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To summarize evidence in the last decade regarding the efficacy of physical therapy interventions to treat tendinopathy, as a single disease entity, as determined in systematic reviews (SRs) and/or meta-analyses (MAs). Electronic search of PubMed, PEDro, and Scopus database was performed from year 2010 to January 2020. The methodological quality of the identified studies was assessed using the AMSTAR 2 tool. Studies scoring 9 points or higher were further analyzed using GRADE principles. 40 SRs and/or MAs were included in qualitative synthesis, whereas only 5 MAs were included in quantitative synthesis. Low-level laser therapy (LLLT) intervention showed a pooled improvement in pain reduction of 1.53 cm; 95% CI, [1.14, 1.91] (I 2 = 1.9%, p = 0.361) on visual analogue scale, and grip strength of 9.59 kg; 95% CI, [5.90, 13.27]. Moderate-quality evidence may support these following interventions: LLLT revealed a statistically and potentially clinically significant improvement in pain and function on the short-term. Extracorporeal shockwave therapy showed a statistically significant enhancement in pain and function at all follow-up durations; however, its clinical significance was undetermined. Eccentric exercise was supported by qualitative evidence only. Caution is advised when interpreting results due to possible pathological differences in tendinopathy at each region. • Systematic reviews and/or meta-analyses published in the last decade were evaluated. • Moderate-quality quantitative evidence was found for some interventions. • Eccentric exercise was supported by qualitative evidence only. • The superior intervention and optimal protocols remain unknown. [ABSTRACT FROM AUTHOR]

Abstract This review was conducted to determine and quantify the efficacy of high-voltage monophasic pulsed current (HVMPC) in the treatment of stage II-IV pressure ulcers (PrUs), identify the details of HVMPC intervention parameters and the superior protocol, and ascertain other potential benefits and the safety of HVMPC intervention. Eleven studies, nine randomized controlled trials (RCTs) and two case series studies, matched the criteria and were included in the systematic review, whereas, only level 1 evidence RCTs were included in the meta-analysis. The percentage of wound surface area reduction per week was 12.39%; 95% CI, [10.43–14.37] for HVMPC plus standard wound care (SWC) and 6.96%; 95% CI, [5.56–8.38] for SWC alone or SWC plus sham HVMPC. The net effect of HVMPC was 5.4% per week (an increase of 78% greater than SWC alone or SWC plus sham HVMPC). Level 1, 2 and 4 evidence studies have consistently indicated that HVMPC plus SWC were more effective than SWC alone or SWC plus sham HVMPC in treating stage II-IV PrUs. Level 1 evidence studies showed that HVMPC intervention improved the healing of PrUs (reduced wound surface area), and combined with SWC, increased the probability of complete healing and almost eliminated the probability of worsening of healing. HVMPC intervention was shown to be relatively safe, with rare adverse reactions. Highlights • A form of electrical stimulation improved the healing of pressure ulcers. • Pressure ulcer healing progressed consistently and steadily. • Complete healing of recalcitrant pressure ulcers was promoted. [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]

Surface chemistry plays an important role in gold nanoparticles (AuNPs) stability and biocompatibility, which are crucial for their implementation into the clinical setting. We evaluated short- (30 min) and long-term (28 days) biodistribution and toxicity of ~ 20 nm citrate- and pentapeptide CALNN-coated AuNPs after a single intravenous injection in rats. The pattern of AuNPs distribution in Cit- and CALNN-AuNPs-injected rats was very similar in the assessed time-points. Both AuNPs were quickly removed from the bloodstream and preferentially accumulated in the liver. At 28 days liver remained the main accumulation site but at significantly lower levels compared to those found at 30 min. Spleen atrophy and hematological findings compatible with mild anemia were observed in CALNN-AuNPs-administered rats. Under our experimental conditions, surface coating had more impact on toxicity rather than on biodistribution of the AuNPs. Improvements in the design of capping peptides need to be done to increase biomedical applicability of peptide-coated AuNPs. From the Clinical Editor The biodistribution and toxicity of ~ 20 nm citrate- and pentapeptide CALNN-coated gold nanoparticles was investigated after a single intravenous injection in rats. Rapid clearance and hepatic accumulation was found at 30-minutes, whereas mild anemia and spleen atrophy was seen 28 days post injection. The authors also concluded that the toxicity was related to the capping proteins as opposed to the biodistribution of the particles, providing important suggestion for future design of gold nanoparticles. [ABSTRACT FROM AUTHOR]

