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Papers by maria castro martinez

Research paper thumbnail of LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4

Metabolism, 2021

Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factor... more Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors-hyperglycemia, dyslipidemia, hypertension and obesity-leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction. Methods: Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs). Results: Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs. Conclusion: These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.

Research paper thumbnail of fr Abbreviated title : Unfolded protein response / microvesicles Word count : 6110 Reference numbers : 34 Greyscale illustrations : 2 Color illustrations

Aims: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from ... more Aims: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T-cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. Results: Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers XBP-1, p-eIF2alpha and CHOP and nuclear translocation of ATF6 on human aortic endothelial cells. MPs decreased in vitro nitric oxide release by human aortic endothelial cells, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomy...

Research paper thumbnail of Factors associated with work ability and intention to leave nursing profession: a nested case-control study

Industrial Health, 2021

Work ability is defined as a worker's physical and mental conditions to cope with the physical an... more Work ability is defined as a worker's physical and mental conditions to cope with the physical and mental demands of work 1-3). Work ability is a measure of the balance between individual resources (health status, functionalities, profes

Research paper thumbnail of Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates With Vascular Risks and Is Involved in Atherosclerosis

Circulation Research, 2020

Rationale:Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular ... more Rationale:Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated.Objective:To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS.Methods and Results:Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migrati...

Research paper thumbnail of Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction

Pharmaceutics, 2020

Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair ov... more Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory ac...

Research paper thumbnail of Cardioprotective effect of sonic hedgehog ligand in pig models of ischemia reperfusion

Research paper thumbnail of Extract Enriched in Flavan-3-ols and Mainly Procyanidin Dimers Improves Metabolic Alterations in a Mouse Model of Obesity-Related Disorders Partially via Estrogen Receptor Alpha

Frontiers in pharmacology, 2018

Red wine polyphenol extracts improve cardiovascular and metabolic disorders linked to obesity. Th... more Red wine polyphenol extracts improve cardiovascular and metabolic disorders linked to obesity. Their vascular protection is mediated by the activation of the alpha isoform of the estrogen receptor (ERα). In the present study, we explored the effects of a grape seed extract (GSE) enriched in the flavan-3-ols procyanidin dimers on obesity-related cardiovascular and metabolic disorders; with a particular interest in the role/contribution of ERα. Ovariectomized wild type or ERα knockout (KO) mice were fed with standard or western diet, supplemented or not with GSE, for 12 weeks. Their body weight was monitored throughout the study, and an echocardiography was performed at the end of the treatment. Blood and tissues were collected for biochemical and functional analysis, including nitric oxide and oxidative stress measurement. Vascular reactivity and liver mitochondrial complexes activity were also analyzed. In western diet-fed mice, GSE reduced adiposity, plasma triglycerides, and oxida...

Research paper thumbnail of Estrogen Receptor α Participates to the Beneficial Effect of Red Wine Polyphenols in a Mouse Model of Obesity-Related Disorders

Frontiers in pharmacology, 2016

Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders asso... more Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders associated with obesity. Previously, we demonstrated that the alpha isoform of estrogen receptor (ERα) triggers the vascular protection of polyphenols. Here, we investigated the contribution of ERα on the effects of polyphenols on cardiovascular and metabolic alterations associated with obesity. We used ovariectomized wild type or ERα-deficient mice receiving standard (SD) or western (WD) diets, or SD and WD containing polyphenols (SD+polyphenols and WD+polyphenols, respectively) over a 12-week period. Body weight was measured during treatment. Echocardiography examination was performed before sacrifice. Blood and tissues were sampled for biochemical and functional analysis with respect to nitric oxide (NO(•)) and oxidative stress. Vascular reactivity and liver mitochondrial complexes were analyzed. In WD-fed mice, polyphenols reduced adiposity, plasma triglycerides and oxidative stress in a...

