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Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.
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Antraciclinas , Neoplasias , Cardiotoxicidade , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.
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Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cardiotoxicidade , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Citoproteção , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Feminino , Genes erbB-2 , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/patologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mutação , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMO
PURPOSE OF REVIEW: Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms. RECENT FINDINGS: The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.
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Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase , Volume Sistólico/fisiologia , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/complicações , Inflamação/complicações , Doença Pulmonar Obstrutiva Crônica/complicaçõesRESUMO
Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.
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Cardiomegalia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/genética , Linhagem Celular , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Junções Comunicantes/metabolismo , Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Camundongos , Camundongos Transgênicos , Niacinamida/farmacologia , Fenótipo , Proteínas Proto-Oncogênicas c-met/genética , Remodelação Ventricular/genéticaRESUMO
Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFß1 (transforming growth factor ß1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.
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Vasos Sanguíneos/enzimologia , Doenças Cardiovasculares/enzimologia , Fator de Crescimento de Hepatócito/metabolismo , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Remodelação Vascular , Remodelação Ventricular , Animais , Apoptose , Autofagia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Fibrose , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/uso terapêutico , Humanos , Tolerância Imunológica , Inflamação/enzimologia , Inflamação/patologia , Inflamação/prevenção & controle , Terapia de Alvo Molecular , Miocárdio/imunologia , Miocárdio/patologia , Neovascularização Fisiológica , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-met/genética , Regeneração , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Pregnancies complicated by severe polyhydramnios are associated with a high rate of underlying fetal anomaly. Amnioreduction may be offered to alleviate maternal symptoms. This is a retrospective study of amnioreductions performed on singleton and twin gestations complicated by symptomatic polyhydramnios between 2010 and 2023 at our tertiary referral center. The indications, procedural techniques and pregnancy and neonatal outcomes were retrieved from an archive database and reviewed with the use of the maternal and child medical record chart, the hospital electronic clinical discharge report and telephone recalls. Our study comprised 86 pregnancies, 65 singletons and 21 twin pregnancies. Fetal anomalies were identified in 79% of cases, mainly gastrointestinal obstructive anomalies; 9.3% of cases were idiopathic. The median gestational age at first amnioreduction was 32.5 weeks, and peri-procedural complications were rare (1 case of placental abruption and 2 cases of preterm delivery). The median gestational age at delivery was 36.5 weeks, with a median prolongation of the pregnancy from the time of first drain until birth of 30 days. Preterm labor < 37 weeks occurred in 48.8% of procedures, with 26.7% of patients delivering before 34 weeks and pPROM < 36 weeks recorded in 23.2% of cases. In conclusion, amnioreduction offered to alleviate maternal symptoms is a reasonably safe procedure with a low complication rate. These pregnancies necessitate management in a tertiary referral center because of their need for a multidisciplinary approach both prenatally and postnatally.
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Soft tissue sarcomas accounts for 1-2% of adult malignancies. Undifferentiated pleomorphic sarcoma (UPS) is a rare subtype that lack immunohistochemical markers for a specific definition. About 18% of sarcomas are at a locally advanced stage, often requiring several cycles of chemotherapy and radiotherapy, in addition to surgery. For a young woman, this can mean delaying pregnancies with a high risk of therapy-induced ovarian damage. For this reason, proper counseling on fertility preservation plays a key role. In addition, all women of childbearing age with cancer, should be informed about the importance of planning a pregnancy to improve maternal and neonatal outcomes. We report a rare case of a 40-year-old woman with a UPS who, during CT scan after chemotherapy to decide on surgery, find out she was pregnant. After counseling, the patient decides to go ahead with the pregnancy.
