspension (SUSP, n = 6), and control (CON, n = 6). All groups, except for CON, were submitted to a hindlimb suspension protocol for 10 days. Then, VIT and PLA underwent 10 days of a rehabilitation protocol consisting of exercise on a treadmill. VIT received vitamin C (250 mg/kg/day) and E (360 mg/kg) during rehabilitation. Samples of soleus and tibialis anterior were prepared for cross-sectional area (CSA) and biochemical analysis. Both VIT (1265.6 m μ 2, 95% CI: 1234.6–1290.3) and PLA (1280.9 m μ 2, 95% CI: 1296.4–1354.9) presented higher CSA of the soleus in relation to CON (816.66 m μ 2, 95% CI: 866.3–904.0, P <  0.05) with no difference between them. Both VIT (1276.9 m μ 2, 95% CI: 1378.7–1484.6) and PLA (1573.3 m μ 2, 95% CI: 1553.9–1651.5) presented higher tibialis anterior CSA in relation to CON (1041.56 m μ 2, 95% CI: 1119.1–1185.2, P <  0.05). In this muscle, CSA of PLA was higher than VIT (P <  0.05). Vitamin's supplementation attenuated tibialis anterior hypertrophy following the rehabilitation protocol. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nonspecific chronic lower back pain (CLBP) is a difficult to manage clinical condition that is more prevalent in adulthood but also affects adolescents, compromising their well-being and activities of daily living. This case report aimed to describe the clinical evolution of a female adolescent with nonspecific and severe CLBP treated successfully through a combination of high-intensity exercise and motor imagery training. Case Description: A 13-year-old girl with CLBP with radicular pain to the lower limbs, spasms, and movement limitations, for whom pharmacological treatment (i.e. analgesic and muscle relaxant agents) and hydrotherapy, hot wet therapy, and muscle relaxation were unsuccessful. After a careful physiotherapy evaluation, the patient underwent a 36-session intervention, performed 3 times/week for 12 weeks, which was composed of high-intensity therapeutic exercise, adjusted for the patient condition, along with motor imagery training. The patient was reevaluated after the intervention and again 3 years later by the same physiotherapist. Outcomes: The intervention led to a favorable clinical outcome, with pain relief, improved posture, and decreased disability. The patient's clinical condition remained stable at the time of the last follow-up evaluation. Conclusion: These results show that the adjusted combined program led to favorable clinical improvement in the condition, with sustained long-term effects after the intervention. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer. [ABSTRACT FROM AUTHOR]

Dear Editors: The authors would like to thank Dr. Seet-Lee and colleagues for their comments on our recently-published manuscript in the International Journal of Sports Medicine 1. Dr. Seet-Lee and colleagues highlighted some inadequacies, specifically when using mean difference or raw mean difference as effect measure. However, when evaluating blood vessel density by different reliable and validated histological procedures, would it be wrong to assume, as we did, that all the obtained measurements from different staining always vary equally, directly and linearly, with the actual parameter under study? Are Dr. Seet-Lee and colleagues assuming that the results of histological observations of blood vessels, marked with different techniques and stains, are neither compatible nor governed by the same measurement scales? We regret, but we are firmly convinced that we proceeded properly. Moreover, we should not assume that standardized effect sizes will make comparisons meaningful 2. Particularly, as the standardized mean difference indicates the difference before and after the intervention in terms of standard deviations instead of actual scores, it assumes that different outcome scales are linear transformation of each other and the standard deviation (SD) is equal across all studies 3. [ABSTRACT FROM AUTHOR]

Epidemiological studies have demonstrated that stress-related disorders, such as the increase on the caloric intake, are twice as common in women as in men, but surprisingly, very few studies have been tested this subject on female experimental animals. Additionally, it has been proposed that regular physical exercise can improve the deleterious effects of stress. Therefore, the present longitudinal study, performed in female rats, aimed to test the influence of chronic stress (ST) imposed by social isolation on the animals' caloric intake and to assess the effect of regular physical exercise of low intensity on this behaviour. In 4 groups of Wistars rats (control sedentary, n = 6; control exercised, n = 6; ST sedentary, n = 6; ST exercised, n = 6), body weight, food intake, abdominal fat weight, adrenal weight, corticosterone metabolites in faeces and plasma insulin levels were measured during the experimental protocol and/or at its end. The results showed that social isolation was not able to modify the amount of abdominal fat and the body weight; however, it promoted significant increases in the corticosterone metabolites and in the amount of caloric intake, which were attenuated in exercised rats. Additionally, exercised groups presented lower levels of fasting insulin than sedentary groups. Therefore, the present study demonstrated that regular physical exercise of low intensity attenuates the corticosterone metabolites and overeating behaviour triggered by social stress. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Oxidative stress has been advanced as one of the major causes of damage to DNA and other macromolecules. Although physical exercise may also increase oxidative stress, an important role has been recognized for regular exercise in improving the overall functionality of the body, as indicated by an increase in maximal aerobic uptake ( [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m2 for infants and 108.9 mg/m2 for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2. [ABSTRACT FROM AUTHOR]