Research paper thumbnail of Temporal cross-talk between endoplasmic reticulum and mitochondria regulates oxidative stress and mediates microparticle-induced endothelial dysfunction

Antioxidants & redox signaling, Jan 8, 2016

Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apopto... more Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T-cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers XBP-1, p-eIF2alpha and CHOP and nuclear translocation of ATF6 on human aortic endothelial cells. MPs decreased in vitro nitric oxide release by human aortic endothelial cells, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase with si...

Research paper thumbnail of Interaction in endothelium of non-muscular myosin light-chain kinase and the NF-κB pathway is critical to lipopolysaccharide-induced vascular hyporeactivity

Clinical science (London, England : 1979), 2015

During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly thro... more During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly through the release of oxidative metabolites by penetrant leukocytes. We reported the non-muscular isoform of myosin light chain kinase (nmMLCK) playing a pivotal role in endotoxin shock injury associated with oxidative and nitrative stresses, and vascular hyporeactivity. The present study was aimed at understanding the molecular mechanism of lipopolysaccharide (LPS)-induced vascular alterations as well as studying a probable functional association of nmMLCK with nuclear factor κ-light-chain enhancer of activated B cells (NF-κB). Aortic rings from mice were exposed in vitro to LPS and, then, vascular reactivity was measured. Human aortic endothelial cells (HAoECs) were incubated with LPS, and interaction of nmMLCK with NF-κB was analysed. We provide evidence that nmMLCK deletion prevents vascular hyporeactivity induced by in vitro LPS treatment but not endothelial dysfunction in the aorta. D...

Research paper thumbnail of Satisfação e saúde no trabalho: aspectos conceituais e metodológicos

Cadernos de Psicologia Social do Trabalho, 2003

Este artigo visa contribuir para a análise e discussão das relações entre satisfação e saúde no t... more Este artigo visa contribuir para a análise e discussão das relações entre satisfação e saúde no trabalho. A partir de uma revisão bibliográfica, apresenta-se uma visão geral sobre conceitos e modelos teóricos selecionados sobre satisfação no trabalho e abordando as relações desta com a saúde do trabalhador. Os referenciais teóricos selecionados resumem uma evolução das concepções no tema, desde aquelas que consideram o trabalhador apenas como reagindo mecanicamente a fatores externos e a satisfação no trabalho existindo unicamente em função de salários, até concepções que contemplam a interação entre aspectos psicossociais no trabalho e as subjetividades, gerando níveis de satisfação que influenciam a saúde do trabalhador. Enfatiza-se que a associação entre satisfação e saúde no trabalho e, em especial, com saúde mental, tem sido demonstrada por meio de estudos transversais, porém, são necessários mais estudos longitudinais que confirmem a relação causal destas associações, bem como mais estudos qualitativos que investiguem a dinâmica destas associações. Finalmente, são ilustradas diretrizes para concepção, implementação ou avaliação de mudanças na concepção e organização do trabalho, com foco nos aspectos psicossociais do trabalho, visando melhorias nos níveis de satisfação e, portanto, a promoção da saúde. Palavras-chave: satisfação no trabalho, fatores psicossociais no trabalho, organização do trabalho, saúde do trabalhador, saúde ocupacional, saúde no trabalho, riscos psicossociais, ambiente psicossocial, metodologia de pesquisa.

Research paper thumbnail of Saúde e capacidade para o trabalho em trabalhadores de área administrativa

Revista de Saúde Pública, 2006

OBJETIVO: Identificar as dimensões da saúde que estão associadas à capacidade para o trabalho e v... more OBJETIVO: Identificar as dimensões da saúde que estão associadas à capacidade para o trabalho e verificar se estas relações são influenciadas por características demográficas ou ocupacionais. MÉTODOS: Trata-se de um estudo transversal realizado com 224 empregados de uma empresa de auto-gestão de planos de previdência privada e de saúde na cidade de São Paulo, em 2001. Foram administrados questionários auto-aplicados referentes a aspectos sociodemográficos e ocupacionais, satisfação no trabalho, saúde e capacidade para o trabalho. As associações entre variáveis foram analisadas por meio do teste qui-quadrado, análise de variância e análise de covariância. RESULTADOS: As variáveis demográficas e relacionadas ao trabalho que apresentaram associação estatisticamente significativa com capacidade para o trabalho foram tempo de emprego (p=0,0423) e satisfação no trabalho (p=0,0072). Todas as dimensões da saúde analisadas apresentaram associação estatisticamente significativa com capacidade...

