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Many cancer therapies produce toxic side effects whose molecular mechanisms await full elucidation. The most feared and studied side effect of chemotherapeutic drugs is cardiotoxicity. Also, skeletal muscle physiology impairment has been recorded after many chemotherapeutical treatments. However, only doxorubicin has been extensively studied for its side effects on skeletal muscle. Chemotherapeutic-induced adverse side effects are, in many cases, mediated by mitochondrial damage. In particular, trastuzumab and sunitinib toxicity is mainly associated with mitochondria impairment and is mostly reversible. Vice versa, doxorubicin-induced toxicity not only includes mitochondria damage but can also lead to a more robust and extensive cell injury which is often irreversible and lethal. Drugs interfering with mitochondrial functionality determine the depletion of ATP reservoirs and lead to subsequent reversible contractile dysfunction. Mitochondrial damage includes the impairment of the respiratory chain and the loss of mitochondrial membrane potential with subsequent disruption of cellular energetic. In a context of increased stress, AMPK has a key role in maintaining energy homeostasis, and inhibition of the AMPK pathway is one of the proposed mechanisms possibly mediating mitochondrial toxicity due to chemotherapeutics. Therapies targeting and protecting cell metabolism and energy management might be useful tools in protecting muscular tissues against the toxicity induced by chemotherapeutic drugs.

The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.

Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeutic modulation of microRNA expression is emerging as a cardioprotective approach in several cardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclines and is involved in cardiac repair. In our previous study, we demonstrated beneficial effects of miR-34a silencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluate the potential cardioprotective properties of a specific antimiR-34a (Ant34a) in an experimental model of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administration of Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXO-induced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients.

Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1–7 (A1–7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1–7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1–7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.

Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD + -dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53 Lys370 , γH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis.

The use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data. We retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1 , 2001 to April 30 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1 , 2002 to March 31 , 2019. Risk factors were classified as \"age greater than 60 years,\" \"therapeutic indication,\" \"renal failure,\" \"organ transplantation,\" \"use of corticosteroid,\" and \"history of side effects\". Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations. A total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was \"age greater than 60 years\" (69.5%), followed by \"therapeutic indication\" (16.9%), \"renal failure\" (5.1%), \"organ transplantation\" (3.4%), \"use of corticosteroid\" (3.4%), and \"history of side effects\" (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63-0.79), neurological (ROR 0.81; 95% CI 0.73-0.90), and psychiatric (ROR 0.55; 95% CI 0.44-0.63) ADRs compared to the third generation of quinolones. Our findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.

The multifunctional role of neuron-specific enolase (NSE) in lung diseases is well established. As the lungs are greatly affected in COVID-19, we evaluated serum NSE levels in COVID-19 patients with and without dyspnea. In this study, we evaluated both SARS-CoV-2-infected and uninfected patients aged >18 years who were referred to hospitals in Catanzaro, Italy from March 30 to July 30, 2020. Epidemiological, clinical, and radiological characteristics, treatment, and outcome data were recorded and reviewed by a trained team of physicians. In total, 323 patients (178 men, 55.1% and 145 women, 44.9%) were enrolled; of these, 128 were COVID-19 patients (39.6%) and 195 were control patients (60.4%). Westergren’s method was used to determine erythroid sedimentation rate. A chemiluminescence assay was used for measurement of interleukin-6, procalcitonin, C-reactive protein, and NSE. We detected significantly higher NSE values (P<0.05) in COVID-19 patients than in controls. Interestingly, within the COVID-19 group, we also observed a further significant increase in dyspnea (Dyspnea Scale and Exercise score: 8.2 ± 0.8; scores ranging from 0 to 10, with higher numbers indicating very severe shortness of breath). These data provide the background for further investigations into the potential role of NSE as a clinical marker of COVID-19 progression.

The renin-angiotensin-aldosterone system (RAAS) firstly considered as a cardiovascular circulating hormonal system, it is now accepted as a local tissue system that works synergistically or independently with the circulating one. Evidence states that tissue RAAS locally generates mediators with regulatory homeostatic functions, thus contributing, at some extent, to organ dysfunction or disease. Specifically, RAAS can be divided into the traditional RAAS pathway (or classic RAAS) mediated by angiotensin II (AII), and the non-classic RAAS pathway mediated by angiotensin 1–7. Both pathways operate in the heart and lung. In the heart, the classic RAAS plays a role in both hemodynamics and tissue remodeling associated with cardiomyocyte and endothelial dysfunction, leading to progressive functional impairment. Moreover, the local classic RAAS may predispose the onset of atrial fibrillation through different biological mechanisms involving inflammation, accumulation of epicardial adipose tissue, and electrical cardiac remodeling. In the lung, the classic RAAS regulates cell proliferation, immune-inflammatory response, hypoxia, and angiogenesis, contributing to lung injury and different pulmonary diseases (including COVID-19). Instead, the local non-classic RAAS counteracts the classic RAAS effects exerting a protective action on both heart and lung. Moreover, the non-classic RAAS, through the angiotensin-converting enzyme 2 (ACE2), mediates the entry of the etiological agent of COVID-19 (SARS-CoV-2) into cells. This may cause a reduction in ACE2 and an imbalance between angiotensins in favor of AII that may be responsible for the lung and heart damage. Drugs blocking the classic RAAS (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) are well known to exert a cardiovascular benefit. They are recently under evaluation for COVID-19 for their ability to block AII-induced lung injury altogether with drugs stimulating the non-classic RAAS. Herein, we discuss the available evidence on the role of RAAS in the heart and lung, summarizing all clinical data related to the use of drugs acting either by blocking the classic RAAS or stimulating the non-classic RAAS.

Despite several innovative medicines gaining worldwide approval in recent years, there are still therapeutic areas for which unsatisfied therapeutic needs persist. For example, high unmet clinical need was observed in patients diagnosed with type 2 diabetes mellitus and hemophilia, as well as in specific age groups, such as the pediatric population. Given the urgent need to improve the therapy of clinical conditions for which unmet clinical need is established, clinical testing, and approval of new medicines are increasingly being carried out through accelerated authorization procedures. Starting from 1992, the Food and Drug Administration and the European Medicines Agency have supported the so-called Early Access Programs (EAPs). Such procedures, which can be based on incomplete clinical data, allow an accelerated marketing authorization for innovative medicines. The growth in pharmaceutical research has also resulted in the development of novel therapeutic approaches, such as biotech drugs and advanced therapy medicinal products, including new monoclonal antibodies for the treatment of asthma, antisense oligonucleotides for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy, and new anticancer drugs that act on genetic biomarkers rather than any specific type of cancer. Even though EAPs and novel therapeutic approaches have brought huge benefits for public health, their implementation is limited by several challenges, including the high risk of safety-related label changes for medicines authorized through the accelerated procedure, the high costs, and the reimbursement and access concerns. In this context, regulatory agencies should provide the best conditions for the implementation of the described new tools.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.