Abstract: Background: Schwannoma is a tumor of the nervous system composed by Schwann cells. It can occur naturally in several tissues of the body in both humans and animals. Diaphragmatic hernia can be congenital or acquired and is defined as a protrusion of abdominal viscera into the thoracic cavity. Materials and methods: The animal was a female rat from an experiment of mammary tumor chemically induced. It was injected with N-methyl-N-nitrosourea (MNU) and died spontaneously at 22 weeks of age. Results: The animal had a diaphragmatic hernia and a hemorrhagic and multicystic mass in the liver herniated lobule. Microscopically the liver displayed a well circumscribed mass that was a tumor with hemorrhagic areas, necrosis and Antoni A and Antoni B patterns. It also displayed occasional positivity to vimentin and diffuse positivity to S-100 and NSE. Conclusion: The tumor was a schwannoma with the origin in the Glisson's capsule. [Copyright &y& Elsevier]

Abstract: Objectives: To analyze the effects of a single bout and repeated bouts of stretching on indirect markers of exercise-induced muscle damage. Design: A randomized controlled clinical trial at a university human research laboratory was conducted. Methods: Fifty-six untrained males were randomly divided into four groups. (I) a single stretching group underwent a single bout of stretching on the quadriceps muscle; (II) an eccentric exercised group underwent eccentric quadriceps muscle contractions until exhaustion; (III) an eccentric exercise group followed by a single bout of stretching; (IV) an eccentric exercised group submitted to repeated bouts of stretching performed immediately and 24, 48, and 72h post-exercise. Muscle stiffness, muscle soreness, maximal concentric peak torque, and plasma creatine kinase activity were assessed before exercise and 1, 24, 48, 72, and 96h post-exercise. Results: All exercised groups showed significant reduction in maximal concentric peak torque and significant increases in muscle soreness, muscle stiffness, and plasma creatine kinase. There were no differences between these groups in all assessed variables, with the exception of markers of muscle stiffness, which were significantly lower in the eccentric exercise group followed by single or repeated bouts. The single stretching group showed no change in any assessed variables during the measurement period. Conclusions: Muscle stretching performed after exercise, either as single bout or as repeated bouts, does not influence the levels of the main markers of exercise-induced muscle damage; however, repeated bouts of stretching performed during the days following exercise may have favorable effects on muscle stiffness. [Copyright &y& Elsevier]

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]

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]

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]

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]

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]

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]

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]

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]

Background Skeletal muscle wasting contributes to the poor functional status and quality of life of patients with pulmonary arterial hypertension (PAH). The present study aims to characterize the molecular mechanism underlying skeletal muscle wasting in experimental PAH induced by monocrotaline (MCT). Methods Male Wistar rats were randomly injected with saline solution (CONT; n = 10) or MCT (MCT; 60 mg/kg, s.c.; n = 15). After 4 weeks of MCT or vehicle administration, animals were anesthetized and submitted to right ventricular (RV) hemodynamic evaluation. Blood and gastrocnemius sample s were collected and stored for analysis. Results MCT group developed PAH (70% increase in RV peak systolic pressure) RV dysfunction (increased end-diastolic pressure and Tau), and body and muscle wasting (reduction of 20%, 16% and 30% on body weight, gastrocnemius mass and fiber cross sectional area, respectively). Muscle atrophy was associated with a decrease in type I MHC. Circulating (C reactive protein, myostatin and IL-1beta) and local catabolic markers (MAFbx/atrogin-1, protease activity) were increased in MCT animals, while Akt/mTOR pathway was preserved. Mitochondria isolated from gastrocnemius of MCT animals showed decreased activity of ATP synthase, lower levels of Tfam, accumulation of oxidatively modified proteins together with reduced levels of paraplegin. Conclusions Our data suggests an anabolic/catabolic imbalance in gastrocnemius from MCT-induced PAH rats. Accumulation of dysfunctional mitochondria due to the inefficiency of protein quality control systems to eliminate damaged proteins could also contribute to muscle atrophy in PAH. [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]

