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1.
Atherosclerosis ; : 117595, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38879387

RESUMO

BACKGROUND AND AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms. METHODS: Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry. RESULTS: Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group. CONCLUSIONS: Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.

2.
Nutr J ; 23(1): 65, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886740

RESUMO

BACKGROUND: Time-restricted eating (TRE), a popular form of intermittent fasting, has shown benefits for improving metabolic diseases and cardiometabolic health. However, the effect of TRE in the regulation of blood pressure in primary hypertension remains unclear. METHODS: A 6-week randomized controlled trial was conducted, in which a total of 74 stage 1 primary hypertensive patients without high-risk were randomly assigned to Dietary Approaches to Stop Hypertension (DASH) group (n = 37) or DASH + TRE group (n = 37). Participants in the DASH + TRE group were instructed to consume their food within an 8-h window. Scientific research platform in We Chat application was used to track participants. The primary outcome was blood pressure. The secondary outcomes included body composition, cardiometabolic risk factors, inflammation-related parameters, urinary Na+ excretion, other clinical variables and safety outcomes. RESULTS: The reduction of systolic blood pressure and diastolic blood pressure were 5.595 ± 4.072 and 5.351 ± 5.643 mm Hg in the DASH group and 8.459 ± 4.260 and 9.459 ± 4.375 mm Hg in the DASH + TRE group. DASH + TRE group improved blood pressure diurnal rhythm. Subjects in DASH + TRE group had decreased extracellular water and increased urinary Na+ excretion. Furthermore, the decrease in blood pressure was associated with a reduction of extracellular water or increase in urinary Na+ excretion. In addition, safety outcomes such as nighttime hunger were also reported. CONCLUSION: Our study demonstrated that 8-h TRE + DASH diet caused a greater decrease in blood pressure in stage 1 primary hypertensive patients than DASH diet. This study may provide novel insights into the benefits of lifestyle modification in the treatment of primary hypertension. TRIAL REGISTRATION: https://www.chictr.org.cn/ (ChiCTR2300069393, registered on March 15, 2023).


Assuntos
Pressão Sanguínea , Abordagens Dietéticas para Conter a Hipertensão , Hipertensão , Humanos , Feminino , Masculino , Abordagens Dietéticas para Conter a Hipertensão/métodos , Pessoa de Meia-Idade , Hipertensão/dietoterapia , Hipertensão/terapia , Jejum , Adulto , Resultado do Tratamento
3.
Cardiovasc Res ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38742661

RESUMO

AIMS: Atrial fibrillation (AF), the most common cardiac arrhythmia favoring ischemic stroke and heart failure involves left atrial remodeling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodeling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. METHODS AND RESULTS: AECs were from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-ß-gal) activity.In AECs, FXa increased ROS formation, senescence (SA-ß-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-ß and collagen-1/3a) and pro-remodeling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which was prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodeling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. CONCLUSIONS: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodeling and pro-fibrotic responses in AECs and in human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodeling and the progression of atrial fibrillation substrate.

4.
Eur J Prev Cardiol ; 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38421615

RESUMO

Recently, a growing body of evidence has highlighted a concerning link between endometriosis and cardiovascular disease. Endometriosis, a chronic, inflammatory hormone-dependent condition affecting 5 to 10% of reproductive-aged women worldwide, has long been associated with reproductive and gynecological consequences. However, emerging research has suggested that it may also contribute to adverse cardiovascular outcomes. This paper aims to shed light on the importance of recognizing cardio-endometriosis as a new and developing sphere of research in the field of cardiology, thereby urging the medical community to address this pressing issue.

5.
J Thromb Haemost ; 22(1): 286-299, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37797691

RESUMO

BACKGROUND: COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated. OBJECTIVES: The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin. METHODS: Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined. RESULTS: Increased plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin. CONCLUSION: In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.