Abstract: Successful application of gold nanoparticles (AuNPs) in biomedicine requires extensive safety assessment for which biokinetic studies are crucial. We evaluated the biodistribution of AuNPs (∼20nm) with different surface coatings: citrate, 11-MUA and 3 pentapeptides, CALNN, CALND and CALNS, after i.v. administration to rats (0.6–1mg Au/kg). Biodistribution was evaluated based on Au tissue content measured by GFAAS. Citrate-AuNPs were rapidly removed from circulation with 60% of the injected dose depositing in the liver. Thirty minutes post-injection, the lungs presented about 6% of the injected dose with levels decreasing to 0.7% at 24h. Gold levels in the spleen were of 2.6%. After 24h, liver presented the highest Au level, followed by spleen and blood. A similar biodistribution profile was observed for MUA-coated AuNPs compared to Cit-AuNPs at 24h post-injection, while significantly higher levels of peptide-capped AuNPs were found in the liver (74–86%) accompanied by a corresponding decrease in blood levels. TEM analysis of liver slices showed AuNPs in Kupffer cells and hepatocytes, trapped inside endosomes. Our data demonstrate that AuNPs are rapidly distributed and that the liver is the preferential accumulation organ. Peptide capping significantly increased hepatic uptake, showing the influence of AuNPs functionalization in biodistribution. [Copyright &y& Elsevier]

Objective: This study aimed to analyse the influence of moderate changes in air temperature and humidity on the acute ventilatory response to exercise in asthmatic children. Design: 7 asthmatics over 15 years old (Experimental Group, EG), and 7 healthy subjects with the same characteristics (Control Group, CG) performed an exercise protocol in 2 different environments, interspaced by 48 hours: hot+humid environment (HH, temperature: 32.6±0.4°C, relative humidity: 42.4±1.6%) and an environment with less humidity+lower temperature (LHLT, temperature: 24.0±0.9°C, relative humidity: 36.3±1.3%). Steady state values of cardiorespiratory parameters were monitored during exercise, being the forced expiratory volume in 1st second (FEV1) and peak expiratory flow (PEF) obtained immediately before exercise and after 5 minutes of recovery. Results: The EG experienced a post-exercise decrease of FEV1 in LHLT (90.6±9.6%, p<0.05) and HH (95.2±5.8%, p<0.05) while CG did not show post-exercise changes in both environments (103.7±11.2% vs. 101.2±4.9%, respectively). The EG showed a post-exercise PEF decrease in the LTLH (94.6±8.8%, p<0.05) and no changes in the HH environment (99.7±4.2%), while CG did not show significant changes in both environments (102.9±12.7% vs. 107.0±9.8%). Conclusion: Results allow concluding that ventilatory response to exercise is influenced by air temperature and humidity, with a HH environment being more favourable for asthmatics. [ABSTRACT FROM AUTHOR]

Abstract: There is an increasing evidence that endothelial dysfunction and vascular wall inflammation are present in all stages of atherosclerosis. Atherosclerosis does not have to necessarily progress to an acute clinical event. Several therapeutic strategies exist, such as exercise training, which mitigates endothelial dysfunction and inflammation. Exercise training consistently improves the nitric oxide bioavailability, and the number of endothelial progenitor cells, and also diminishes the level of inflammatory markers, namely pro-inflammatory cytokines and C-reactive protein. However, the mechanisms by which exercise improves endothelial function in coronary artery disease patients are not fully clarified. Several mechanisms have been proposed to explain the positive effect of exercise on the disease progression. They include the decrease in cytokine production by the adipose tissue, skeletal muscles, endothelial cells, and blood mononuclear cells, and also, the increase in the bioavailability of nitric oxide, antioxidant defences, and regenerative capacity of endothelium. This study aims to provide a critical review of the literature linking exercise, inflammation, and endothelial dysfunction in coronary artery patients, and to discuss the potential mechanisms behind the exercise-training improvement of endothelial function and inflammatory status. [Copyright &y& Elsevier]