Research paper thumbnail of Work ability among hospital food service professionals: multiple associated variables require comprehensive intervention

Work (Reading, Mass.), 2012

The work of hospital food service is characterized by demands that can be associated with work ab... more The work of hospital food service is characterized by demands that can be associated with work ability--WA. The aim of this study was to evaluate factors associated with WA among hospital food service professionals and recommend intervention measures. This is a cross sectional study carried out in 2009, conducted in a hospital of São Paulo, Brazil. Participants were 76 (96.2%) of the eligible. They filled out a questionnaire including socio-demographic data, life styles, working conditions and WA. Multivariate linear regression analyses were performed. Factors associated with WA were age (p = 0.051), over commitment (p = 0.011), effort-reward ratio (p = 0.002) and work injuries (p < 0.001). In spite was a young population, age was associated with WA. Association with work injuries is consistent with the theoretical model that…

Research paper thumbnail of Implantação de um protocolo para gerenciamento de quedas em hospital: resultados de quatro anos de seguimento

Revista da Escola de Enfermagem da USP, 2012

Quedas em pacientes hospitalizados são eventos frequentes com efeitos negativos para pacientes e ... more Quedas em pacientes hospitalizados são eventos frequentes com efeitos negativos para pacientes e instituições. Este estudo descritivo objetivou apresentar os resultados de um protocolo de gerenciamento de quedas implantado em um hospital privado na cidade de São Paulo, Brasil. O seguimento foi feito por meio do índice de quedas e foi feita uma análise descritiva dos dados. Foram incluídos os pacientes internados entre 2005 e 2008, representando 284 quedas em 207.067 pacientes-dia. O índice apresentou variabilidade mensal, com diminuições subsequentes à implantação das intervenções e elevações após ações gerenciais e treinamentos. Em 2008, as quedas foram mais frequentes entre os pacientes de unidades clínicas de maior complexidade - idosos - fazendo uso de medicamentos que alteram o sistema nervoso central ou com dificuldade de marcha. As ações realizadas refletiram no índice de quedas e a caracterização dos eventos permitiu redirecionar intervenções voltadas aos pacientes mais susc...

Research paper thumbnail of Exaggerated apoptosis andNF‐KBactivation in pancreatic and tracheal cystic fibrosis cells

The FASEB Journal, 2007

The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The ... more The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The effects of proapoptotic agents on pancreatic and tracheal cell lines expressing wild-type CFTR (PANC-1 and NT-1, respectively) or the homozygous CFTR⌬F508 mutation (CFPAC-1 and CFT-2, respectively) were assessed. An increased susceptibility to apoptosis was observed in CFPAC-1 and CFT-2 cells. Apoptosis was reduced by treatment with a pan-caspase inhibitor and by incubation at 27°C, allowing recruitment of CFTR⌬F508 at the plasma membrane. Inhibition of CFTR function in wild-type cells induced an increase of apoptosis. Apoptosis in CFPAC-1, but not in CFT-2 cells, was associated with overexpression of the proinflammatory mediators interleukin-6 and interleukin-8. In CF cells, apoptosis was linked to NF-B pathway activation. Conditioned medium from actinomycin D-treated CFPAC-1 cells produced an increase in apoptosis of wild-type cells, suggesting that proinflammatory mediators secreted by mutant cells promote apoptosis. This was confirmed through the induction of apoptosis in wild-type cells by exogenous interleukin-6 and interleukin-8. These results suggest that CFTR⌬F508 mutation, apoptosis, and activation of the NF-B pathway contribute to the self-perpetuating inflammatory cycle, at least in pancreatic cells, and provide evidence that excessive apoptosis may account for the exaggerated proinflammatory response observed in CF patients.

