Exercise training counteracts the cardiac metabolic remodelling induced by experimental pulmonary arterial hypertension.

Exercise training provides several cardiovascular benefits in both physiological and pathological conditions; however, its use as a therapeutic tool for pulmonary arterial hypertension (PAH) has been poorly explored. This study aimed to extend the comprehension of the cardioprotective effects of exercise training in the set of PAH focusing on the metabolic changes promoted by exercise in the right ventricle (RV). The monocrotaline animal model of PAH was used and male Wistar rats were submitted to two weeks of treadmill exercise training (5 days/week, 60 min/day, 25 m/min) following disease establishment. Trained rats showed an improved diastolic function (lower end-diastolic pressure and tau) despite the presence of cardiac overload (increased peak systolic pressure, end-diastolic pressure and arterial elastance). This enhanced hemodynamic response was paralleled by an increased uptake of glucose to cardiomyocytes through glucose transporter type 4 (GLUT4) followed by increased lactate dehydrogenase (LDH) activity. Exercise did not reverse the decrease of fatty acid oxidation related to PAH but increased the content of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Two weeks of exercise did not modulate the changes in amino acid metabolism secondary to PAH. Our work suggests that continuous aerobic exercise of moderate intensity, despite its short-term duration and application in a late stage of the disease, supports the RV response to PAH by promoting a shift in the cardiac metabolic phenotype.

Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators?

BACKGROUND: Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. AIMS: To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. METHODS: A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. RESULTS: Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. CONCLUSION: The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes.

Coronary Artery Disease and Aortic Valve Stenosis: A Urine Proteomics Study.

Coronary artery disease (CAD) and the frequently coexisting aortic valve stenosis (AVS) are heart diseases accounting for most cardiac surgeries. These share many risk factors, such as age, diabetes, hypertension, or obesity, and similar pathogenesis, including endothelial disruption, lipid and immune cell infiltration, inflammation, fibrosis, and calcification. Unsuspected CAD and AVS are sometimes detected opportunistically through echocardiography, coronary angiography, and magnetic resonance. Routine biomarkers for early detection of either of these atherosclerotic-rooted conditions would be important to anticipate the diagnosis. With a noninvasive collection, urine is appealing for biomarker assessment. We conducted a shotgun proteomics exploratory analysis of urine from 12 CAD and/or AVS patients and 11 controls to identify putative candidates to differentiate these diseases from healthy subjects. Among the top 20 most dysregulated proteins, TIMP1, MMP2 and vWF stood out, being at least 2.5× increased in patients with CAD/AVS and holding a central position in a network of protein-protein interactions. Moreover, their assessment in an independent cohort (19 CAD/AVS and 10 controls) evidenced strong correlations between urinary TIMP1 and vWF levels and a common cardiovascular risk factor - HDL (r = 0.59, p < 0.05, and r = 0.64, p < 0.01, respectively).

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach.

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.

Exercise training protects against cancer-induced cardiac remodeling in an animal model of urothelial carcinoma.

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.

Exercise Training Impacts Cardiac Mitochondrial Proteome Remodeling in Murine Urothelial Carcinoma.

Cardiac dysfunction secondary to cancer may exert a negative impact in patients' tolerance to therapeutics, quality of life, and survival. The aim of this study was to evaluate the potential therapeutic effect of exercise training on the heart in the setting of cancer, after diagnosis. Thus, the molecular pathways harbored in heart mitochondria from a murine model of chemically-induced urothelial carcinoma submitted to 8-weeks of high intensity treadmill exercise were characterized using mass spectrometry-based proteomics. Data highlight the protective effects of high intensity exercise training in preventing left ventricle diastolic dysfunction, fibrosis, and structural derangement observed in tumor-bearing mice. At the mitochondrial level, exercise training counteracted the lower ability to produce ATP observed in the heart of animals with urothelial carcinoma and induced the up-regulation of fatty acid oxidation and down-regulation of the biological process "cardiac morphogenesis". Taken together, our data support the prescription of exercise training after cancer diagnosis for the management of disease-related cardiac dysfunction.