The aim of this study was to investigate the temporal involvement of different proteolytic systems and muscle proteome changes during experimental disuse atrophy (up to 1 week hindlimb suspension, HS) in murine gastrocnemius muscle. The results showed that proteolysis, cytoprotection mechanisms and signs of cellular infiltration occurred very early. After 1 day of HS, signals of lysosomal activation, rather than programmed cell death (apoptosis), seem to trigger protein breakdown in the whole skeletal muscle. Moreover, the ubiquitin-proteasome pathway remained elevated later whereas all other proteolytic parameters returned to control values when atrophy was fully established. Using proteomics, evidence is provided for metabolic alterations toward glycolysis and for cytoskeleton remodelling suggestive of reduced capacity for force generation. Overall, our data highlight an early and coordinated time-dependent activation of proteolysis, which explains the global proteome alterations observed in gastrocnemius under atrophic conditions. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to investigate the mechanisms of cell death (apoptosis vs. necrosis) during muscle atrophy induced by 1 week of hindlimb suspension. Biochemical and morphological parameters were examined in murine soleus and gastrocnemius muscles. A total of 70 male Charles River CD1 mice were randomly assigned to seven groups (n = 10/group): Cont (loading control conditions) and 6HS, 12HS, 24HS, 48HS, 72HS and 1wkHS with respect to the period of hindlimb suspension (HS). Compared to the Cont, skeletal muscle atrophy was confirmed by a significant decrease of 44 and of 17% in fiber cross-sectional areas in the gastrocnemius and soleus, respectively. A significant increase in caspase-3 activity was noticed in 6HS (196%, P < 0.05) and in 12HS (201%, P < 0.05), as well as the amount of cytosolic mono- and oligonucleosomes at 12HS (142%, P < 0.05) and 24HS (203%, P < 0.05) in the gastrocnemius and soleus, respectively. The profile of necrotic markers showed a peak of myeloperoxidase activity at 24HS (170%, P < 0.05) and at 72HS (114%, P < 0.05) in the gastrocnemius and soleus, respectively. The analysis of N-acetylglucosaminidase activity evidenced more increment in the soleus at 72HS (60%, P < 0.05). The analysis of the basal values of these parameters suggested that apoptosis prevailed in the slow-twitch muscle analyzed, whereas lysosomic activity seemed to be more pronounced in the gastrocnemius. The morphological data supported the biochemical results pointing towards a shift from apoptosis to necrosis, which seems to corroborate the aponecrosis theory. [ABSTRACT FROM AUTHOR]

The comprehension of the cellular mechanisms underlying skeletal muscle atrophy has been the aim of several experimental studies. However, the majority of them focused on alterations of the myocytes induced by different experimental conditions yet disregarding the contribution of other cells such as endothelial cells and fibroblasts. In this sense, 70 Charles River CD1 male mice were randomly assigned to seven groups (n=10 per group): control and 6, 12, 24, 48, 72 h and 1 week with respect to the period of hindlimb suspension. Forty-eight hours before sacrifice, the animals were injected with bromodeoxyuridine (BrdU) in order to identify proliferating cells. Immunohistochemistry and south-western blotting techniques were used to evaluate across the whole gastrocnemius muscle BrdU incorporation into the different proliferating cells. The contribution of the apoptotic response was also measured in order to ascertain whether the balance between cell survival and death was preserved. The results observed during 1 week of unloading-induced atrophy evidenced an intense peak of proliferating activity only after 6 h, mainly due to the duplication of satellite cells. Consequently to this unexpected activation of satellite cells, the addition of nuclei to the fibre syncytium was recognized at 12 h of unloading. After 48 h of weightlessness, the proliferating activity observed was largely due to an interstitial fibrosis. According to the apoptotic index profile observed during the analysed unloading period, this general proliferative activity was balanced by apoptosis, which strongly suggests the existence of a regulatory feedback response between anabolic and catabolic events in unloading-induced skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

