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1.
Arterioscler Thromb Vasc Biol ; 39(3): 387-401, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651003

RESUMO

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.


Assuntos
Aterosclerose/prevenção & controle , Furina/antagonistas & inibidores , Placa Aterosclerótica/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Animais , Aorta/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Artéria Carótida Primitiva , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Furina/genética , Furina/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Metaloproteinase 2 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Remodelação Vascular , alfa 1-Antitripsina/farmacologia
2.
Int J Mol Sci ; 20(10)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109146

RESUMO

Cardiovascular diseases are the leading cause of mortality worldwide. It is widely known that non-resolving inflammation results in atherosclerotic conditions, which are responsible for a host of downstream pathologies including thrombosis, myocardial infarction (MI), and neurovascular events. Macrophages, as part of the innate immune response, are among the most important cell types in every stage of atherosclerosis. In this review we discuss the principles governing macrophage function in the healthy and infarcted heart. More specifically, how cardiac macrophages participate in myocardial infarction as well as cardiac repair and remodeling. The intricate balance between phenotypically heterogeneous populations of macrophages in the heart have profound and highly orchestrated effects during different phases of myocardial infarction. In the early "inflammatory" stage of MI, resident cardiac macrophages are replaced by classically activated macrophages derived from the bone marrow and spleen. And while the macrophage population shifts towards an alternatively activated phenotype, the inflammatory response subsides giving way to the "reparative/proliferative" phase. Lastly, we describe the therapeutic potential of cardiac macrophages in the context of cell-mediated cardio-protection. Promising results demonstrate innovative concepts; one employing a subset of yolk sac-derived, cardiac macrophages that have complete restorative capacity in the injured myocardium of neonatal mice, and in another example, post-conditioning of cardiac macrophages with cardiosphere-derived cells significantly improved patient's post-MI diagnoses.


Assuntos
Doenças Cardiovasculares/imunologia , Imunidade Inata , Macrófagos/imunologia , Miocárdio/imunologia , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Coração/fisiopatologia , Humanos , Macrófagos/patologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Miocárdio/citologia , Miocárdio/patologia , Fatores de Proteção , Remodelação Ventricular
3.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443187

RESUMO

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Quinazolinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Projetos Piloto , Suínos , Função Ventricular Esquerda/efeitos dos fármacos
4.
J Immunol ; 197(7): 2589-97, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27549172

RESUMO

Extracellular RNA (exRNA) has been characterized as a molecular alarm signal upon cellular stress or tissue injury and to exert biological functions as a proinflammatory, prothrombotic, and vessel permeability-regulating factor. In this study, we investigated the contribution of exRNA and its antagonist RNase1 in a chronic inflammatory joint disease, rheumatoid arthritis (RA). Upon immunohistochemical inspection of RA, osteoarthritis (OA), and psoriatic arthritis synovium, exRNA was detectable only in the RA synovial lining layer, whereas extracellular DNA was detectable in various areas of synovial tissue. In vitro, exRNA (150-5000 nt) was released by RA synovial fibroblasts (RASF) under hypoxic conditions but not under normoxia or TNF-α treatment. RNase activity was increased in synovial fluid from RA and OA patients compared with psoriatic arthritis patients, whereas RNase activity of RASF and OASF cultures was not altered by hypoxia. Reduction of exRNA by RNase1 treatment decreased adhesion of RASF to cartilage, but it had no influence on their cell proliferation or adhesion to endothelial cells. In vivo, treatment with RNase1 reduced RASF invasion into coimplanted cartilage in the SCID mouse model of RA. We also analyzed the expression of neuropilins in synovial tissue and SF, as they may interact with vascular endothelial growth factor signaling and exRNA. The data support the concepts that the exRNA/RNase1 system participates in RA pathophysiology and that RASF are influenced by exRNA in a prodestructive manner.