HMGB1 down-regulation mediates terameprocol vascular anti-proliferative effect in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.

Cellular interplay in pulmonary arterial hypertension: implications for new therapies.

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future.

Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach.

Pulmonary arterial hypertension (PAH) is responsible for the premature death mainly because of progressive and severe heart failure. This disease is characterized by increased pulmonary vascular tone, inflammatory cell infiltration, vascular remodeling and occlusion of vessels with thrombi, frequently leading to right heart failure. Aiming to better comprehend the complexity of PAH and find novel therapeutic strategies or improve the existing ones, a variety of preclinical models have emerged. Although there is no ideal preclinical model of PAH currently available, animal models have been used to assist in the identification of the molecular pathways underlying PAH development and progression, and in the identification of novel therapeutics. Among preclinical models of PAH, monocrotaline (MCT) animal model offers the advantage of mimic several key aspects of human PAH, including vascular remodeling, proliferation of smooth muscle cells, endothelial dysfunction, upregulation of inflammatory cytokines, and right ventricle failure, requiring a single drug injection. This review summarizes the advantages and limitations of MCT animal model to the study of the molecular mechanisms underlying PAH pathogenesis, envisioning to improve the diagnosis and management of this complex disease.

The contribution of mitochondria to age-related skeletal muscle wasting: A sex-specific perspective.

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.

Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let's talk about sex.

Sarcopenia is associated with reduced quality of life and premature mortality. The sex disparities in the processes underlying sarcopenia pathogenesis, which include mitochondrial dysfunction, are ill-understood and can be decisive for the optimization of sarcopenia-related interventions. To improve the knowledge regarding the sex differences in skeletal muscle aging, the gastrocnemius muscle of young and old female and male rats was analyzed with a focus on mitochondrial remodeling through the proteome profiling of mitochondria-enriched fractions. To the best of our knowledge, this is the first study analyzing sex differences in skeletal muscle mitochondrial proteome remodeling. Data demonstrated that age induced skeletal muscle atrophy and fibrosis in both sexes. In females, however, this adverse skeletal muscle remodeling was more accentuated than in males and might be attributed to an age-related reduction of 17beta-estradiol signaling through its estrogen receptor alpha located in mitochondria. The females-specific mitochondrial remodeling encompassed increased abundance of proteins involved in fatty acid oxidation, decreased abundance of the complexes subunits, and enhanced proneness to oxidative posttranslational modifications. This conceivable accretion of damaged mitochondria in old females might be ascribed to low levels of Parkin, a key mediator of mitophagy. Despite skeletal muscle atrophy and fibrosis, males maintained their testosterone levels throughout aging, as well as their androgen receptor content, and the age-induced mitochondrial remodeling was limited to increased abundance of pyruvate dehydrogenase E1 component subunit beta and electron transfer flavoprotein subunit beta. Herein, for the first time, it was demonstrated that age affects more severely the skeletal muscle mitochondrial proteome of females, reinforcing the necessity of sex-personalized approaches towards sarcopenia management, and the inevitability of the assessment of mitochondrion-related therapeutics.

Exploring the role of post-translational modifications on protein-protein interactions with survivin.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family with crucial roles in apoptosis and cell cycle regulation. Post-translational modifications (PTMs) have a ubiquitous role in the regulation of a diverse range of proteins' cellular functions and survivin is not an exception. Phosphorylation, acetylation and ubiquitination seem to regulate survivin anti-apoptotic and mitotic roles and also its nuclear localization. In the present review we explore the role of PTMs on protein-protein interactions focused on survivin to provide new insights into the functions and cell localization of this IAP in pathophysiological conditions, which might help the envisioning of novel targeted therapies for diseases characterized by impaired survivin activity. Protein-protein interaction analysis was performed with bioinformatics tools based on published data aiming to give an integrated perspective of this IAP's role in the cell.

Exercise training impacts skeletal muscle remodelling induced by metabolic syndrome in ZSF1 rats through metabolism regulation.