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Hepatocyte Growth Factor (HGF) controls growth and differentiation in different cell types, including cardiac cells. However, its downstream effectors are poorly understood. To investigate the transcriptional targets of HGF, we analyzed the hearts of neonatal mice with cardiomyocyte-specific HGF overexpression with whole genome DNA microarrays. When comparing HGF expressing versus control hearts, we found a total of 249 transcripts with significant gene expression changes (210 upregulated and 39 downregulated). Gene Ontology (GO) annotation analysis revealed that the transcripts modulated by HGF were enriched for metabolic functions including: protein translation, vesicle-mediated transport, regulation of transcription, regulation of muscle development. Using an automated literature meta-analysis approach, we obtained a co-occurrence network oriented to the positive regulatory role of Myc and Notch1 in controlling some of the genes which are downstream to HGF. GO analysis of this network returned genes involved in the regulation of heart development. HGF positively controls MyocD, an activator of cardiac gene expression, and Hdac5, an inhibitor of cardiac growth. These results may unveil a new role of HGF in the modulation of signaling pathways implicated in the activation or repression of cardiomyogenesis.
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Redes Reguladoras de Genes , Coração/fisiologia , Fator de Crescimento de Hepatócito/genética , Proteínas Proto-Oncogênicas c-met/genética , Animais , Animais Recém-Nascidos , Doxiciclina/farmacologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Genes myc , Fator de Crescimento de Hepatócito/metabolismo , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais/genética , Transativadores/genética , Transativadores/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
Cardioactive glycosides exert positive inotropic effects on cardiomyocytes through the inhibition of Na(+)/K(+)-ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na(+)/K(+)-ATPase-independent effects. In the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 (ATP-binding cassette protein A1) transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, digoxin and ouabain simultaneously enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.
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Trifosfato de Adenosina/biossíntese , Colesterol/biossíntese , Digoxina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Receptores Nucleares Órfãos/fisiologia , Ouabaína/farmacologia , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Linhagem Celular , Transporte de Elétrons/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipoproteínas HDL/metabolismo , Receptores X do Fígado , Masculino , Ácido Mevalônico/metabolismo , Camundongos , Ratos , Ubiquinona/biossínteseRESUMO
OBJECTIVES: The authors aimed to assess the characteristics and integration of immunization services into the prenatal care provided by maternity care units (MCUs) in Italy. METHODS: A cross-sectional nationwide study using a web-based survey was conducted from June to August 2021. The study population consisted of 342 obstetricians/gynecologists (OB/GYNs), members of the Italian Society of Gynecology and Obstetrics, and heads of MCUs. The main outcome was to assess the performance of several vaccine-related services among the surveyed MCUs. RESULTS: Overall, 112 of 342 MCUs completed the survey, for an overall response rate of 32.7%. Almost all MCUs (96.4%) provided vaccine information, but only 22% had an onsite vaccination clinic. Less than half (43.8%) offered vaccines during prenatal visits and 75% of those sites required women to set up an extra appointment for vaccination. Although 68% MCUs recorded vaccines administered, only 20% of them managed to record vaccines in their own medical records. The institutional-logistic issues were the most voted vaccination barrier (40.2%). CONCLUSIONS: Institutional barriers and lack of certain vaccine-related services offered during prenatal care in Italian MCUs might be responsible for many missed vaccination opportunities. Embedding maternal immunization programs within the current prenatal care services might optimize vaccine coverage.
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Serviços de Saúde Materna , Obstetrícia , Vacinas , Feminino , Humanos , Gravidez , Estudos Transversais , Vacinação , Imunização , Itália , Programas de ImunizaçãoRESUMO
In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed by docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without a cure. A molecular link between Cx32 dysfunction and CMT1X pathogenesis is still missing. Here, we describe the high-resolution cryo-electron cryo-myography (cryo-EM) structures of the Cx32 GJC and HC, along with two CMT1X-linked mutants, W3S and R22G. While the structures of wild-type and mutant GJCs are virtually identical, the HCs show a major difference: In the W3S and R22G mutant HCs, the amino-terminal gating helix partially occludes the pore, consistent with a diminished HC activity. Our results suggest that HC dysfunction may be involved in the pathogenesis of CMT1X.
