324 research outputs found
Sex-related differences in COVID-19 lethality
No full textMany countries have been affected by the worldwide outbreak of COVID-19. Among Western countries, Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere, women seem to be less affected than men by severe/fatal COVID-19 infection, regardless of their age. Although women and men are affected differently by this infection, very few studies consider different therapeutic approaches for the two sexes. Understanding the mechanisms underlying these differences may help to find appropriate and sex specific therapies. Here, we consider that other mechanisms are involved to explain this difference, in addition to the protection attributable to oestrogens. Several X-linked genes (such as ACE2) and Y-linked genes (SRY and SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex-independent, non-genetic factors that can change susceptibility and mortality is enormous, and many other factors should be considered, including gender and cultural habits in different countries
Signaling from Ras to Rac and beyond: not just a matter of GEFs
No full textMembers of a family of intracellular molecular switches, the small GTPases, sense modifications of the extracellular environment and transduce them into a variety of homeostatic signals. Among small GTPases, Ras and the Rho family of proteins hierarchically and/or coordinately regulate signaling pathways leading to phenotypes as important as proliferation, differentiation and apoptosis. Ras and Rho-GTPases are organized in a complex network of functional interactions, whose molecular mechanisms are being elucidated. Starting from the simple concept of linear cascades of events (GTPase-->activator--> GTPase), the work of several laboratories is uncovering an increasingly complex scenario in which upstream regulators of GTPases also function as downstream effectors and influence the precise biological outcome. Furthermore, small GTPases assemble into macromolecular machineries that include upstream activators, downstream effectors, regulators and perhaps even final biochemical targets. We are starting to understand how these macromolecular complexes work and how they are regulated and targeted to their proper subcellular localization. Ultimately, the acquisition of a cogent picture of the various levels of integration and regulation in small GTPase-mediated signaling should define the physiology of early signal transduction events and the pathological implication of its subversion
In vivo metabolism of nitroaspirin (NCX 4016), a nitric oxide donating derivative of aspirin, after oral administration to male healthy subjects
No full textCardiovascular safety of the tyrosine kinase inhibitor nintedanib
No full textThe intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology
Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs
No full textHeart failure (HF) is a complication of oncological treatments that may have dramatic clinical impact. It may acutely worsen a patient's condition or it may present with delayed onset, even years after treatment, when cancer has been cured or is in stable remission. Several studies have addressed the mechanisms of cancer therapy-related HF and some have led to the definition of disease models that hold valid for other and more common types of HF. Here, we review these models of HF based on the cardiotoxicity of antineoplastic drugs and classify them in cardiomyocyte-intrinsic, paracrine, or potentially secondary to effects on cardiac progenitor cells. The first group includes HF resulting from the combination of oxidative stress, mitochondrial dysfunction, and activation of the DNA damage response, which is typically caused by anthracyclines, and HF resulting from deranged myocardial energetics, such as that triggered by anthracyclines and sunitinib. Blockade of the neuregulin-1/ErbB4/ErbB2, vascular endothelial growth factor/vascular endothelial growth factor receptor and platelet-derived growth factor /platelet-derived growth factor receptor pathways by trastuzumab, sorafenib and sunitinib is proposed as paradigm of cancer therapy-related HF associated with alterations of myocardial paracrine pathways. Finally, anthracyclines and trastuzumab are also presented as examples of antitumor agents that induce HF by affecting the cardiac progenitor cell population
LC-MS/MS profiling of urinary metabolites of nitroaspirin (NCX 4016) in healthy volunteers following oral administration
No full textThe urinary metabolic profile of nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX4016), the lead compound of a new class of NO-releasing non steroidal anti-inflammatory drugs (NO-NSAIDs), has been studied for the first time in a Phase I, open, single oral dose (1600 mg, sachet) metabolism and excretion study involving 8 healthy male Caucasian subjects, mean age 27 (range 22-39), mean BMI 23 (range 19-27). Urine samples were collected before treatment (pre-dose) and at the following time intervals: 0-6, 6-12, 12-24, 24-48 and 48-72 h.