Assuntos
Artrite Reumatoide/metabolismo , Adesão Celular , Movimento Celular , Espaço Extracelular/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , RNA/metabolismo , Membrana Sinovial/patologia , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos SCID , RNA/genética , RNA/isolamento & purificação
5.
Lipids Health Dis ; 17(1): 44, 2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523150

RESUMO

BACKGROUND: Primary cultures endothelial cells have been used as models of endothelial related diseases such atherosclerosis. Biological behavior of primary cultures is donor-dependent and data could not be easily reproducible; endothelial cell lines are emerging options, particularly, human dermal microvascular endothelial cells (HMEC-1), that should be validated to substitute primary cultures for the study of HDL functions. METHODS: Morphology, size and granularity of cells were assessed by phase contrast microscopy and flow cytometry of HMEC-1. The adhesion molecules, ICAM-1and VCAM-1 after TNF-α stimulation, and endothelial markers CD105 endoglin, as well as HDL receptor SR-BI were determined by flow cytometry. Internalization of HDL protein was demonstrated by confocal microscopy using HDL labeled with Alexa Fluor 488. HUVECs were used as reference to compared the characteristics with HMEC-1. RESULTS: HMEC-1 and HUVEC had similar morphologies, size and granularity. HMEC-1 expressed endothelial markers as HUVECs, as well as functional SR-B1 receptor since the cell line was able to internalize HDL particles. HMEC-1 effectively increased ICAM-1 and VCAM-1 expression after TNF-α stimulation. HUVECs showed more sensibility to TNF-α stimulus but the range of ICAM-1 and VCAM-1 expression was less homogeneous than in HMEC-1, probably due to biological variation of the former. Finally, the expression of adhesion molecules in HMEC-1 was attenuated by co-incubation with HDL. CONCLUSION: HMEC-1 possess characteristics of endothelial cells, similar to HUVECs, being a cell line suitable to evaluate the functionality of HDL vis-à-vis the endothelium.


Assuntos
Endotélio Vascular/citologia , Lipoproteínas HDL/metabolismo , Linhagem Celular Transformada , Endoglina/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Pele/citologia , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
6.
Cardiology ; 138(4): 249-253, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898876

RESUMO

BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. METHODS: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. RESULTS: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. CONCLUSION: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Bases de Dados Factuais/estatística & dados numéricos , Arquivamento/estatística & dados numéricos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Clopidogrel , Humanos , Segurança do Paciente , Cloridrato de Prasugrel/efeitos adversos , Ticagrelor , Ticlopidina/efeitos adversos , Ticlopidina/análogos & derivados , Estados Unidos , United States Food and Drug Administration
7.
Mediators Inflamm ; 2017: 4029641, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804220

RESUMO

Extracellular bacterial ribonucleases such as binase from Bacillus pumilus possess cytotoxic activity against tumor cells with a potential for clinical application. Moreover, they may induce activation of tumor-derived macrophages either into the M1-phenotype with well-documented functions in the regulation of the antitumor immune response or into M2-macrophages that may stimulate tumor growth, metastasis, and angiogenesis. In this study, binase or endogenous RNase1 (but not RNA or short oligonucleotides) stimulated the expression of activated NF-κB p65 subunit in macrophages. Since no changes in MyD88 and TRIF adaptor protein expression were observed, toll-like receptors may not be involved in RNase-related NF-κB pathway activation. In addition, short exposure (0.5 hr) to binase induced the release of cytokines such as IL-6, МСР-1, or TNF-α (but not IL-4 and IL-10), indicative for the polarization into antitumor M1-macrophages. Thus, we revealed increased expression of activated NF-κB p65 subunit in macrophages upon stimulation by binase and RNase1, but not RNA or short oligonucleotides.


Assuntos
Bacillus pumilus/enzimologia , Proteínas de Bactérias/farmacologia , Endorribonucleases/farmacologia , Macrófagos/efeitos dos fármacos , Ribonucleases/farmacologia , Células A549 , Animais , Linhagem Celular , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Basic Res Cardiol ; 111(1): 7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26667317

RESUMO

Recent advances in basic cardiovascular research as well as their translation into the clinical situation were the focus at the last "New Frontiers in Cardiovascular Research meeting". Major topics included the characterization of new targets and procedures in cardioprotection, deciphering new players and inflammatory mechanisms in ischemic heart disease as well as uncovering microRNAs and other biomarkers as versatile and possibly causal factors in cardiovascular pathogenesis. Although a number of pathological situations such as ischemia-reperfusion injury or atherosclerosis can be simulated and manipulated in diverse animal models, also to challenge new drugs for intervention, patient studies are the ultimate litmus test to obtain unequivocal information about the validity of biomedical concepts and their application in the clinics. Thus, the open and bidirectional exchange between bench and bedside is crucial to advance the field of ischemic heart disease with a particular emphasis of understanding long-lasting approaches in cardioprotection.