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Doença de Charcot-Marie-Tooth , Conexinas , Humanos , Conexinas/genética , Canais Iônicos , Doença de Charcot-Marie-Tooth/genética , Junções Comunicantes/genética , Proteína beta-1 de Junções ComunicantesRESUMO
Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli, some of which might finally lead up to a maladaptive state. An integral part of the pathogenesis of the hypertrophic cardiomyopathy disease (HCM) is the activation of the rat sarcoma (RAS)/RAF/MEK (mitogen-activated protein kinase kinase)/MAPK (mitogen-activated protein kinase) cascade. Therefore, the molecular signaling involving RAS has been the subject of intense research efforts, particularly after the identification of the RASopathies. These constitute a class of developmental disorders caused by germline mutations affecting proteins contributing to the RAS pathway. Among other phenotypic features, a subset of these syndromes is characterized by HCM, prompting researchers and clinicians to delve into the chief signaling constituents of cardiac hypertrophy. In this review, we summarize current advances in the knowledge of the molecular signaling events involved in the pathogenesis of cardiac hypertrophy through work completed on patients and on genetically manipulated animals with HCM and RASopathies. Important insights are drawn from the recognition of parallels between cardiac hypertrophy and cancer. Future research promises to further elucidate the complex molecular interactions responsible for cardiac hypertrophy, possibly pointing the way for the identification of new specific targets for the treatment of HCM.
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Cardiomegalia/metabolismo , Cardiomegalia/patologia , Transdução de Sinais , Proteínas ras/metabolismo , Animais , Cardiomegalia/fisiopatologia , Cardiomegalia/terapia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Cardiomiopatia Hipertrófica/terapia , Humanos , Camundongos , Mutação/genética , Neoplasias/genética , Neoplasias/patologia , Proteínas ras/genéticaRESUMO
Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as ß2-adrenergic receptor (ß2-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by ß2-ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a ß2-AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.
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Regulador de Condutância Transmembrana em Fibrose Cística , Fosfatidilinositol 3-Quinase , Animais , Classe Ib de Fosfatidilinositol 3-Quinase , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Inflamação , Camundongos , Peptídeos/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
In order to study the effects of Hepatocyte Growth Factor (HGF) in the heart, two transgenic mice were developed, one carrying a bidirectional HGF-TetO-GFP responder construct and the other carrying a α-MHC-tTA transactivator construct. Crosses were carried out between heterozygotes, so that litters contained bitransgenic α-MHC-tTA/HGF-TetO-GFP+, thus expressing HGF and GFP exclusively in the heart and only in the absence of Doxycycline. Our data show that the expression of HGF was indeed restricted to the heart and that the expression was limited to the timeframe of the absence of Doxycycline. Surprisingly the expression was variable even between bitransgenic littermates. In the setting of a model of ischemia-reperfusion, the expression of HGF ameliorates cardiac functionality, enhances proliferation and diminishes the scarred area, proving that this is a good model to study the beneficial influences and functional roles of HGF in the heart.
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Doxiciclina/farmacologia , Coração/fisiopatologia , Fator de Crescimento de Hepatócito/metabolismo , Animais , Western Blotting , Linhagem Celular , Proliferação de Células , Colágeno/metabolismo , Cruzamentos Genéticos , Meios de Cultivo Condicionados/metabolismo , Cães , Ecocardiografia , Feminino , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/metabolismo , Coração/efeitos dos fármacos , Fator de Crescimento de Hepatócito/genética , Heterozigoto , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Modelos Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Gravidez , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.
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Cachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve our understanding of the underlying mechanisms. Increasing evidence links the wasting of the cardiac and skeletal muscles to metabolic alterations, primarily increased energy expenditure, and to increased proteolysis, ensuing from activation of the major proteolytic machineries of the cell, including ubiquitin-dependent proteolysis and autophagy. This review aims at providing an overview of the key mechanisms of cancer cachexia, with a major focus on those that are shared by the skeletal and cardiac muscles.