Research paper thumbnail of Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Respiratory Research, 2009

Multiple evidences indicate that inflammation is an event occurring prior to infection in patient... more Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-κB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRΔF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-κB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes...

Research paper thumbnail of Microparticles Carrying Sonic Hedgehog Favor Neovascularization through the Activation of Nitric Oxide Pathway in Mice

PLoS ONE, 2010

Background: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation ... more Background: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs Shh+) that are able to regulate in vitro angiogenesis. Methodology/Principal Findings: Here, we investigated the ability of MPs Shh+ to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs Shh+ , MPs Shh+ plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs Shh+-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs Shh+-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs Shh+ increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs Shh+ enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs Shh+ on eNOS pathway. Quantitative RT-PCR revealed that MPs Shh+ treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of a5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFb1, TGFb2, TSP-1 and VCAM-1, in ischemic muscles. Conclusions/Significance: These findings suggest that MPs Shh+ may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis.

Research paper thumbnail of Increased Oxidative Stress Induces Apoptosis in Human Cystic Fibrosis Cells

PLoS ONE, 2011

Oxidative stress results in deleterious cell function in pathologies associated with inflammation... more Oxidative stress results in deleterious cell function in pathologies associated with inflammation. Here, we investigated the generation of superoxide anion as well as the anti-oxidant defense systems related to the isoforms of superoxide dismutases (SOD) in cystic fibrosis (CF) cells. Pro-apoptotic agents induced apoptosis in CF but not in control cells that was reduced by treatment with SOD mimetic. These effects were associated with increased superoxide anion production, sensitive to the inhibition of IkB-a phosphorylation, in pancreatic but not tracheal CF cells, and reduced upon inhibition of either mitochondrial complex I or NADPH oxidase. CF cells exhibited reduced expression, but not activity, of both Mn-SOD and Cu/Zn-SOD when compared to control cells. Although, expression of EC-SOD was similar in normal and CF cells, its activity was reduced in CF cells. We provide evidence that high levels of oxidative stress are associated with increased apoptosis in CFTR-mutated cells, the sources being different depending on the cell type. These observations underscore a reduced anti-oxidant defense mechanism, at least in part, via diminished EC-SOD activity and regulation of Cu/Zn-SOD and Mn-SOD expressions. These data point to new therapeutic possibilities in targeting anti-oxidant pathways to reduce oxidative stress and apoptosis in CF cells.

Research paper thumbnail of PPARα Is Essential for Microparticle-Induced Differentiation of Mouse Bone Marrow-Derived Endothelial Progenitor Cells and Angiogenesis

PLoS ONE, 2010

Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovasculari... more Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovascularization. We hypothesized that microparticles (MPs), small fragments generated from the plasma membrane, can activate angiogenic programming of EPCs. Methodology/Principal Findings: We studied the effects of MPs obtained from wild type (MPs PPARa+/+) and knockout (MPs PPARa2/2) mice on EPC differentiation and angiogenesis. Bone marrow-derived cells were isolated from WT or KO mice and were cultured in the presence of MPs PPARa+/+ or MPs PPARa2/2 obtained from blood of mice. Only MPs PPARa+/+ harboring PPAR a significantly increased EPC, but not monocytic, differentiation. Bone marrow-derived cells treated with MPs PPARa+/+ displayed increased expression of pro-angiogenic genes and increased in vivo angiogenesis. MPs PPARa+/+ increased capillarylike tube formation of endothelial cells that was associated with enhanced expressions of endothelial cell-specific markers. Finally, the effects of MPs PPARa+/+ were mediated by NF-kB-dependent mechanisms. Conclusions/Significance: Our results underscore the obligatory role of PPARa carried by MPs for EPC differentiation and angiogenesis. PPARa-NF-kB-Akt pathways may play a pivotal stimulatory role for neovascularization, which may, at least in part, be mediated by bone marrow-derived EPCs. Improvement of EPC differentiation may represent a useful strategy during reparative neovascularization.