Metabolic syndrome (MetS), characterized by a set of conditions that include obesity, hypertension, and dyslipidemia, is associated with increased cardiovascular risk. Exercise training (EX) has been reported to improve MetS management, although the underlying metabolic adaptations that drive its benefits remain poorly understood. This work aims to characterize the molecular changes induced by EX in skeletal muscle in MetS, focusing on gastrocnemius metabolic remodelling. 1H NMR metabolomics and molecular assays were employed to assess the metabolic profile of skeletal muscle tissue from lean male ZSF1 rats (CTL), obese sedentary male ZSF1 rats (MetS-SED), and obese male ZF1 rats submitted to 4 weeks of treadmill EX (5 days/week, 60 min/day, 15 m/min) (MetS-EX). EX did not counteract the significant increase of body weight and circulating lipid profile, but had an anti-inflammatory effect and improved exercise capacity. The decreased gastrocnemius mass observed in MetS was paralleled with glycogen degradation into small glucose oligosaccharides, with the release of glucose-1-phosphate, and an increase in glucose-6-phosphate and glucose levels. Moreover, sedentary MetS animals' muscle exhibited lower AMPK expression levels and higher amino acids' metabolism such as glutamine and glutamate, compared to lean animals. In contrast, the EX group showed changes suggesting an increase in fatty acid oxidation and oxidative phosphorylation. Additionally, EX mitigated MetS-induced fiber atrophy and fibrosis in the gastrocnemius muscle. EX had a positive effect on gastrocnemius metabolism by enhancing oxidative metabolism and, consequently, reducing susceptibility to fatigue. These findings reinforce the importance of prescribing EX programs to patients with MetS.

Exploring the Role of Oxidative Stress in Sperm Motility: A Proteomic Network Approach.

Significance: Infertility is a major global health problem, with nearly half of the cases being associated with male factors. Although reactive oxygen species (ROS) are crucial for sperm cell normal physiological processes, an imbalance between ROS production and antioxidants can lead to oxidative stress that can impair sperm function. Indeed, high semen ROS levels are reported in 30%-80% of infertile men. Recent Advances: Male oxidative stress infertility is an uprising classification for idiopathic infertility. Proteomic approaches, including quantitative mass spectrometry (MS)-based proteomics, are being utilized to explore the molecular mechanisms associated with oxidative stress in male infertility. Critical Issues: In this review, proteome data were collected from articles available on PubMed centered on MS-based proteomic studies, performed in seminal plasma and sperm cell samples, and enrolling men with impaired semen parameters. The bioinformatic analysis of proteome data with Cytoscape (ClueGO+CluePedia) and STRING tools allowed the identification of the biological processes more prevalent in asthenozoospermia, with focus on the ones related to oxidative stress. Future Directions: The identification of the antioxidant proteins in seminal plasma and sperm cells that can protect sperm cells from oxidative stress is crucial not only for a better understanding of the molecular mechanisms associated with male infertility but specially to guide new therapeutic possibilities. Antioxid. Redox Signal. 37, 501-520.

Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart.

Heart failure (HF) is growing in prevalence, due to an increase in aging and comorbidities. Heart failure with reduced ejection fraction (HFrEF) is more common in men, whereas heart failure with preserved ejection fraction (HFpEF) has a higher prevalence in women. However, the reasons for these epidemiological trends are not clear yet. Since HFpEF affects mostly postmenopausal women, sex hormones should play a pivotal role in HFpEF development. Furthermore, for HFpEF, contrary to HFrEF, effective therapeutic approaches are missing. Interestingly, studies evidenced that some therapies can have better results in women than in HFpEF men, emphasizing the necessity of understanding these observations at a molecular level. Thus, herein, we review the molecular mechanisms of estrogen and androgen actions in the heart in physiological conditions and explain how its dysregulation can lead to disease development. This clarification is essential in the road for an effective personalized management of HF, particularly HFpEF, towards the development of sex-specific therapeutic approaches.

Exosome-Derived Mediators as Potential Biomarkers for Cardiovascular Diseases: A Network Approach.