This review aimed to systematize and quantify the existing evidence about the effect of tumor vascularization on its growth, in preclinical studies. A computerized research on databases PubMed, Scopus and EBSCO was performed to identify studies that evaluate both the vascularization parameters and the development of the tumors in animal models and the mean differences were calculated through a random effects model. Thirteen studies met the inclusion criteria and were included in the systematic review, of which, 6 studies were included in the meta-analysis. Besides tumor vascular density that all studies evaluated, 3 studies analysed the tumor perfusion, 2 studies the tumor hypoxia and 3 studies assessed the grade of vessel maturation. Most of the studies (11) related decreased tumor vascularization and a concomitant inhibition of tumor growth or metastasis development. Quantitatively, the decrease in tumor vascularization contributed to a significant decrease in the tumor growing rate of 5.23 (-9.20, -1.26). A reduced level of tumor vascularization seems to be able to inhibit tumor growth and progression. [ABSTRACT FROM AUTHOR]

The aim of the present study was to analyze the acute effect of a resistance exercise session on cardiovascular and perceptual responses using the slow movement speed compared to the traditional movement speed in hypertensive elderly women. Experimental research was carried out with eleven elderly women (66.5± 4.8 years) active and with medication-controlled hypertension in the city of Tabuleiro do Norte, Ceará, Brazil. The elderly women were randomly submitted to a RE session with 60% of 1 RM with slow movement speed or traditional. Systolic blood pressure, diastolic blood pressure, heart rate, mean blood pressure, and double product were measured before exercise and after sessions for one hour. The postexercise analysis showed a more marked reduction in systolic blood pressure, heart rate, mean blood pressure, and double product values (p< 0.05) in slow movement speed compared to baseline values, however, there were no significant differences in post-exercise hypotension between contraction speeds (p> 0.05). Differences were found in the rating of perceived exertion (p= 0.007). Slow movement speed and traditional movement speed prom women on medication. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors with high prevalence among adult populations and elevated costs for public health systems worldwide. Despite the lack of consensus regarding the syndrome definition and diagnosis criteria, it is characterized by the coexistence of risk factors such as abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, a prothrombotic and pro-inflammatory state, insulin resistance (IR), and higher glucose levels, factors indubitably linked to an increased risk of developing chronic conditions, such as type 2 diabetes (T2D) and cardiovascular disease (CVD). The syndrome has a complex and multifaceted origin not fully understood; however, it has been strongly suggested that sedentarism and unbalanced dietary patterns might play a fundamental role in its development. The purpose of this review is to provide an overview from the syndrome epidemiology, costs, and main etiological traits from its relationship with unhealthy diet patterns and sedentary lifestyles. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxypyrovalerone (MDPV) is consumed worldwide, despite its potential to cause toxicity in several organs and even death. There is a recognized need to clarify the biological pathways through which MDPV elicits general and target-organ toxicity. In this work, a comprehensive untargeted GC–MS-based metabolomics analysis was performed, aiming to detect metabolic changes in putative target organs (brain, heart, kidneys and liver) but also in urine of mice after acute exposure to human-relevant doses of MDPV. Male CD-1 mice received binge intraperitoneal administrations of saline or MDPV (2.5 mg/kg or 5 mg/kg) every 2 h, for a total of three injections. Twenty-four hours after the first administration, target organs, urine and blood samples were collected for metabolomics, biochemical and histological analysis. Hepatic and renal tissues of MDPV-treated mice showed moderate histopathological changes but no significant differences were found in plasma and tissue biochemical markers of organ injury. In contrast, the multivariate analysis significantly discriminated the organs and urine of MDPV-treated mice from the control (except for the lowest dose in the brain), allowing the identification of a panoply of metabolites. Those levels were significantly deviated in relation to physiological conditions and showed an organ specific response towards the drug. Kidneys and liver showed the greatest metabolic changes. Metabolites related with energetic metabolism, antioxidant defenses and inflammatory response were significantly changed in the liver of MDPV-dosed animals, while the kidneys seem to have developed an adaptive response against oxidative stress caused by MDPV. On the other hand, the dysregulation of metabolites that contribute to metabolic acidosis was also observed in this organ. The heart showed an increase of fatty acid biosynthesis, possibly as an adaptation to maintain the cardiac energy homeostasis. In the brain, changes in 3-hydroxybutyric acid levels may reflect the activation of a neurotoxic pathway. However, the increase in metabolites with neuroprotective properties seems to counteract this change. Metabolic profiling of urine from MDPV-treated mice suggested that glutathione-dependent antioxidant pathways may be particularly involved in the compensatory mechanism to counteract oxidative stress induced by MDPV. Overall, this study reports, for the first time, the metabolic profile of liver, kidneys, heart, brain, and urine of MDPV-dosed mice, providing unique insights into the biological pathways of toxicity. Our findings also underline the value of toxicometabolomics as a robust and sensitive tool for detecting adaptive/toxic cellular responses upon exposure to a physiologically relevant dose of a toxic agent, earlier than conventional toxicity tests. [ABSTRACT FROM AUTHOR]