This manuscript highlights and critically analyses clinical and forensic signs related to chemical burns. Signs that may lead to suspicion of a particular chemical are thoroughly discussed regarding its underlying mechanisms. Burns due to sulfuric, hydrofluoric, nitric, hydrochloric (muriatic) and acetic (including derivatives) acids, hydrogen sulphide, sodium (caustic soda) and calcium (cement) hydroxides, paraquat, burns after inflation and rupture of airbags, povidone–iodine, chlorhexidine/alcohol (in preterm infants), laxatives, and vesicants (warfare agents), will be reviewed since these are the most common agents found in daily practice, for which relevant and timed information may be helpful in formulating an emergency treatment protocols and toxicological analysis. [ABSTRACT FROM AUTHOR]

Current evidence points to a high prevalence of urinary incontinence among female athletes. In this context, this study aims to assess if structural and biomechanical characteristics of the pubovisceral muscles may lead to urine leakage. Clinical and demographic data were collected, as well as pelvic Magnetic Resonance Imaging. Furthermore, computational models were built to verify if they were able to reproduce similar biomechanical muscle response as the one measured by dynamic imaging during active contraction by means of the percent error. Compared to the continent ones (n=7), incontinent athletes (n=5) evidenced thicker pubovisceral muscles at the level of the midvagina (p=0.019 and p=0.028 for the right and left sides, respectively). However, there were no differences neither in the strength of contraction in the Oxford Scale or in the displacement of the pelvic floor muscles during simulation of voluntary contraction, which suggests that urine leakage may be related with alterations in the intrafusal fibers than just the result of thicker muscles. Additionally, we found similar values of displacement retrieved from dynamic images and numerical models (6.42±0.36 mm vs. 6.10±0.47 mm; p=0.130), with a percent error ranging from 1.47% to 17.20%. However, further refinements in the mechanical properties of the striated skeletal fibers of the pelvic floor muscles and the inclusion of pelvic organs, fascia and ligaments would reproduce more realistically the pelvic cavity. [ABSTRACT FROM AUTHOR]

Cardiac cachexia is a serious complication of chronic heart failure, characterized by significant weight loss and body wasting. Chronic heart failure-related muscle wasting results from a chronic imbalance in the activation of anabolic or catabolic pathways, caused by a series of immunological, metabolic, and neurohormonal processes. In spite of the high morbidity and mortality associated to this condition, there is no universally accepted definition or specific biomarkers for cardiac cachexia, which makes its diagnosis and treatment difficult. Several hormonal, inflammatory and oxidative stress molecules have been proposed as serological markers of prognosis in cardiac cachexia but with doubtful success. As individual biomarkers may have limited sensitivity and specificity, multimarker strategies involving mediators of the biological processes modulated by cardiac cachexia will strongly contribute for the diagnosis and management of the disease, as well as for the establishment of new therapeutic targets. An integrated analysis of the biomarkers proposed so far for cardiac cachexia is made in the present review, highlighting the biological processes to which they are related. [ABSTRACT FROM AUTHOR]