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Cystic fibrosis (CF) is the most common amongst rare genetic diseases, affecting more than 70.000 people worldwide. CF is characterized by a dysfunctional chloride channel, termed cystic fibrosis conductance regulator (CFTR), which leads to the production of a thick and viscous mucus layer that clogs the lungs of CF patients and traps pathogens, leading to chronic infections and inflammation and, ultimately, lung damage. In recent years, the use of peptides for the treatment of respiratory diseases, including CF, has gained growing interest. Therapeutic peptides for CF include antimicrobial peptides, inhibitors of proteases, and modulators of ion channels, among others. Peptides display unique features that make them appealing candidates for clinical translation, like specificity of action, high efficacy, and low toxicity. Nevertheless, the intrinsic properties of peptides, together with the need of delivering these compounds locally, e.g. by inhalation, raise a number of concerns in the development of peptide therapeutics for CF lung disease. In this review, we discuss the challenges related to the use of peptides for the treatment of CF lung disease through inhalation, which include retention within mucus, proteolysis, immunogenicity and aggregation. Strategies for overcoming major shortcomings of peptide therapeutics will be presented, together with recent developments in peptide design and optimization, including computational analysis and high-throughput screening.
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Fibrose Cística/tratamento farmacológico , Peptídeos/uso terapêutico , Humanos , Peptídeos/químicaRESUMO
INTRODUCTION: The term placenta praevia defines a placenta that lies over the internal os, whereas the term low-lying placenta identifies a placenta that is partially implanted in the lower uterine segment with the inferior placental edge located at 1-20 mm from the internal cervical os (internal-os-distance). The most appropriate mode of birth in women with low-lying placenta is still controversial, with the majority of them undergoing caesarean section. The current project aims to evaluate the rate of vaginal birth and caesarean section in labour due to bleeding by offering a trial of labour to all women with an internal-os-distance >5 mm as assessed by transvaginal sonography in the late third trimester. METHODS AND ANALYSIS: The MODEL-PLACENTA is a prospective, multicentre, 1:3 matched case-control study involving 17 Maternity Units across Lombardy and Emilia-Romagna regions, Italy. The study includes women with a placenta located in the lower uterine segment at the second trimester scan. Women with a normally located placenta will be enrolled as controls. A sample size of 30 women with an internal-os-distance >5 mm at the late third trimester scan is needed at each participating Unit. Since the incidence of low-lying placenta decreases from 2% in the second trimester to 0.4% at the end of pregnancy, 150 women should be recruited at each centre at the second trimester scan. A vaginal birth rate ≥60% in women with an internal-os-distance >5 mm will be considered appropriate to start routinely admitting to labour these women. ETHICS AND DISSEMINATION: Ethical approval for the study was given by the Brianza Ethics Committee (No 3157, 2019). Written informed consent will be obtained from study participants. Results will be disseminated by publication in peer-reviewed journals and presentation in international conferences. TRIAL REGISTRATION NUMBER: NCT04827433 (pre-results stage).
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Cesárea , Placenta Prévia , Estudos de Casos e Controles , Feminino , Humanos , Estudos Multicêntricos como Assunto , Placenta/diagnóstico por imagem , Placenta Prévia/diagnóstico por imagem , Placenta Prévia/epidemiologia , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal/métodosRESUMO
Significance: The cardiac side effects of hematological treatments are a major issue of the growing population of cancer survivors, often affecting patient survival even more than the tumor for which the treatment was initially prescribed. Among the most cardiotoxic drugs are anthracyclines (ANTs), highly potent antitumor agents, which still represent a mainstay in the treatment of hematological and solid tumors. Unfortunately, diagnosis, prevention, and treatment of cardiotoxicity are still unmet clinical needs, which call for a better understanding of the molecular mechanism behind the pathology. Recent Advances: This review article will discuss recent findings on the pathomechanisms underlying the cardiotoxicity of ANTs, spanning from DNA and mitochondrial damage to calcium homeostasis, autophagy, and apoptosis. Special emphasis will be given to the role of reactive oxygen species and their interplay with major signaling pathways. Critical Issues: Although new promising therapeutic targets and new drugs have started to be identified, their efficacy has been mainly proven in preclinical studies and requires clinical validation. Future Directions: Future studies are awaited to confirm the relevance of recently uncovered targets, as well as to identify new druggable pathways, in more clinically relevant models, including, for example, human induced pluripotent stem cell-derived cardiomyocytes.
Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Cardiotoxicidade/complicações , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy. OBJECTIVE: The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs. METHODS: The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted. RESULTS: Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release. CONCLUSION: Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.