Assuntos
Doenças Cardiovasculares , Pesquisa Translacional Biomédica , Animais , Humanos
9.
Basic Res Cardiol ; 111(6): 69, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27743118

RESUMO

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome.


Assuntos
Cardiologia/tendências , Doenças Cardiovasculares , Nanomedicina Teranóstica/tendências , Animais , Cardiologia/métodos , Humanos
10.
Circulation ; 129(5): 598-606, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24201302

RESUMO

BACKGROUND: Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice. METHODS AND RESULTS: The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44±9 versus 70±7 mU/mg protein; P=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein; P<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the proinflammatory mediators tumor necrosis factor-α, arginase-2, interleukin-1ß, interleukin-6, and interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (ApoE(-/-)) mice, treatment with RNase1 diminished the increased plasma level of eRNA evidenced after injury. Likewise, RNase1 administration reduced neointima formation in comparison with vehicle-treated ApoE(-/-) controls (25.0±6.2 versus 46.9±6.9×10(3) µm(2), P=0.0339) and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro and inhibited leukocyte recruitment to injured carotid arteries in vivo. CONCLUSIONS: Because eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.


Assuntos
Líquido Extracelular/fisiologia , Placa Aterosclerótica/sangue , RNA/fisiologia , Ribonucleases/fisiologia , Animais , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Aterosclerose/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Líquido Extracelular/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/tratamento farmacológico , RNA/sangue , Ribonucleases/uso terapêutico
11.
BMC Biol ; 12: 21, 2014 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-24661562

RESUMO

BACKGROUND: The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2(-/-)). RESULTS: We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2(-/-) mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. CONCLUSIONS: Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/progenitor cells during lung regeneration in both homeostatic turnover and repair after injury.


Assuntos
Proteína HMGA2/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Via de Sinalização Wnt , Animais , Diferenciação Celular , Proliferação de Células , Embrião de Mamíferos/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/embriologia , Epitélio/metabolismo , Receptores Frizzled/metabolismo , Fator de Transcrição GATA6/metabolismo , Proteína HMGA2/deficiência , Camundongos , Camundongos Knockout , Fenótipo
12.
Cell Tissue Res ; 355(3): 635-45, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24626811

RESUMO

Different types of high and low molecular weight extracellular RNA (eRNA) are liberated from cells upon conditions of tissue damage or vascular diseases and have been demonstrated in vivo and in vitro to influence the integrity and barrier function of the vascular endothelium. Among the types of self eRNA studied in this respect, ribosomal RNA appears to engage cytokines to promote hyperpermeability, while counteracting RNase1 serves as a potent vessel-protective factor. Different microRNAs may change the expression program of endothelial cells with consequences for cellular contacts and stability. Non-self viral RNAs are recognized by Toll-like receptors that transmit intracellular inflammation signals to disturb the vascular barrier function, largely in connection with infectious diseases. Although derived from the same nucleotide building blocks, the various forms of eRNA exhibit a multitude of molecular interactions with the endothelium that may drastically change its phenotypical characteristics. The impact of eRNA on vascular integrity in health and disease is summarized in this concise review.