Abstract: Alterations in muscle mitochondrial bioenergetics during cancer cachexia were previously suggested; however, the underlying mechanisms are not known. So, the goal of this study was to evaluate mitochondrial phospholipid remodeling in cancer-related muscle wasting and its repercussions to respiratory chain activity and fiber susceptibility to apoptosis. An animal model of urothelial carcinoma induced by exposition to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and characterized by significant body weight loss due to skeletal muscle mass decrease was used. Morphological evidences of muscle atrophy were associated to decreased respiratory chain activity and increased expression of mitochondrial UCP3, which altogether highlight the lower ability of wasted muscle to produce ATP. Lipidomic analysis of isolated mitochondria revealed a significant decrease of phosphatidic acid, phosphatidylglycerol and cardiolipin in BBN mitochondria, counteracted by increased phosphatidylcholine levels. Besides the impact on membrane fluidity, this phospholipid remodeling seems to justify, at least in part, the lower oxidative phosphorylation activity observed in mitochondria from wasted muscle and their increased susceptibility to apoptosis. Curiously, no evidences of lipid peroxidation were observed but proteins from BBN mitochondria, particularly the metabolic ones, seem more prone to carbonylation with the consequent implications in mitochondria functionality. Overall, data suggest that bladder cancer negatively impacts skeletal muscle activity specifically by affecting mitochondrial phospholipid dynamics and its interaction with proteins, ultimately leading to the dysfunction of this organelle. The regulation of phospholipid biosynthetic pathways might be seen as potential therapeutic targets for the management of cancer-related muscle wasting. [Copyright &y& Elsevier]

Highlights: [•] The formulation has a reduced toxicity to C. vulgaris when compared to Gramoxone®. [•] The highest protection was achieved at the proportion of 1:8 (PQ/LAS). [•] LAS conferred a protection of approximately 1.8 fold (% of inhibition of growth). [•] Salicylic acid is biotransformed by C. vulgaris after 48h, and not detectable at 96h. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac cachexia (CC) affects a large proportion of patients with chronic heart failure, a major public health issue in western countries. The pathophysiology of CC is complex and multifactorial, resulting from several factors interacting in a complex system with metabolic, immune and neurohormonal consequences, triggered to protect the heart and the circulation from damage. Despite the adverse clinical effects, CC diagnosis is not straightforward and has not specifically been targeted, with therapeutic strategies only comprising interventions with appetite stimulants, and anti-inflammatory substances. Here we review the molecular pathways underlying CC-related muscle wasting aiming to provide clues for the definition of CC-specific biomarkers and for the development of drugs that prevent and/or counteract muscle impairment, which will certainly impact the management of cardiovascular disorders. [Copyright &y& Elsevier]

Abstract: Myocardial mitochondria dysfunction seems to represent an important pathogenic factor underlying cardiomyopathy, a common complication of type 1 diabetes mellitus (T1DM). Despite significant progress in the understanding of the molecular mechanisms of mitochondrial function in the heart, the interplay between phospholipids and membrane proteins of this organelle is still poorly comprehended. Using a well-characterized animal model of T1DM obtained by the administration of streptozotocin, phospholipid profiling of isolated mitochondria was performed using MS-based approaches, which was analyzed together with oxidative phosphorylation (OXPHOS) complexes activities and their susceptibility to oxidation, and the expression of cytochrome c, the uncoupling protein UCP-3 and the mitochondrial transcription factor Tfam. Although in higher amounts, mitochondria from T1DM heart presented lower OXPHOS activity and lower transcription ability. This profile was related to phospholipid (PL) remodeling characterized by higher phosphatidylcholine levels, lower phosphatidylglycerol, phosphatidylinositol and sphingomyelin content, higher amounts of long fatty acyl side chains and increased lipid peroxidation, particularly of cardiolipin (CL). CL peroxidation was paralleled by lower cytochrome c content. Though in higher levels, UCP-3 does not seem to protect heart mitochondrial PL and membrane proteins from the oxidative damage induced by four weeks of hyperglycemia. Taken together, our data suggest that PL remodeling of heart mitochondria is an early event in T1DM pathogenesis and is related with OXPHOS dysfunction. [Copyright &y& Elsevier]

Abstract: Loss of skeletal muscle is a serious consequence of cancer as it leads to weakness and increased risk of death. To better understand the interplay between urothelial carcinoma and skeletal muscle wasting, cancer-induced catabolic profile and its relationship with muscle mitochondria dynamics were evaluated using a rat model of chemically induced urothelial carcinogenesis by the administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). The histologic signs of non-muscle-invasive bladder tumors observed in BBN animals were related to 17% loss of body weight and high serum levels of IL-1β, TNF-α, TWEAK, C-reactive protein, myostatin and lactate and high urinary MMPs activities, suggesting a catabolic phenotype underlying urothelial carcinoma. The 12% loss of gastrocnemius mass was related to mitochondrial dysfunction, manifested by decreased activity of respiratory chain complexes due to, at least partially, the impairment of protein quality control (PQC) systems involving the mitochondrial proteases paraplegin and Lon. This was paralleled by the accumulation of oxidatively modified mitochondrial proteins. In overall, our data emphasize the relevance of studying the regulation of PQC systems in cancer cachexia aiming to identify therapeutic targets to counteract muscle wasting. [Copyright &y& Elsevier]