Research paper thumbnail of Circulating microparticles from obstructive sleep apnea syndrome patients induce endothelin-mediated angiogenesis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2014

Research paper thumbnail of LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4

Metabolism, 2021

Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factor... more Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors-hyperglycemia, dyslipidemia, hypertension and obesity-leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction. Methods: Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs). Results: Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs. Conclusion: These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.

Research paper thumbnail of fr Abbreviated title : Unfolded protein response / microvesicles Word count : 6110 Reference numbers : 34 Greyscale illustrations : 2 Color illustrations

Aims: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from ... more Aims: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T-cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. Results: Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers XBP-1, p-eIF2alpha and CHOP and nuclear translocation of ATF6 on human aortic endothelial cells. MPs decreased in vitro nitric oxide release by human aortic endothelial cells, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomy...

Research paper thumbnail of Factors associated with work ability and intention to leave nursing profession: a nested case-control study

Industrial Health, 2021

Work ability is defined as a worker's physical and mental conditions to cope with the physical an... more Work ability is defined as a worker's physical and mental conditions to cope with the physical and mental demands of work 1-3). Work ability is a measure of the balance between individual resources (health status, functionalities, profes

Research paper thumbnail of Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates With Vascular Risks and Is Involved in Atherosclerosis

Circulation Research, 2020

Rationale:Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular ... more Rationale:Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated.Objective:To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS.Methods and Results:Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migrati...

Research paper thumbnail of Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction

Pharmaceutics, 2020

Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair ov... more Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory ac...

Research paper thumbnail of Cardioprotective effect of sonic hedgehog ligand in pig models of ischemia reperfusion

Research paper thumbnail of Extract Enriched in Flavan-3-ols and Mainly Procyanidin Dimers Improves Metabolic Alterations in a Mouse Model of Obesity-Related Disorders Partially via Estrogen Receptor Alpha

Frontiers in pharmacology, 2018

Red wine polyphenol extracts improve cardiovascular and metabolic disorders linked to obesity. Th... more Red wine polyphenol extracts improve cardiovascular and metabolic disorders linked to obesity. Their vascular protection is mediated by the activation of the alpha isoform of the estrogen receptor (ERα). In the present study, we explored the effects of a grape seed extract (GSE) enriched in the flavan-3-ols procyanidin dimers on obesity-related cardiovascular and metabolic disorders; with a particular interest in the role/contribution of ERα. Ovariectomized wild type or ERα knockout (KO) mice were fed with standard or western diet, supplemented or not with GSE, for 12 weeks. Their body weight was monitored throughout the study, and an echocardiography was performed at the end of the treatment. Blood and tissues were collected for biochemical and functional analysis, including nitric oxide and oxidative stress measurement. Vascular reactivity and liver mitochondrial complexes activity were also analyzed. In western diet-fed mice, GSE reduced adiposity, plasma triglycerides, and oxida...

Research paper thumbnail of Estrogen Receptor α Participates to the Beneficial Effect of Red Wine Polyphenols in a Mouse Model of Obesity-Related Disorders

Frontiers in pharmacology, 2016

Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders asso... more Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders associated with obesity. Previously, we demonstrated that the alpha isoform of estrogen receptor (ERα) triggers the vascular protection of polyphenols. Here, we investigated the contribution of ERα on the effects of polyphenols on cardiovascular and metabolic alterations associated with obesity. We used ovariectomized wild type or ERα-deficient mice receiving standard (SD) or western (WD) diets, or SD and WD containing polyphenols (SD+polyphenols and WD+polyphenols, respectively) over a 12-week period. Body weight was measured during treatment. Echocardiography examination was performed before sacrifice. Blood and tissues were sampled for biochemical and functional analysis with respect to nitric oxide (NO(•)) and oxidative stress. Vascular reactivity and liver mitochondrial complexes were analyzed. In WD-fed mice, polyphenols reduced adiposity, plasma triglycerides and oxidative stress in a...