As people age, their skeletal muscle (SkM) experiences a decline in mitochondrial functionality and density, which leads to decreased energy production and increased generation of reactive oxygen species. This cascade of events, in turn, might determine the loss of SkM mass, strength and quality. Even though the mitochondrial processes dysregulated by aging, such as oxidative phosphorylation, mitophagy, antioxidant defenses and mtDNA transcription, are the same in both sexes, mitochondria age differently in the SkM of men and women. Indeed, the onset and magnitude of the impairment of these processes seem to be influenced by sex-specific factors. Sexual hormones play a pivotal role in the regulation of SkM mass through both genomic and non-genomic mechanisms. However, the precise mechanisms by which these hormones regulate mitochondrial plasticity in SkM are not fully understood. Although the presence of estrogen receptors in mitochondria is recognized, it remains unclear whether androgen receptors affect mitochondrial function. This comprehensive review critically dissects the current knowledge on the interplay of sex in the aging of SkM, focusing on the role of sex hormones and the corresponding signaling pathways in shaping mitochondrial plasticity. Improved knowledge on the sex dimorphism of mitochondrial aging may lead to sex-tailored interventions that target mitochondrial health, which could be effective in slowing or preventing age-related muscle loss. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4–7 and 6–11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study. [ABSTRACT FROM AUTHOR]

Purpose: Although resistance exercise (RE) is now recognized as an adjuvant in cancer treatment because of its capacity to prevent muscle wasting, weakness, and cachexia, it is unknown whether RE can mitigate tumor development. Two solid adenocarcinoma models (Walker-256 and Ehrlich) were used to investigate the effects of RE on tumor cell proliferation, growth, and aggressiveness parameters in tumor-bearing animals' life span. Methods: Walker-256 tumor-bearing rats and Ehrlich tumor-bearing mice were subjected to RE, which consisted of climbing a ladder apparatus with loads tied to their tails. After 4 wk, animals were euthanized, and tumors were excised and assessed for tumor microenvironment evaluation such as cell proliferation and apoptosis determination, collagen deposit, and presence of malignant tumor morphology. Results: Our data demonstrate that RE mitigated tumor growth and favored tumor end points such as lower Scarff–Bloom–Richardson histological grade tumor, denoting slow cell aberrant form and division, decreased tumor cell proliferation (evaluated by nucleus marked with antigen ki-67), and lower viable tumor area in both types of tumors studied. In addition, RE stimulated tumor microvessel density in Walker-256 tumor-bearing rats, but there was no change in their life span. Conclusion: RE may mitigate tumor growth and tumor malignancy parameters such as lower histopathological grade, assuming less nuclear pleomorphism and mitotic cells, smaller viable tumor area, and decreased tumor cell proliferation in both adenocarcinomas. In addition, RE induced tumor vascularization. [ABSTRACT FROM AUTHOR]