Abstract: Psychiatric deviations resulting from alcohol and illegal drug abuse may be considered a major risk factor for suicidal behavior. This report describes a suicide by hanging, under the influence of ketamine and alcohol. The victim was a 29-year-old man, found dead hanging by the neck from a metallic beam in the ceiling of his workplace. Besides characteristic signs of hanging seen at the autopsy, toxicological analysis revealed a femoral blood concentration of ketamine and ethanol of 1.3mg/L and 0.66g/L, respectively. Positive qualitative results for ketamine were also detected, in a powder found near the victim and on the victim''s nostrils, which suggests nasal inhaling as administration route. The hallucinogenic effects caused by ketamine, associated with an increased sensitivity of N-methyl-d-aspartate (NMDA) receptors to ketamine as result of the previous history of alcoholism should be considered as potential inducing factors in suicide behaviors. [Copyright &y& Elsevier]

Abstract: Hyperglycaemia-related mitochondrial impairment is suggested as a contributor to skeletal muscle dysfunction. Aiming a better understanding of the molecular mechanisms that underlie mitochondrial dysfunction in type 1 diabetic skeletal muscle, the role of the protein quality control system in mitochondria functionality was studied in intermyofibrillar mitochondria that were isolated from gastrocnemius muscle of streptozotocin (STZ)-induced diabetic rats. Hyperglycaemic rats showed more mitochondria but with lower ATP production ability, which was related with increased carbonylated protein levels and lower mitochondrial proteolytic activity assessed by zymography. LC-MS/MS analysis of the zymogram bands with proteolytic activity allowed the identification of an AAA protease, Lon protease; the metalloproteases PreP, LAP-3 and MIP; and cathepsin D. The content and activity of the Lon protease was lower in the STZ animals, as well as the expression of the m-AAA protease paraplegin, evaluated by western blotting. Data indicated that in muscle from diabetic rats the mitochondrial protein quality control system was compromised, which was evidenced by the decreased activity of AAA proteases, and was accompanied by the accumulation of oxidatively modified proteins, thereby causing adverse effects on mitochondrial functionality. [Copyright &y& Elsevier]

Abstract: In cardiac tissue two mitochondria subpopulations, the subsarcolemmal and the intermyofibrillar mitochondria, present different functional emphasis, although limited information exists about the underlying molecular mechanisms. Our study evidenced higher OXPHOS activity of intermyofibrillar compared to subsarcolemmal mitochondria, paralleled by distinct membrane proteins susceptibility to oxidative damage and not to quantitative differences of OXPHOS composition. Indeed, subsarcolemmal subunits of respiratory chain complexes were more prone to carbonylation while intermyofibrillar mitochondria were more susceptible to nitration. Among membrane protein targets to posttranslational modifications, ATP synthase subunits alpha and beta were notoriously more carbonylated in both subpopulations, although more intensely in subsarcolemmal mitochondria. Our data highlight a localization dependence of cardiac mitochondria OXPHOS activity and susceptibility to posttranslational modifications. [Copyright &y& Elsevier]