Assuntos
Células Endoteliais/fisiologia , Endotélio Vascular/fisiologia , RNA/metabolismo , Animais , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Humanos , Transdução de Sinais
14.
J Proteome Res ; 12(12): 5598-608, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24175614

RESUMO

Alveolar type-II cells (ATII cells) are lung progenitor cells responsible for regeneration of alveolar epithelium during homeostatic turnover and in response to injury. Characterization of ATII cells will have a profound impact on our understanding and treatment of lung disease. The identification of novel ATII cell-surface proteins can be used for sorting and enrichment of these cells for further characterization. Here we combined a high-resolution mass spectrometry-based membrane proteomic approach using lungs of the SILAC mice with an Affymetrix microarray-based transcriptome analysis of ATII cells. We identified 16 proteins that are enriched in the membrane fraction of ATII cells and whose genes are highly expressed in these cells. Interestingly, we confirmed our data for two of these genes, integrin beta 2 and 6 (Itgb2 and Itgb6), by qRT-PCR expression analysis and Western blot analysis of protein extracts. Moreover, flow cytometry and immunohistochemistry in adult lung revealed that ITGB2 and ITGB6 are present in subpopulations of surfactant-associated-protein-C-positive cells, suggesting the existence of different types of ATII cells. Furthermore, analysis of the Itgb2(-/-) mice showed that Itgb2 is required for proper WNT signaling regulation in the lung.


Assuntos
Antígenos CD18/genética , Células Epiteliais/metabolismo , Cadeias beta de Integrinas/genética , Proteoma/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Via de Sinalização Wnt/genética , Animais , Antígenos CD18/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Células Epiteliais/citologia , Regulação da Expressão Gênica , Cadeias beta de Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Anotação de Sequência Molecular , Ligação Proteica , Proteína C/genética , Proteína C/metabolismo , Proteoma/metabolismo , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Análise Serial de Tecidos
15.
J Muscle Res Cell Motil ; 34(5-6): 357-68, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24037259

RESUMO

In the present study, we analyze the influence of chronic undernutrition on protein expression, muscle fiber type composition, and fatigue resistance of the fast extensor digitorum longus (EDL) muscle of male juvenile rats (45 ± 3 days of life; n = 25 and 31 rats for control and undernourished groups, respectively). Using 2D gel electrophoresis and mass spectrometry, we identified in undernourished muscles 12 proteins up-regulated (8 proteins of the electron transport chain and the glycolytic pathway, 2 cross-bridge proteins, chaperone and signaling proteins that are related to the stress response). In contrast, one down-regulated protein related to the fast muscle contractile system and two other proteins with no changes in expression were used as charge controls. By means of COX and alkaline ATPase histochemical techniques and low-frequency fatigue protocols we determined that undernourished muscles showed a larger proportion (15% increase) of Type IIa/IId fibers (oxidative-glycolytic) at the expense of Type IIb (glycolytic) fibers (15.5% decrease) and increased fatigue resistance (55.3%). In addition, all fiber types showed a significant reduction in their cross-sectional area (slow: 64.4%; intermediate: 63.9% and fast: 61.2%). These results indicate that undernourished EDL muscles exhibit an increased expression of energy metabolic and myofibrillar proteins which are associated with the predominance of oxidative and Type IIa/IId fibers and to a higher resistance to fatigue. We propose that such alterations may act as protective and/or adaptive mechanisms that counterbalance the effect of chronic undernourishment.


Assuntos
Privação de Alimentos/fisiologia , Fibras Musculares de Contração Rápida/fisiologia , Músculo Esquelético/fisiologia , Animais , Doença Crônica , Feminino , Masculino , Fibras Musculares de Contração Rápida/metabolismo , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade
16.
Discoveries (Craiova) ; 11(3): e174, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38405426