Assuntos
COVID-19 , Doenças Vasculares , Animais , Humanos , COVID-19/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Síndrome de COVID-19 Pós-Aguda , Espécies Reativas de Oxigênio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/farmacologia , Suínos , Trombina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Food Chem Toxicol ; 179: 113981, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37549806

RESUMO

Various cardiovascular diseases are associated with endothelial senescence, and a recent study showed that fine dust (FD)-induced premature endothelial senescence and dysfunction is associated with increased oxidative stress. The aim of the present study was to investigate protective effect of rice bran extract (RBE) and its major component of γ-Oryzanol (γ-Ory) against FD-induced premature endothelial senescence. Porcine coronary artery endothelial cells (PCAECs) were treated with FD alone or with RBE or γ-Ory. Senescence-associated ß-galactosidase (SA-ß-gal) activity, expression of cell cycle regulatory proteins, and oxidative stress levels were evaluated. The results indicated that SA-ß-gal activity in the FD-treated PCAECs was attenuated by RBE and γ-Ory. Additionally, γ-Ory inhibited FD-induced cell cycle arrest, restored cell proliferation, and reduced the expression of cell cycle regulatory proteins. γ-Ory also inhibited oxidative stress and prevented senescence-associated NADPH oxidase and LAS activity in FD-exposed ECs suggesting that γ-Ory could protect against FD-induced ECs senescence and dysfunction.


Assuntos
Poeira , Células Endoteliais , Suínos , Animais , Senescência Celular , Estresse Oxidativo , Proteínas de Ciclo Celular/metabolismo
7.
ESC Heart Fail ; 10(4): 2183-2199, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37430483

RESUMO

Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical aortic valve replacement for patients with symptomatic severe aortic stenosis in elderly and comorbid population. Significant improvement in heart function has been observed in patients undergoing TAVI, but numerous patients are readmitted to hospital for heart failure (HF). Moreover, repeat HF hospitalization is strongly associated with an adverse prognosis and increases the financial burden of health care. Although studies have identified pre-existing and post-procedural factors that contribute to HF hospitalization after TAVI, there is a paucity of data regarding optimal post-procedural pharmacological treatments. This review aims to provide an overview of the current understanding of mechanisms, determinants, and potential treatments of HF following TAVI. We first review the pathophysiology of left ventricular (LV) remodelling, coronary microcirculation disorder, and endothelial dysfunction in patients with aortic stenosis and then examine the impact of TAVI on these conditions. We then present evidence of various factors and complications that may interplay with LV remodelling and contribute to HF events after TAVI. Next, we describe the triggers and predictors of early and late HF rehospitalizations following TAVI. Lastly, we discuss the potential of conventional pharmacological treatments, including renin-angiotensin blockers, beta-blockers, and diuretics in TAVI patients. The paper explores the potential of newer drugs, including sodium-glucose co-transporter 2 inhibitors, anti-inflammatory drugs, and ion supplementation. Comprehensive knowledge in this field may aid in recognizing successful existing therapies, developing effective new treatments, and establishing dedicated patient care strategies during follow-up after TAVI.


Assuntos
Estenose da Valva Aórtica , Insuficiência Cardíaca , Substituição da Valva Aórtica Transcateter , Humanos , Idoso , Substituição da Valva Aórtica Transcateter/efeitos adversos , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Resultado do Tratamento , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia
8.
Sci Rep ; 13(1): 6256, 2023 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-37069192

RESUMO

Nano plastics (NPs) have been a significant threat to human health and are known to cause premature endothelial senescence. Endothelial senescence is considered one of the primary risk factors contributing to numerous cardiovascular disorders. Recent studies have suggested that inhibition of sodium glucose co-transporter (SGLT2) ameliorates endothelial senescence and dysfunction. Therefore, our study intends to explore the role of SGLT2 in NPs-induced endothelial senescence and dysfunction. Porcine coronary artery and its endothelial cells were treated with NPs in the presence or absence of Enavogliflozin (ENA), a SGLT2 inhibitor and then SGLTs expression, senescence markers and vascular function were evaluated. NPs significantly up-regulated SGLT2 and ENA significantly decreased NPs-induced senescence-associated-ß-gal activity, cell-cycle arrest, and senescence markers p53 and p21 suggesting that inhibition of SGLT2 prevents NPs-induced endothelial senescence. In addition, ENA decreased the formation of reactive oxygen species with the downregulation of Nox2, and p22phox. Furthermore, SGLT2 inhibition also up regulated the endothelial nitric oxide synthase expression along with improving vascular function. In conclusion, premature endothelial senescence by NPs is, at least in part, associated with SGLT2 and it could be a potential therapeutic target for preventing and/or treating environmental pollutants-induced cardiovascular disorders mediated by endothelial senescence and dysfunction.


