Antioxidative and antisenescent effects of cardiac rehabilitation in heart failure patients

2014 - 2015Exercise-based cardiac rehabilitation (CR) is effectively used as an adjuvant therapy in a number of cardiovascular diseases (CVDs), including chronic heart failure (CHF), and it is recommended by the American and European Society of Cardiology guidelines. Exercise training (ET) increases physical and functional capacity, ameliorates quality of life, decreases symptoms (fatigue and dyspnoea) and, more importantly, reduces the incidence of acute cardiac events, mortality and hospitalization rates. Recently, it has been shown that a moderate exercise is able to induce the recovery of antioxidant defences, whose expression changes with aging and during CVDs. Despite the number of evidences underling the CR-associated cardiovascular protection, CR itself is still an underused medical resource and the mechanisms accounting for such benefits are not completely elucidated yet. The present study aimed at investigating whether a well-structured rehabilitation program of 4 weeks was able to modify systemic antioxidant potential in HF patients, and at examining the mechanisms by which exercise improves cardiovascular function. For this purpose, 50 subjects with diagnosis of CHF (NYHA class II and III) were recruited from the Cardiac Rehabilitation Unit of “San Gennaro dei Poveri” Hospital in Naples. On admission, patients underwent case history recording, clinical examination, electrocardiogram, chest X-Ray, echocardiogram, cardiopulmonary stress test and a 6-minute walking test, blood sample collection for routinary and experimental analysis. The CR program consisted in ET of 30' on cycloergometer, respiratory gymnastic along with educational meetings, for a meantime of 4 weeks. Blood samples were collected at baseline and at the end of CR, and oxidants (TBARS and 8-hydroxy-2-deoxyguanosine), antioxidants (catalase, Cat, and superoxide dismutase, SOD), and bioavailability of nitric oxide (NO) were measured in patients’ sera, whereas Sirtuin 1 (Sirt1) activity was quantified in patients’ lymphocytes. Human endothelial cells (ECs), exposed or not to H2O2-oxidative stress, were conditioned with patients’ sera, and cellular redox state and senescence were evaluated. A similar approach in an animal model of post-ischemic HF was used to confirm and assess the effect of exercise on senescence. Finally, inhibitors of Sirt1 (EX-527) and Cat (ATZ) activities were used to investigate the roles of these proteins in modulating endothelial cell senescence. The results demonstrated that CR stimulated an increase of oxidants with concomitant rise of Sirt1 activity, antioxidants and NO bioavailability. Moreover, CR prevented the ECs senescence via Sirt1 and Cat activation while the inhibition of these enzymes eliminated such effect, both in humans and in the animal model. Lastly, Sirt1 and Cat activities were, respectively, inversely and directly associated with cardiopulmonary stress test duration. Taken together, these findings suggest that CR triggers cellular adaptations leading to enhance systemic antioxidant effectiveness. Circulating levels of Sirt1 and Cat activity are suggested to be promising markers for assessing the efficacy of CR program. [edited by author]XIV n.s

Regulation of inflammation and oxidative stress by formyl peptide receptors in cardiovascular disease progression

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases

Una descripción de empresas de software según uso y producción de software libre y open source (FLOSS-Free/Libre Open source Software)

Fil: Morero, Hernán Alejandro. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Morero, Hernán Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Estudios sobre Cultura y Sociedad (CIECS); Argentina.Fil: Ortiz, Pablo. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas. Instituto de Estadística y Demografía; Argentina.Fil: Fernández, Ana Valentina. Universidad Nacional de Rafaela; Argentina.Fil: Manzo, Florencia. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.La aparición del Software Libre y de Código Abierto o Free/Libre Open Source Software (FLOSS) ha modificado las actividades de la cadena de valor de toda la industria del software. Pequeñas y grandes empresas han visto desafiadas sus posibilidades y estrategias de negocios por la expansión de la actividad FLOSS, estimulando muy diversas respuestas en materia organizacional y estrategias de negocios (Dahlander y Magnusson, 2005, Harison y Koski, 2010). No hay empresa productora de software cuya actitud con respecto al uso o producción de FLOSS en su labor productiva sea neutral sobre su desempeño económico e innovativo. Sin embargo, la literatura en economía de la innovación y economía industrial no ha desarrollado una manera de clasificar las empresas de software según su uso y producción de FLOSS, además factible de ser implementada mediante encuestas tecnológicas y económicas. Aparecen de este modo determinadas anomalías en las estadísticas, como ser la virtual invisibilidad de la producción del software libre y sus servicios derivados como actividad productiva dentro del sector de producción de software, la anulación de información de su participación dentro del sector, así como la falta de consideración de ciertas especificidades innovativas que posee la propia actividad del FLOSS (tales como particulares medidas de output de innovación o esfuerzos innovativos no tradicionalmente medidos en las encuestas que siguen los estándares del Manual de Oslo).Por ende, se vuelve necesario contar con criterios para clasificar a las empresas de software en algún tipo de taxonomía, factible de implementarse mediante encuestas, permitiendo distinguir las firmas FLOSS de las que mantienen su núcleo de negocios alrededor del software privativo en distintas intensidades. El presente artículo se propone contribuir a cubrir este vacío, procurando realizar una caracterización de grupos de empresas de software argentina según el uso y producción de FLOSS, a partir de una encuesta de innovación muy reciente (2017).Fil: Morero, Hernán Alejandro. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Morero, Hernán Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Estudios sobre Cultura y Sociedad (CIECS); Argentina.Fil: Ortiz, Pablo. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas. Instituto de Estadística y Demografía; Argentina.Fil: Fernández, Ana Valentina. Universidad Nacional de Rafaela; Argentina.Fil: Manzo, Florencia. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Organización Industria