Cardiovascular diseases (CVDs) are widely recognized as the leading cause of mortality worldwide. Despite the advances in clinical management over the past decades, the underlying pathological mechanisms remain largely unknown. Exosomes have drawn the attention of researchers for their relevance in intercellular communication under both physiological and pathological conditions. These vesicles are suggested as complementary prospective biomarkers of CVDs; however, the role of exosomes in CVDs is still not fully elucidated. Here, we performed a literature search on exosomal biogenesis, characteristics, and functions, as well as the different available exosomal isolation techniques. Moreover, aiming to give new insights into the interaction between exosomes and CVDs, network analysis on the role of exosome-derived mediators in coronary artery disease (CAD) and heart failure (HF) was also performed to incorporate the different sources of information. The upregulated exosomal miRNAs miR-133a, miR-208a, miR-1, miR-499-5p, and miR-30a were described for the early diagnosis of acute myocardial infarction, while the exosome-derived miR-192, miR-194, miR-146a, and miR-92b-5p were considered as potential biomarkers for HF development. In CAD patients, upregulated exosomal proteins, including fibrinogen beta/gamma chain, inter-alpha-trypsin inhibitor heavy chain, and alpha-1 antichymotrypsin, were assessed as putative protein biomarkers. From downregulated proteins in CAD patients, albumin, clusterin, and vitamin D-binding protein were considered relevant to assess prognosis. The Vesiclepedia database included miR-133a of exosomal origin upregulated in patients with CAD and the exosomal miR-192, miR-194, and miR-146a upregulated in patients with HF. Additionally, Vesiclepedia included 5 upregulated and 13 downregulated exosomal proteins in patients in CAD. The non-included miRNAs and proteins have not yet been identified in exosomes and can be proposed for further research. This report highlights the need for further studies focusing on the identification and validation of miRNAs and proteins of exosomal origin as biomarkers of CAD and HF, which will enable, using exosomal biomarkers, the guiding of diagnosis/prognosis in CVDs.

Sex differences on adipose tissue remodeling: from molecular mechanisms to therapeutic interventions.

Sexual dimorphism greatly influences adipose tissue remodeling, which is characterized by changes in the activity, number, and/or size of adipocytes in response to distinct stimuli, including lifestyle and anti-obesity drugs. This sex dependence seems to be due to the anatomical and endocrine disparities between men and women. At the molecular level, sex hormones are believed to mediate such differences and involve estrogen and androgen receptor-induced gene expression. The signaling pathways that regulate adipose tissue metabolism and function include peroxisome proliferator-activated receptor gamma, uncoupling protein 1 (UCP1), 5' adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial oxidative phosphorylation (OXPHOS), among other molecular players. Sex hormone-related pathways also interplay with adrenergic signaling, probably the most well-characterized molecular mechanism implicated in the remodeling of white adipose tissue. This review overviews and integrates the signaling pathways behind sexual dimorphism in adipose tissue remodeling, hoping to increase the knowledge on the pathogenesis of diseases, such as obesity and related comorbidities, and consequently, to drive future studies to investigate the regulation of this tissue homeostasis, either in men or women.

Bioinformatics to Tackle the Biological Meaning of Human Cerebrospinal Fluid Proteome.

Cerebrospinal fluid (CSF) is a source of valuable information concerning brain disorders. The technical advances of high-throughput omics platforms to analyze body fluids can generate a huge amount of data, whose translation to biological meaning is a challenge. Several bioinformatic tools have emerged to help handling this data into systems biology comprehensively. Herein, we describe a step-by-step tutorial for CSF proteome data analysis in the set of neurodegenerative diseases using (1) ClueGO+CluePedia tool to perform cluster-based analysis envisioning the characterization of the biological processes dysregulated in neurodegenerative diseases including Alzheimer's and Parkinson's diseases; (2) Cytoscape to map disease-specific proteins; (3) SecretomeP to inquire the secretion pathway of CSF proteins; and (4) STRING to identify biological processes modulated by secreted CSF proteins based on protein-protein interaction analysis. This step-by-step guide might help researchers to better characterize disease pathogenesis and to identify putative disease biomarkers.