Amanita phalloides is one of the most toxic mushrooms worldwide, and it is involved in the majority of human fatal cases of mushroom poisoning. α-Amanitin, the most deleterious toxin of A. phalloides to humans, inhibits RNA polymerase II (RNAPII), causing hepatic and renal failure. Previously, we have shown that polymyxin B (polB) reverts α-amanitin inhibition of RNAPII, although it was not able to guarantee the full survival of α-amanitin-intoxicated mice or prevent α-amanitin pro-inflammatory effects. α-Amanitin is also a substrate of the organic-anion-transporting polypeptide 1B3 (OATP1B3) and Na(+)-taurocholate cotransporter polypeptide (NTCP) transporters. Therefore, in the present work, we used a combination of polB [(2.5 mg/kg intraperitoneal (i.p.)] with the anti-inflammatory and NTCP inhibitor drug, methylprednisolone (MP) (10 mg/kg i.p.), as an attempt to fully revert α-amanitin-induced toxicity (0.33 mg/kg i.p.) in CD-1 mice. Results showed that the administration of the polB + MP combination, 4 h after α-amanitin, led to the full survival of the intoxicated animals, with a significant attenuation of α-amanitin-induced renal and hepatic necrosis. Also, the combination polB + MP led to a decrease of aminotransferase plasma levels, of the renal myeloperoxidase activity and of renal inflammatory cell infiltrate promoted by α-amanitin, although not preventing any of the hepatic pro-inflammatory effect of the toxin. The obtained results indicate that this combination may represent an important and valuable therapeutic approach to be used against α-amanitin intoxication. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticles (ION) have great potential for an increasing number of medical and biological applications, particularly those focused on nervous system. Although ION seem to be biocompatible and present low toxicity, it is imperative to unveil the potential risk for the nervous system associated to their exposure, especially because current data on ION effects on human nervous cells are scarce. Thus, in the present study potential toxicity associated with silica-coated ION (S-ION) exposure was evaluated on human A172 glioblastoma cells. To this aim, a complete toxicological screening testing several exposure times (3 and 24 h), nanoparticle concentrations (5–100 μg/ml), and culture media (complete and serum-free) was performed to firstly assess S-ION effects at different levels, including cytotoxicity – lactate dehydrogenase assay, analysis of cell cycle and cell death production – and genotoxicity – H2AX phosphorylation assessment, comet assay, micronucleus test and DNA repair competence assay. Results obtained showed that S-ION exhibit certain cytotoxicity, especially in serum-free medium, related to cell cycle disruption and cell death induction. However, scarce genotoxic effects and no alteration of the DNA repair process were observed. Results obtained in this work contribute to increase the knowledge on the impact of ION on the human nervous system cells. [ABSTRACT FROM AUTHOR]

Limiting cancer-induced cardiac damage has become an increasingly important issue to improve survival rates and quality of life. Exercise training has been shown to reduce cardiovascular complications in several diseases; however, its therapeutic role against cardiovascular consequences of cancer is in its infancy. In order to add new insights on the potential therapeutic effect of exercise training on cancer-related cardiac dysfunction, we used an animal model of urothelial carcinoma submitted to 13 weeks of treadmill exercise after 20 weeks of exposure to the carcinogenic N -butyl- N -(4-hydroxybutyl)-nitrosamine (BBN). Data showed that 13 weeks of treadmill exercise reverted cancer-induced cardiomyocytes atrophy and fibrosis, improved cardiac oxidative capacity given by citrate synthase activity and MnSOD content, and increased the levels of the mitochondrial biogenesis markers PGC-1α and mtTFA. Moreover, exercise training reverted cancer-induced decrease of cardiac c-kit levels suggesting enhanced regenerative ability of heart. These cardiac adaptations to exercise were related to a lower incidence of malignant urothelial lesions and less signs of inflammation. Taken together, data from the present study support the beneficial effect of exercise training when started after cancer diagnosis, envisioning the improvement of the cardiovascular function. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls ( n = 9), tumor-bearing ( n = 9), exercised ( n = 9), and tumor-bearing exercised ( n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 107 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage. [ABSTRACT FROM AUTHOR]

Objective 'Krokodil' is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. Methods Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a 'domestic' protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. Results It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil-mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. Conclusions These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. [ABSTRACT FROM AUTHOR]

Aims Well-characterized animal tumor models of cancer cachexia are warranted to elucidate underlying mechanisms and provide a better approach to the human scenario. We aimed to investigate whether solid Ehrlich carcinoma reproduces clinical, functional and biological conditions of tumor-induced cachexia in mice. Methods Eight-week old female Swiss mice were subcutaneously inoculated with Ehrlich tumor cells (tumor-bearing, TB group) or vehicle (sham) into the right flank and monitored for 28 days. Tumor histopathological features and tumor–host interaction, including tissue weight, muscle structure, strength and biochemical parameters were carried out. Key findings Tumor growth curve demonstrated a linear pattern with no difference in final carcass weight between groups. A well-defined capsule composed by connective tissue infiltrated by inflammatory and neoplastic cells surrounded the tumors. The TB group had reduced handgrip strength, aside from lower cross sectional area (CSA) and critically reduced parametrial fat pads. Plasma parameters of lactate dehydrogenase (LDH), creatine kinase (CK) and tumor necrosis factor-α (TNF-α) were higher in the TB group, suggesting predominance of catabolic and pro-inflammatory activities. Conversely, food intake and tissue weight did not differ between groups. Significance Our data elucidated that the solid Ehrlich tumor model is feasible and effective in reproducing some of the relevant issues experienced by cancer patients with cachexia. The solid Ehrlich carcinoma emerges as an alternative tool against more aggressive cancer cachexia models during preclinical research. [ABSTRACT FROM AUTHOR]