Research paper thumbnail of Temporal cross-talk between endoplasmic reticulum and mitochondria regulates oxidative stress and mediates microparticle-induced endothelial dysfunction

Antioxidants & redox signaling, Jan 8, 2016

Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apopto... more Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T-cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers XBP-1, p-eIF2alpha and CHOP and nuclear translocation of ATF6 on human aortic endothelial cells. MPs decreased in vitro nitric oxide release by human aortic endothelial cells, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase with si...

Research paper thumbnail of Interaction in endothelium of non-muscular myosin light-chain kinase and the NF-κB pathway is critical to lipopolysaccharide-induced vascular hyporeactivity

Clinical science (London, England : 1979), 2015

During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly thro... more During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly through the release of oxidative metabolites by penetrant leukocytes. We reported the non-muscular isoform of myosin light chain kinase (nmMLCK) playing a pivotal role in endotoxin shock injury associated with oxidative and nitrative stresses, and vascular hyporeactivity. The present study was aimed at understanding the molecular mechanism of lipopolysaccharide (LPS)-induced vascular alterations as well as studying a probable functional association of nmMLCK with nuclear factor κ-light-chain enhancer of activated B cells (NF-κB). Aortic rings from mice were exposed in vitro to LPS and, then, vascular reactivity was measured. Human aortic endothelial cells (HAoECs) were incubated with LPS, and interaction of nmMLCK with NF-κB was analysed. We provide evidence that nmMLCK deletion prevents vascular hyporeactivity induced by in vitro LPS treatment but not endothelial dysfunction in the aorta. D...

Research paper thumbnail of Satisfação e saúde no trabalho: aspectos conceituais e metodológicos

Cadernos de Psicologia Social do Trabalho, 2003

Este artigo visa contribuir para a análise e discussão das relações entre satisfação e saúde no t... more Este artigo visa contribuir para a análise e discussão das relações entre satisfação e saúde no trabalho. A partir de uma revisão bibliográfica, apresenta-se uma visão geral sobre conceitos e modelos teóricos selecionados sobre satisfação no trabalho e abordando as relações desta com a saúde do trabalhador. Os referenciais teóricos selecionados resumem uma evolução das concepções no tema, desde aquelas que consideram o trabalhador apenas como reagindo mecanicamente a fatores externos e a satisfação no trabalho existindo unicamente em função de salários, até concepções que contemplam a interação entre aspectos psicossociais no trabalho e as subjetividades, gerando níveis de satisfação que influenciam a saúde do trabalhador. Enfatiza-se que a associação entre satisfação e saúde no trabalho e, em especial, com saúde mental, tem sido demonstrada por meio de estudos transversais, porém, são necessários mais estudos longitudinais que confirmem a relação causal destas associações, bem como mais estudos qualitativos que investiguem a dinâmica destas associações. Finalmente, são ilustradas diretrizes para concepção, implementação ou avaliação de mudanças na concepção e organização do trabalho, com foco nos aspectos psicossociais do trabalho, visando melhorias nos níveis de satisfação e, portanto, a promoção da saúde. Palavras-chave: satisfação no trabalho, fatores psicossociais no trabalho, organização do trabalho, saúde do trabalhador, saúde ocupacional, saúde no trabalho, riscos psicossociais, ambiente psicossocial, metodologia de pesquisa.

Research paper thumbnail of Saúde e capacidade para o trabalho em trabalhadores de área administrativa

Revista de Saúde Pública, 2006

OBJETIVO: Identificar as dimensões da saúde que estão associadas à capacidade para o trabalho e v... more OBJETIVO: Identificar as dimensões da saúde que estão associadas à capacidade para o trabalho e verificar se estas relações são influenciadas por características demográficas ou ocupacionais. MÉTODOS: Trata-se de um estudo transversal realizado com 224 empregados de uma empresa de auto-gestão de planos de previdência privada e de saúde na cidade de São Paulo, em 2001. Foram administrados questionários auto-aplicados referentes a aspectos sociodemográficos e ocupacionais, satisfação no trabalho, saúde e capacidade para o trabalho. As associações entre variáveis foram analisadas por meio do teste qui-quadrado, análise de variância e análise de covariância. RESULTADOS: As variáveis demográficas e relacionadas ao trabalho que apresentaram associação estatisticamente significativa com capacidade para o trabalho foram tempo de emprego (p=0,0423) e satisfação no trabalho (p=0,0072). Todas as dimensões da saúde analisadas apresentaram associação estatisticamente significativa com capacidade...