Opposite Response to Vitamin K Antagonists: A Report of Two Cases and Systematic Review of Literature

Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high response variability hamper their management. Several patients experience fluctuations in dose–response and are at increased risk of over- or under-anticoagulation. Therefore, it is essential to monitor the prothrombin time/international normalized ratio to determine the so-called stable dose and to adjust the dosage accordingly. Three polymorphisms, CYP2C9∗2, CYP2C9∗3 and VKORC1-1639G>A, are associated with increased sensitivity to VKAs. Other polymorphisms are associated with a request for a higher dose and VKA resistance. We described the clinical cases of two patients who were referred to the Clinical Pharmacology and Pharmacogenetics Unit of the University Hospital of Salerno for pharmacological counseling. One of them showed hypersensitivity and the other one was resistant to VKAs. A systematic review was performed to identify randomized clinical trials investigating the impact of pharmacogenetic testing on increased sensitivity and resistance to VKAs. Although international guidelines are available and information on the genotype-guided dosing approach has been included in VKA drug labels, VKA pharmacogenetic testing is not commonly required. The clinical cases and the results of the systematically reviewed RCTs demonstrate that the pharmacogenetic-based VKA dosing model represents a valuable resource for reducing VKA-associated adverse events

Anomalous Kv 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2 S and persulfidation in skeletal muscle.

BACKGROUND AND PURPOSE: Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β-synthase (CBS)-derived H2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv 7 channels, expressed in skeletal muscle, may be a molecular target for H2 S. Here, we have investigated the role of Kv 7 channels in MH. EXPERIMENTAL APPROACH: Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of Kv 7 channels and polysulfide levels were measured. KEY RESULTS: Kv 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv 7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of Kv 7.4 channels was significantly higher in MHS than in MHN biopsies. CONCLUSIONS AND IMPLICATIONS: In skeletal muscle of MHS patients, CBS-derived H2 S induced persulfidation of Kv 7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome

Identification of Drug Interaction Adverse Events in Patients With COVID-19: A Systematic Review

IMPORTANCE During the COVID-19 pandemic, urgent clinical management of patients has mainly included drugs currently administered for other diseases, referred to as repositioned drugs. As a result, some of these drugs have proved to be not only ineffective but also harmful because of adverse events associated with drug-drug interactions (DDIs).OBJECTIVE To identify DDIs that led to adverse clinical outcomes and/or adverse drug reactions in patients with COVID-19 by systematically reviewing the literature and assessing the value of drug interaction checkers in identifying such events.EVIDENCE REVIEW After identification of the drugs used during the COVID-19 pandemic, the drug interaction checkers Drugs.com, COVID-19 Drug Interactions, LexiComp, Medscape, and WebMD were consulted to analyze theoretical DDI-associated adverse events in patients with COVID-19 from March 1, 2020, through February 28, 2022. A systematic literature review was performed by searching the databases PubMed, Scopus, and Cochrane for articles published from March 1, 2020, through February 28, 2022, to retrieve articles describing actual adverse events associated with DDIs. The drug interaction checkers were consulted again to evaluate their potential to assess such events.FINDINGS The DDIs identified in the reviewed articles involved 46 different drugs. In total, 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) were reported. The drugs most involved in DDIs were lopinavir and ritonavir. Of the 6917 identified studies, 20 met the inclusion criteria. These studies, which enrolled 1297 patients overall, reported 115 DDI-related adverse events: 15 (26%) were identifiable by all tools analyzed, 29 (50%) were identifiable by at least 1 of them, and 14 (24%) remained nonidentifiable.CONCLUSIONS AND RELEVANCE The main finding of this systematic review is that the use of drug interaction checkers could have identified several DDI-associated adverse drug reactions, including severe and life-threatening events. Both the interactions between the drugs used to treat COVID-19 and between the COVID-19 drugs and those already used by the patients should be evaluated

Phosphodiesterases S-sulfhydration contributes to human skeletal muscle function

The increase in intracellular calcium is influenced by cyclic nucleotides (cAMP and cGMP) content, which rating is governed by phosphodiesterases (PDEs) activity.Despite it has been demonstrated a beneficial effect of PDEs inhibitors in different pathological conditions involving SKM, not much is known on the role exerted by cAMP-cGMP/PDEs axis in human SKM contractility. Here, we show that Ssulfhydration of PDEs modulates human SKM contractility in physiological and pathological conditions. Having previously demonstrated that, in the rare human syndrome Malignant Hyperthermia (MH), there is an overproduction of hydrogen sulfide (H2S) within SKM contributing to hyper-contractility, here we have used MH negative diagnosed biopsies (MHN) as healthy SKM, and MH susceptible diagnosed biopsies (MHS) as a pathological model of SKM hypercontractility. The study has been performed on MHS and MHN human biopsies after diagnosis has been made and on primary SKM cells derived from both MHN and MHS biopsies. Our data demonstrate that in normal conditions PDEs are S-sulfhydrated in both quadriceps' biopsies and primary SKM cells. This post translational modification (PTM) negatively regulates PDEs activity with consequent increase of both cAMP and cGMP levels. In hypercontractile biopsies, due to an excessive H2S content, there is an enhanced Ssulfhydration of PDEs that further increases cyclic nucleotides levels contributing to SKM hyper-contractility. Thus, the identification of a new endogenous PTM modulating PDEs activity represents an advancement in SKM physiopathology understanding

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course.

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 and autoimmune disorders, but they target different chemokines than those in COVID-19. Finally, monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and are predictive of lack of long COVID