This work investigated the effects of creatine supplementation on different pathways related to the pathogenesis of non-alcoholic fatty liver disease and alcoholic liver disease. To induce alcoholic liver disease, male Swiss mice were divided into three groups: control, ethanol and ethanol supplemented with creatine. To induce non-alcoholic fatty liver disease, mice were divided into three groups: control, high-fat diet and high-fat diet supplemented with creatine. Each group consisted of eight animals. In both cases, creatine monohydrate was added to the diets (1 %; weight/vol). Creatine supplementation prevented high-fat diet-induced non-alcoholic fatty liver disease progression, demonstrated by attenuated liver fat accumulation and liver damage. On the other hand, when combined with ethanol, creatine supplementation up-regulated key genes related to ethanol metabolism, oxidative stress, inflammation and lipid synthesis, and exacerbated ethanol-induced liver steatosis and damage, demonstrated by increased liver fat accumulation and histopathological score, as well as elevated oxidative damage markers and inflammatory mediators. Our results clearly demonstrated creatine supplementation exerts different outcomes in relation to non-alcoholic fatty liver disease and alcoholic liver disease, namely it protects against high-fat diet-induced non-alcoholic fatty liver disease but exacerbates ethanol-induced alcoholic liver disease. The exacerbating effects of the creatine and ethanol combination appear to be related to oxidative stress and inflammation-mediated up-regulation of ethanol metabolism. • Creatine supplementation has been demonstrated to prevent nonalcoholic fatty liver progression. • We hypostatized creatine supplementation would prevent ethanol-induced fatty liver and hepatic damage. • Creatine exerts different outcomes, by protecting against HFD-induced NAFLD but exacerbating ethanol-induced ALD. • Creatine exacerbates liver injury by increasing oxidative stress and inflammation-mediated up-regulation of ethanol metabolism. [ABSTRACT FROM AUTHOR]

The use of the herbicide paraquat (1,1′-dimethyl-4,4′-bipyridylium dichloride; PQ) has been fiercely challenged due to its severe acute toxicity, putative neurotoxicity after long-term exposure and lack of antidotes. Breakthrough research on PQ is therefore required for an effective risk control and to allow a safer use of PQ in the future. The silencing or inhibition of quinone oxidoreductase 2, a NAD(P)H-independent flavoenzyme, was shown to significantly attenuate PQ toxicity in vitro, in primary pneumocytes and astroglial U373 cells, and to strongly antagonize PQ-induced systemic toxicity and animal mortality. The novel results reported in this issue of BJP, added to recent findings using sodium salicylate and lysine acetylsalicylate, in which full survival of PQ-intoxicated rats was also achieved, open the door for new preventative and therapeutic strategies that may lead to safer use of this effective pesticide. LINKED ARTICLE This article is a commentary on Janda et al., pp. 46-59 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01870.x [ABSTRACT FROM AUTHOR]

Amanita phalloides is one of the most toxic mushrooms worldwide, being responsible for the majority of human fatal cases of mushroom intoxications. α-Amanitin, the most deleterious toxin of A. phalloides , inhibits RNA polymerase II (RNAP II), causing hepatic and renal failure. Herein, we used cyclosporine A after it showed potential to displace RNAP II α-amanitin in silico. That potential was not confirmed either by the incorporation of ethynyl-UTP or by the monitoring of fluorescent RNAP II levels. Nevertheless, concomitant incubation of cyclosporine A with α-amanitin, for a short period, provided significant protection against its toxicity in differentiated HepaRG cells. In mice, the concomitant administration of α-amanitin [0.45 mg/kg intraperitoneal (i.p.)] with cyclosporine A (10 mg/kg i.p. plus 2 × 10 mg/kg cyclosporine A i.p. at 8 and 12 h post α-amanitin) resulted in the full survival of α-amanitin-intoxicated mice, up to 30 days after the toxin's administration. Since α-amanitin is a substrate of the organic-anion-transporting polypeptide 1B3 and cyclosporine A inhibits this transporter and is a potent anti-inflammatory agent, we hypothesize that these mechanisms are responsible for the protection observed. These results indicate a potential antidotal effect of cyclosporine A, and its safety profile advocates for its use at an early stage of α-amanitin intoxications. • Cyclosporine A has a potential to displace α-amanitin from RNAP II in silico. • Cyclosporine A does not displace α-amanitin from RNAP II in vitro. • Brief concomitant incubation of cyclosporine A with α-amanitin protects differentiated HepaRG cells. • In mice, the concomitant use of cyclosporine A with α-amanitin leads to full survival. [ABSTRACT FROM AUTHOR]