Research paper thumbnail of Work ability among hospital food service professionals: multiple associated variables require comprehensive intervention

Work (Reading, Mass.), 2012

The work of hospital food service is characterized by demands that can be associated with work ab... more The work of hospital food service is characterized by demands that can be associated with work ability--WA. The aim of this study was to evaluate factors associated with WA among hospital food service professionals and recommend intervention measures. This is a cross sectional study carried out in 2009, conducted in a hospital of São Paulo, Brazil. Participants were 76 (96.2%) of the eligible. They filled out a questionnaire including socio-demographic data, life styles, working conditions and WA. Multivariate linear regression analyses were performed. Factors associated with WA were age (p = 0.051), over commitment (p = 0.011), effort-reward ratio (p = 0.002) and work injuries (p < 0.001). In spite was a young population, age was associated with WA. Association with work injuries is consistent with the theoretical model that…

Research paper thumbnail of Implantação de um protocolo para gerenciamento de quedas em hospital: resultados de quatro anos de seguimento

Revista da Escola de Enfermagem da USP, 2012

Quedas em pacientes hospitalizados são eventos frequentes com efeitos negativos para pacientes e ... more Quedas em pacientes hospitalizados são eventos frequentes com efeitos negativos para pacientes e instituições. Este estudo descritivo objetivou apresentar os resultados de um protocolo de gerenciamento de quedas implantado em um hospital privado na cidade de São Paulo, Brasil. O seguimento foi feito por meio do índice de quedas e foi feita uma análise descritiva dos dados. Foram incluídos os pacientes internados entre 2005 e 2008, representando 284 quedas em 207.067 pacientes-dia. O índice apresentou variabilidade mensal, com diminuições subsequentes à implantação das intervenções e elevações após ações gerenciais e treinamentos. Em 2008, as quedas foram mais frequentes entre os pacientes de unidades clínicas de maior complexidade - idosos - fazendo uso de medicamentos que alteram o sistema nervoso central ou com dificuldade de marcha. As ações realizadas refletiram no índice de quedas e a caracterização dos eventos permitiu redirecionar intervenções voltadas aos pacientes mais susc...

Research paper thumbnail of Exaggerated apoptosis andNF‐KBactivation in pancreatic and tracheal cystic fibrosis cells

The FASEB Journal, 2007

The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The ... more The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The effects of proapoptotic agents on pancreatic and tracheal cell lines expressing wild-type CFTR (PANC-1 and NT-1, respectively) or the homozygous CFTR⌬F508 mutation (CFPAC-1 and CFT-2, respectively) were assessed. An increased susceptibility to apoptosis was observed in CFPAC-1 and CFT-2 cells. Apoptosis was reduced by treatment with a pan-caspase inhibitor and by incubation at 27°C, allowing recruitment of CFTR⌬F508 at the plasma membrane. Inhibition of CFTR function in wild-type cells induced an increase of apoptosis. Apoptosis in CFPAC-1, but not in CFT-2 cells, was associated with overexpression of the proinflammatory mediators interleukin-6 and interleukin-8. In CF cells, apoptosis was linked to NF-B pathway activation. Conditioned medium from actinomycin D-treated CFPAC-1 cells produced an increase in apoptosis of wild-type cells, suggesting that proinflammatory mediators secreted by mutant cells promote apoptosis. This was confirmed through the induction of apoptosis in wild-type cells by exogenous interleukin-6 and interleukin-8. These results suggest that CFTR⌬F508 mutation, apoptosis, and activation of the NF-B pathway contribute to the self-perpetuating inflammatory cycle, at least in pancreatic cells, and provide evidence that excessive apoptosis may account for the exaggerated proinflammatory response observed in CF patients.