RESUMO

BACKGROUND: Platelet Inhibition and Clinical Outcomes (PLATO) was a multicenter, randomized double-blind trial assessing efficacy and safety of ticagrelor versus clopidogrel in patients with acute coronary syndrome. The reported mortality benefit of ticagrelor in the PLATO trial has been challenged for over decade, and never confirmed in later trials. OBJECTIVE: To compare if there were any differences when deaths were reported to the FDAby the sponsors or by independent Contract Research Organizations (CRO). METHODS: We obtained the complete PLATO deaths dataset reported to the FDA and revealed that some events were inaccurately reported favoring ticagrelor. The entire FDA list contains precisely detailed 938 PLATO deaths. The CRO reported outcomes from the USA, Russia, Georgia, and most of Ukraine, while sites in 39 other countries were controlled by the trial sponsors. We compared vascular- (code "11"), non-vascular- (code "12"), and unknown (code "97") deaths triaged by the reporting source. RESULTS: Overall, most PLATO deaths were vascular (n=677), less non-vascular (n=159) andunexpectedly many of "other" (n=7) or "unknown" (n=95) origin reported either by sponsors (n=807) or CRO (n=131). The trial sponsors reported more clopidogrel deaths from vascular (313 vs.239), non-vascular (86 vs.58) and unknown (53 vs. 26) causes.In contrast, CRO-monitored sites reported significantly (72 vs. 53; p<0.01) more ticagrelordeaths than after clopidogrel from vascular (51 vs.39), non-vascular (8 vs.7) and unknown (10 vs. 4) causes. CONCLUSION: Deaths were reported differently by sponsors and CRO within the same trial. Since some deaths were misreported by PLATO sponsors, only the CRO data seems mostly reliable. Among all countries, the CRO - reported PLATO-USA outcomes represent the largest and most realistic dataset of realistic evidence suggesting ticagrelor inferiority to clopidogrel for all primary endpoint components including vascular death.

18.
Cond Med ; 3(1): 18-30, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34268485

RESUMO

Acute myocardial infarction (AMI), and the heart failure (HF) that often follows, are leading causes of death and disability worldwide. Crucially, there are currently no effective treatments, other than myocardial reperfusion, for reducing myocardial infarct (MI) size and preventing HF following AMI. Thus, there is an unmet need to discover novel cardioprotective therapies to reduce MI size, and prevent HF in AMI patients. Although a large number of therapies have been shown to reduce MI size in experimental studies, the majority have failed to benefit AMI patients. Failure to deliver cardioprotective therapy to the ischemic heart in sufficient concentrations following AMI is a major factor for the lack of success observed in previous clinical cardioprotection studies. Therefore, new strategies are needed to improve the delivery of cardioprotective therapies to the ischemic heart following AMI. In this regard, nanoparticles have emerged as drug delivery systems for improving the bioavailability, delivery, and release of cardioprotective therapies, and should result in improved efficacy in terms of reducing MI size and preventing HF. In this article, we provide a review of currently available nanoparticles, some of which have been FDA-approved, in terms of their use as drug delivery systems in cardiovascular disease and cardioprotection.

19.
Arch Med Res ; 51(3): 268-277, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143939

RESUMO

BACKGROUND: There is evidence that the pharmacokinetics of certain drugs in Mexicans may differ with respect to other ethnic groups. On the other hand, there is controversy about the existence of interethnic variability in the pharmacokinetics of ciprofloxacin. AIM OF THE STUDY: To study oral ciprofloxacin pharmacokinetics in Mexicans at various dose levels and make comparisons with other populations in order to gain insight on interethnic variability. METHODS: Healthy Mexican volunteers received oral ciprofloxacin as 250 mg and 500 mg immediate-release tablets or a 1,000 mg extended-release formulation. Plasma concentration against time curves were constructed, and pharmacokinetic parameters were compared with those reported for other populations. RESULTS: Ciprofloxacin pharmacokinetics in Mexicans was linear and no significant differences between males and females were detected. When several populations were compared, it appeared that bioavailability in Mexicans was similar to that of Caucasians, being lower than that of Asians. These variations were attenuated when data were normalized by body weight. CONCLUSIONS: Ciprofloxacin pharmacokinetics exhibit interethnic variability, Asians exhibiting an increased bioavailability with regard to Mexicans and Caucasians. Data suggest that these differences are due to body weight.


Assuntos
Ciprofloxacina/sangue , Ciprofloxacina/farmacocinética , Voluntários Saudáveis/estatística & dados numéricos , Administração Oral , Adulto , Povo Asiático , Disponibilidade Biológica , Peso Corporal/fisiologia , Etnicidade , Feminino , Humanos , Masculino , México , População Branca , Adulto Jovem
20.
Cardiovasc Res ; 115(7): 1117-1130, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30825305

RESUMO

New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/imunologia , Animais , Anti-Inflamatórios/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/metabolismo , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
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