Cardiac Regeneration using Growth Factors: Advances and Challenges

Abstract Myocardial infarction is the most significant manifestation of ischemic heart disease and is associated with high morbidity and mortality. Novel strategies targeting at regenerating the injured myocardium have been investigated, including gene therapy, cell therapy, and the use of growth factors. Growth factor therapy has aroused interest in cardiovascular medicine because of the regeneration mechanisms induced by these biomolecules, including angiogenesis, extracellular matrix remodeling, cardiomyocyte proliferation, stem-cell recruitment, and others. Together, these mechanisms promote myocardial repair and improvement of the cardiac function. This review aims to address the strategic role of growth factor therapy in cardiac regeneration, considering its innovative and multifactorial character in myocardial repair after ischemic injury. Different issues will be discussed, with emphasis on the regeneration mechanisms as a potential therapeutic resource mediated by growth factors, and the challenges to make these proteins therapeutically viable in the field of cardiology and regenerative medicine

Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Ivermectin is an FDA-approved broad-spectrum antiparasitic agent with demonstrated antiviral activity against a number of DNA and RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite this promise, the antiviral activity of ivermectin has not been consistently proven in vivo. While ivermectin's activity against SARS-CoV-2 is currently under investigation in patients, insufficient emphasis has been placed on formulation challenges. Here, we discuss challenges surrounding the use of ivermectin in the context of coronavirus disease-19 (COVID-19) and how novel formulations employing micro- and nanotechnologies may address these concerns

The Novel Serine/Threonine Protein Kinase LmjF.22.0810 from Leishmania major may be Involved in the Resistance to Drugs such as Paromomycin

Submitted by Paulo Silva ([email protected]) on 2019-12-02T14:05:21Z No. of bitstreams: 1 The Novel Serine.pdf: 10258908 bytes, checksum: 2a6ea64e9b63768b832399807b341710 (MD5)Approved for entry into archive by Paulo Silva ([email protected]) on 2019-12-03T12:12:43Z (GMT) No. of bitstreams: 1 The Novel Serine.pdf: 10258908 bytes, checksum: 2a6ea64e9b63768b832399807b341710 (MD5)Made available in DSpace on 2019-12-03T12:12:43Z (GMT). No. of bitstreams: 1 The Novel Serine.pdf: 10258908 bytes, checksum: 2a6ea64e9b63768b832399807b341710 (MD5) Previous issue date: 2019Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil / Universidade de Pernambuco. Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada. Recife. PE, Brasil.Universidade de Tartu. Instituto de Química. Tartu, Estônia.Universidade de Navarra. Instituto de Saúde Tropical. Instituto Navarra de Pesquisa em Saúde. Departamento de Microbiologia e Parasitologia. Pamplona. Navarra, Espanha.The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania

Development and in vitro characterization of polymeric nanoparticles containing recombinant adrenomedullin-2 intended for therapeutic angiogenesis.

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Growth factor therapy has emerged as novel therapeutic strategy under investigation for CVD. In this sense, adrenomedullin-2 (ADM-2) has been recently identified as a new angiogenic factor able to regulate the regional blood flow and cardiovascular function. However, the therapeutic value of ADM-2 is limited by its short biological half-life and low plasma stability. Poly (lactic-co-glycolic acid) (PLGA) micro- and nanoparticles have been investigated as growth factor delivery systems for cardiac repair. In this study, we aimed to develop PLGA nanoparticles containing ADM-2 intended for therapeutic angiogenesis. PLGA nanoparticles containing ADM-2 were prepared by a double emulsion modified method, resulting in 300 nm-sized stable particles with zeta potential around ? 30 mV. Electron microscopy analysis by SEM and TEM revealed spherical particles with a smooth surface. High encapsulation efficiency was reached (ca.70%), as quantified by ELISA. ADM-2 associated to polymer nanoparticles was also determined by EDS elemental composition analysis, SDS-PAGE and LC-MS/MS for peptide identification. In vitro release assays showed the sustained release of ADM-2 from polymer nanoparticles for 21 days. Cell viability experiments were performed in J774 macrophages and H9c2 cardiomyocyte cells, about which PLGA nanoparticles loaded with ADM-2 did not cause toxicity in the range 0.01?1 mg/ml. Of note, encapsulated ADM-2 significantly induced cell proliferation in EA.hy926 endothelial cells, indicating the ADM-2 bioactivity was preserved after the encapsulation process. Collectively, these results demonstrate the feasibility of using PLGA nanoparticles as delivery systems for the angiogenic peptide ADM-2, which could represent a novel approach for therapeutic angiogenesis in CVD using growth factor therapy

Inhaled braylin regulates Th2 response and induces relaxant effects in the airway muscles in a model of ovalbumin-induced asthma

Background: Coumarins are compounds with wide and relevant pharmacological properties, being considered one of the most important chemical classes among natural compounds. Braylin (6-methoxyseselin) is a coumarin whose pharmacological properties have not yet been extensively explored. Previous studies have shown its anti-inflammatory and immunomodulatory activities, potentially associated with glucocorticoid receptors, plus it is a phosphodiesterase 4 inhibitor. Thus, the present study was designed to investigate the pharmacological potential of braylin for asthma treatment. Methods: Mice induced to an asthma model using ovalbumin (OVA) were treated with vehicle, braylin, or dexamethasone via intraperitoneal injection or inhalation, and the bronchoalveolar lavage (BAL) was collected to evaluate infiltration of inflammatory cells, and cytokine levels. Histopathological and morphometric analysis of lung tissue were also conducted, while ex vivo isometric measurement assessed the effect of braylin on tracheal relaxation. Results: Braylin (50 mg/kg) showed similar efficacy in reducing the total count of inflammatory cells in the BAL of asthmatic mice by inhalation or intraperitoneal route. Inhaled braylin reduced, in a dose-dependent manner (25 to 100 mg/kg), the total count of inflammatory cells in the BAL of OVA-induced mice, more specifically eosinophils and neutrophils. Plus, inhaled braylin reduced the BAL levels of IL-4, IL-5, and IL-13, cytokines involved in asthma Th2 response. It also reduced pulmonary inflammatory infiltrate and the occurrence of goblet cell metaplasia. In a set of ex vivo assays, braylin was able to induce concentration-dependent relaxation of the trachea from mice with or without OVA-induced asthma. Conclusions: The present results suggest that braylin may be a promising candidate for the treatment of asthma by regulating the Th2 response, inducing relaxant effects in the airway muscles, and presenting efficacy by inhalation route