Research paper thumbnail of Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Respiratory Research, 2009

Multiple evidences indicate that inflammation is an event occurring prior to infection in patient... more Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-κB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRΔF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-κB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes...

Research paper thumbnail of Microparticles Carrying Sonic Hedgehog Favor Neovascularization through the Activation of Nitric Oxide Pathway in Mice

PLoS ONE, 2010

Background: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation ... more Background: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs Shh+) that are able to regulate in vitro angiogenesis. Methodology/Principal Findings: Here, we investigated the ability of MPs Shh+ to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs Shh+ , MPs Shh+ plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs Shh+-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs Shh+-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs Shh+ increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs Shh+ enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs Shh+ on eNOS pathway. Quantitative RT-PCR revealed that MPs Shh+ treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of a5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFb1, TGFb2, TSP-1 and VCAM-1, in ischemic muscles. Conclusions/Significance: These findings suggest that MPs Shh+ may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis.

Research paper thumbnail of Increased Oxidative Stress Induces Apoptosis in Human Cystic Fibrosis Cells

PLoS ONE, 2011

Oxidative stress results in deleterious cell function in pathologies associated with inflammation... more Oxidative stress results in deleterious cell function in pathologies associated with inflammation. Here, we investigated the generation of superoxide anion as well as the anti-oxidant defense systems related to the isoforms of superoxide dismutases (SOD) in cystic fibrosis (CF) cells. Pro-apoptotic agents induced apoptosis in CF but not in control cells that was reduced by treatment with SOD mimetic. These effects were associated with increased superoxide anion production, sensitive to the inhibition of IkB-a phosphorylation, in pancreatic but not tracheal CF cells, and reduced upon inhibition of either mitochondrial complex I or NADPH oxidase. CF cells exhibited reduced expression, but not activity, of both Mn-SOD and Cu/Zn-SOD when compared to control cells. Although, expression of EC-SOD was similar in normal and CF cells, its activity was reduced in CF cells. We provide evidence that high levels of oxidative stress are associated with increased apoptosis in CFTR-mutated cells, the sources being different depending on the cell type. These observations underscore a reduced anti-oxidant defense mechanism, at least in part, via diminished EC-SOD activity and regulation of Cu/Zn-SOD and Mn-SOD expressions. These data point to new therapeutic possibilities in targeting anti-oxidant pathways to reduce oxidative stress and apoptosis in CF cells.

Research paper thumbnail of PPARα Is Essential for Microparticle-Induced Differentiation of Mouse Bone Marrow-Derived Endothelial Progenitor Cells and Angiogenesis

PLoS ONE, 2010

Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovasculari... more Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for neovascularization. We hypothesized that microparticles (MPs), small fragments generated from the plasma membrane, can activate angiogenic programming of EPCs. Methodology/Principal Findings: We studied the effects of MPs obtained from wild type (MPs PPARa+/+) and knockout (MPs PPARa2/2) mice on EPC differentiation and angiogenesis. Bone marrow-derived cells were isolated from WT or KO mice and were cultured in the presence of MPs PPARa+/+ or MPs PPARa2/2 obtained from blood of mice. Only MPs PPARa+/+ harboring PPAR a significantly increased EPC, but not monocytic, differentiation. Bone marrow-derived cells treated with MPs PPARa+/+ displayed increased expression of pro-angiogenic genes and increased in vivo angiogenesis. MPs PPARa+/+ increased capillarylike tube formation of endothelial cells that was associated with enhanced expressions of endothelial cell-specific markers. Finally, the effects of MPs PPARa+/+ were mediated by NF-kB-dependent mechanisms. Conclusions/Significance: Our results underscore the obligatory role of PPARa carried by MPs for EPC differentiation and angiogenesis. PPARa-NF-kB-Akt pathways may play a pivotal stimulatory role for neovascularization, which may, at least in part, be mediated by bone marrow-derived EPCs. Improvement of EPC differentiation may represent a useful strategy during reparative neovascularization.

Research paper thumbnail of Circulating microparticles from obstructive sleep apnea syndrome patients induce endothelin-mediated angiogenesis

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2014