Abstract: Sodium salicylate (NaSAL) has been shown to be a promising antidote for the treatment of paraquat (PQ) poisonings. The modulation of the pro-oxidant and pro-inflammatory pathways, as well as the anti-thrombogenic properties of NaSAL are probably essential features for the healing effects provided by this drug. Nevertheless, a possible direct chemical reactivity between PQ and NaSAL is also a putative pathway to be considered, this hypothesis being the ground of the present study. In accordance, it is shown, for the first time that PQ and NaSAL react immediately in aqueous medium and within 2–3min in the solid state. Photographs and scanning electron photomicrographs indicated that a new chemical entity is formed when both compounds are mixed. This assumption was corroborated by the evaluation of the melting point, and through several analytical techniques, namely ultraviolet/visible spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS), liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry (LC/ESI/MS/MS) and infrared spectroscopy, which revealed that stable charge-transfer complexes are formed when PQ is mixed with NaSAL. LC/ESI/MS/MS allowed obtaining the stoichiometry of the charge-transfer complexes. In order to increase resolution, single value decomposition, acting as a filter, showed that the charge-transfer complexes with m/z 483, 643 and 803 correspond to the pseudo-molecular ions, respectively 1:2, 1:3 and 1:4 (PQ:NaSAL). In conclusion, these results provided a new and important mechanism of action of NaSAL against the toxicity mediated by PQ. [Copyright &y& Elsevier]

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) is frequently consumed at “rave” parties by polydrug users that usually take this drug in association with ethanol. In addition, many young people are repeatedly exposed to ethanol, which likely leads to tolerance phenomena. Both compounds are metabolized in the liver, with formation of hepatotoxic metabolites, which gives high relevance to the evaluation of their putative toxicological interaction. Therefore, the aim of this study was to evaluate the toxicity induced by 0.8 and 1.6mM MDMA to freshly isolated hepatocytes obtained from ethanol-treated mice whose tap drinking water was replaced by a 5% ethanol solution for 1week and, afterwards, by a 12% ethanol solution for 8weeks (ethanol group) comparatively to non-treated animals (non-ethanol group). The hepatocytes were incubated under normothermic and hyperthermic conditions in order to simulate in vitro the hyperthermic response induced in vivo by MDMA, a condition that has been recognized as a life-threatening effect associated with MDMA exposure and implicated in its hepatotoxicity. Six mice treated under the same protocol as the ethanol group were used for histological analysis, and compared to non-ethanol-treated animals. The pre-treatment of mice with ethanol caused a significant decrease in the hepatocytes yield in the isolation procedure comparatively to the non-ethanol group, which can be explained by an increase in collagen deposition along the hepatic parenchyma as observed in the histological analysis. The initial cell viability of hepatocytes suspensions was similar between ethanol and non-ethanol groups. However, the ethanol group showed a higher GSH oxidation rate, which was enhanced under hyperthermia. Additionally, a concentration-dependent MDMA-induced loss of cell viability and ATP depletion was observed for both groups, at 41°C. In conclusion, the repeated treatment with ethanol seems to increase the vulnerability of freshly isolated mice hepatocytes towards pro-oxidant conditions, as ascertained by the increase in collagen deposition, lower hepatocyte yield and decreased glutathione levels. However, MDMA toxicity to the isolated hepatocytes was independent of ethanol pre-treatment, while significantly dependent on incubation temperature. [Copyright &y& Elsevier]

Abstract: An increasing body of data has been demonstrating that mammalian cells have elaborate networks of molecular signalling in counteracting heat shock and in developing adaptation to oxidative stress to avoid cell death. However, the precise mechanisms linking heat shock, oxidative stress and cell survival/cell death mechanisms are not yet clearly understood. The purpose of this study was thus to study the time course of hyperthermia-induced oxidative stress and cellular signalling through the activation of heat shock factor 1 (HSF1) and heat shock protein 70 (HSP70), using freshly isolated mouse hepatocytes. The results accomplished in this work demonstrated that mild continuous hyperthermia (41°) leads to oxidative stress and loss of cellular viability in a time-dependent manner, with significant effects already observed at the first hour of incubation. These toxic effects developed concomitantly with activation of HSF1 and emerged before the formation of HSP70 levels. Thus, although cell signalling was triggered through the transcriptional activation of HSP70 via HSF1, this putative protective process did not modify the trend of hepatotoxic effects mediated by this type of hyperthermic challenging. [Copyright &y& Elsevier]

• FD is more determinant than PI in MS and NAFLD development. • PI potentiate the NAFLD clinical parameters induced by fat diet. • FD and PI showed synergistic effect in NAFLD progress. [ABSTRACT FROM AUTHOR]