Os efeitos benéficos da prática regular de exercício físico na melhoria do controlo glicémico em doentes com diabetes mellitus do tipo 2 (DM2) estão relativamente bem documentados na literatura, nomeadamente em programas de curta duração (4 a 16 semanas). Menor consenso existe sobre a influência dos efeitos no longo prazo. No presente estudo, procurou-se avaliar os efeitos de um programa de exercício físico regular de longa duração no controlo glicémico e na resistência à insulina, em doentes com DM2 do Centro de Saúde de Bragança. A amostra foi constituída por um grupo de referência (GR) (n=102, 53 mulheres e 49 homens, idade média de 65,1±8,7 anos) e um grupo de intervenção (GI) (n=23, 15 mulheres e 8 homens, idade média de 63,7±6,9 anos), todos com DM2 diagnosticada. Os indivíduos do GI foram sujeitos a um programa de exercícios de longa duração (32 meses), predominantemente aeróbio (caminhada a ±6 km·h-1 e exercícios de hidroginástica), 5 vezes por semana (4 sessões em meio terrestre e 1 em meio aquático por semana), com uma duração de 55 minutos por sessão. Foram realizadas avaliações de 4 em 4 meses, num total de 9. Os elementos do GR não participaram em nenhum programa de exercícios, tendo sido avaliados apenas 1 vez. Entre cada momento de avaliação, foi observado um efeito significativo do programa na redução dos valores médios da glicemia de jejum [-0,119 mmol·L-1 (IC 95%: -0,193 -- -0,046)], da resistência à insulina (homeostasis assessment model insulin resistance -- HOMA-IR) [-0,080 unidades (IC 95%: -0,142 -- -0,019)] e da glicemia crónica (hemoglobina glicada A1c -- HbA1c) [-0,073% (IC 95%: -0,130 -- -0,016)]. Foi também identificada uma associação direta e significativa da assiduidade ao programa nas reduções da glicemia de jejum, da insulina de jejum, do HOMA-IR e da HbA1c. O programa de exercício, mantido no longo prazo, consistiu numa forma auxiliar de tratamento segura e eficaz na melhoria do controlo glicémico. [ABSTRACT FROM AUTHOR]

Background Exercise training has been recognized as a non-pharmacological therapeutic approach in several chronic diseases; however it remains to be tested if exercise preconditioning can positively interfere with the natural history of pulmonary arterial hypertension (PAH). This is important since the majority of these patients are diagnosed at advanced stages of the disease, when right ventricle (RV) impairment is already present. Objectives In the current study, we evaluated the preventive effect of exercise preconditioning on RV failure secondary to PAH, with a focus on the signaling pathways modulated by pro-inflammatory cytokines from TNF superfamily. Methods We analyzed the RV muscle from adult male Wistar rats exposed to a 4-week treadmill exercise training or sedentary regime, prior to the administration of monocrotaline (MCT) to induce PAH or with saline solution (controls). Results Data indicate that exercise preconditioning prevented cardiac hypertrophy and RV diastolic dysfunction. At a molecular level, exercise modulated the TWEAK/NF-κB signaling axis and prevented the shift in MHC isoforms towards an increased expression of beta-MHC. Exercise preconditioning also prevented the increase of atrogin-1 expression, and induced a shift of MMP activity from MMP-9 to MMP-2 activity. Conclusions Altogether, data support exercise as a preventive strategy for the management of PAH, which is of particular relevance for the familial form of PAH that is manifested by greater severity or earlier onset. [ABSTRACT FROM AUTHOR]