Characterization of metabolites was achieved by reverse-phase LC coupled with electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) with positive and negative ion detection. All analyses were performed on urine samples extracted (2 vol) with CH3CN: 2M H3PO4 (99:1; v/v) using a ThermoFinnigan Surveyor system equipped with a quaternary pump, a Surveyor UV/VIS diode array programmable detector (6000 LP), a Surveyor autosampler, a vacuum degasser and connected to a Thermo Finnigan LCQ Advantage ion trap mass spectrometer. Separations for MS analysis were done in gradient elution from 95% A (H2O:CH3CN: CH3COOH; 95:5:0.1 v/v/v) to 62 % B (CH3CN) in 30 min (flow rate 0.2 ml min-1). For quantitation of metabolites (UV-DAD detection), CH3COOH in phase A was replaced by H3PO4 (0.1%, v/v). LC-MS/MS analysis indicates that no unchanged drug and free metabolites are excreted in urines at any observation time; 4 main conjugated metabolites have been characterized, arising from different metabolic steps involving a) cleavage of the ester bond with formation of salicylic acid (SA) and benzenemethanol,3-hydroxy--nitrate (NCX4015); b) alcohol oxidation; c) conjugation with glucuronic acid or aminoacids. Metabolites 1 and 2 have been identified as glycine conjugate derivatives of SA (salicyluric acid) and of 3-hydroxybenzoic acid, metabolite 3 as glucuronic acid derivative of NCX 4015, and metabolite 4 as a mercapturic acid derivative, arising from NCX4015 through the nucleophilic displacement by GSH of the leaving ONO2- group. Quantitative determination indicates that the urinary excretion of the metabolites in the overall 72 h-interval accounts for approximately 51.2% of the administered dose (range 30-75%), the bulk of excretion being within 12 h
A recommended practical approach to the management of anthracycline-based chemotherapy cardiotoxicity: An opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology
No full textAnthracyclines are the mainstay of treatment of a variety of haematological malignancies and solid tumours. Unfortunately, the clinical use of these drugs is limited by cumulative, dose-related cardiotoxicity which may ultimately lead to a severe and irreversible form of cardiomyopathy. Thus, there is an increasing need for close cooperation among cardiologists, oncologists and haemato-oncologists. As anthracyclines save lives, the logical goal of this cooperation, besides preventing or mitigating cardiotoxicity, is to promote an acceptable balance between the potential cardiac side effects and the vital benefit of anticancer treatment. This manuscript, which is specifically addressed to the cardiologist who has not accumulated much experience in the field of cancer therapy, focuses on several topics, that is old and new mechanisms of cardiac toxicity, late cardiac toxicity, the importance of overall risk assessment, the key role of a cardiology consult before starting cancer therapy, and the pros and cons of primary and secondary prevention programmes
A Two-Component regulatory system with opposite effects on glycopeptide antibiotic biosynthesis and resistance
No full textThe glycopeptide A40926, produced by the actinomycete Nonomuraea gerenzanensis, is the precursor of dalbavancin, a second-generation glycopeptide antibiotic approved for clinical use in the USA and Europe in 2014 and 2015, respectively. The final product of the biosynthetic pathway is an O-acetylated form of A40926 (acA40926). Glycopeptide biosynthesis in N. gerenzanensis is dependent upon the dbv gene cluster that encodes, in addition to the two essential positive regulators Dbv3 and Dbv4, the putative members of a two-component signal transduction system, specifically the response regulator Dbv6 and the sensor kinase Dbv22. The aim of this work was to assign a role to these two genes. Our results demonstrate that deletion of dbv22 leads to an increased antibiotic production with a concomitant reduction in glycopeptide resistance. Deletion of dbv6 results in a similar phenotype, although the effects are not as strong as in the Δdbv22 mutant. Consistently, quantitative RT-PCR analysis showed that Dbv6 and Dbv22 negatively regulate the regulatory genes (dbv3 and dbv4), as well as some dbv biosynthetic genes (dbv23 and dbv24), whereas Dbv6 and Dbv22 positively regulate transcription of the single, cluster-associated resistance gene. Finally, we demonstrate that exogenously added acA40926 and its precursor A40926 can modulate transcription of dbv genes but with an opposite extent: A40926 strongly stimulates transcription of the Dbv6/Dbv22 target genes while acA40926 has a neutral or negative effect on transcription of those genes. We propose a model in which glycopeptide biosynthesis in N. gerenzanensis is modulated through a positive feedback by the biosynthetic precursor A40926 and a negative feedback by the final product acA40926. In addition to previously reported control systems, this sophisticated control loop might help the producing strain cope with the toxicity of its own product. This work, besides leading to improved glycopeptide producing strains, enlarges our knowledge on the regulation of glycopeptide biosynthesis in actinomycetes, setting N. gerenzanensis and its two-component system Dbv6-Dbv22 apart from other glycopeptide producers
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