Assuntos
Células Endoteliais , Microplásticos , Animais , Senescência Celular/fisiologia , Células Endoteliais/metabolismo , Microplásticos/metabolismo , Estresse Oxidativo/fisiologia , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Suínos
9.
Phytomedicine ; 105: 154370, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35977457

RESUMO

BACKGROUND: Hypertension is a major cardiovascular risk factor that affects most countries including those of Africa. Although Carissa edulis Vahl, Diodia scandens Sw. and Cleome gynandra L. are traditionally used in Benin as antihypertensive treatments with some efficacy mentioned by the local population, their biological activity on the cardiovascular system remains poorly studied. AIM: The study investigated the vasoreactivity of the plants and assessed the underlying mechanisms using isolated arteries. STUDY DESIGN: Aqueous-ethanolic extracts of aerial parts of C. edulis, D. scandens and C. gynandra were prepared by maceration before being subjected to multi-step liquid-liquid fractionation with solvents of increasing polarity. The vasoreactivity of the extracts and fractions were assessed on isolated porcine coronary artery and rat aorta using organ chambers, the role of nitric oxide (NO) using NG-nitro-L-arginine (NO synthase inhibitor), prostanoids using indomethacin (cyclooxygenases inhibitor) and endothelium-dependent hyperpolarization using TRAM-34 plus UCL 1684 (inhibitors of calcium-dependent K+ channels), and the vascular uptake of polyphenols using Neu reagent. RESULTS: The aqueous-ethanolic crude extract of C. edulis (CECE) induced potent relaxations that were exclusively endothelium-dependent and more pronounced than those to D. scandens and C. gynandra. The n-butanolic fraction of C. edulis (CEBF) was more active than the cyclohexane, dichloromethane, and ethyl acetate fractions. The relaxation induced by CECE and CEBF were inhibited by NG-nitro-L-arginine and affected neither by TRAM-34 plus UCL 1684 nor by indomethacin. CEBF induced sustained endothelium-dependent relaxations for at least 60 min, and inhibited, in a concentration-dependent manner, contractions to KCl, CaCl2, U46619 and serotonin in rings with endothelium. Analysis of CEBF by LCHRMS indicated the presence of polyphenols, terpenes, and alkaloids. Exposure of coronary artery and aorta rings to CEBF caused the accumulation of polyphenols predominantly in the endothelium. CONCLUSION: C. edulis leaf extract induced pronounced endothelium-dependent relaxations and inhibited contractile responses by stimulating the endothelial formation of NO. LCHRMS analysis of the most active fraction, the butanolic fraction, revealed the presence of numerous compounds including polyphenols, terpenes, and alkaloids. The polyphenols of CEBF accumulated preferentially in the endothelium of the arterial wall. Thus, these observations support the folkloric use of C. edulis in hypertension.


Assuntos
Apocynaceae , Hipertensão , Plantas Medicinais , Animais , Arginina , Benin , Vasos Coronários , Endotélio Vascular , Indometacina , Óxido Nítrico , Polifenóis , Suínos , Terpenos , Vasodilatação
10.
Vascul Pharmacol ; 146: 107095, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35944842

RESUMO

SGLT2 inhibitors (SGLT2i) showed pronounced beneficial effects in patients with heart failure but the underlying mechanisms remain unclear. We evaluated the effect of empagliflozin, selective SGLT2i, on hypertension-induced cardiac and vascular dysfunction. Male Wistar rats received diet with or without empagliflozin (30 mg/kg/day). After 1 week, a hypertensive dose of Ang II (0.4 mg/kg/day) was administered using osmotic mini-pumps for 4 weeks. Systolic blood pressure was determined by sphygmomanometry, the cardiac function by echocardiography and ex vivo (coronary microvascular endothelial cell activation, LV remodeling and fibrosis responses), and the systemic micro and macrovascular endothelial cell activation ex vivo. Empagliflozin treatment did not affect the Ang II-induced hypertensive response. Ang II treatment increased LV mass and induced LV diastolic dysfunction, fibrosis, collagen I and ANP expression, and infiltration of macrophages. In the vasculature, it caused eNOS upregulation in the aorta and down-regulation in mesenteric microvessels associated with increased oxidative stress, ACE, AT1R, VCAM-1, MCP-1, MMP-2, and MMP-9 and collagen I expression, increased endothelial SGLT1 staining in the aorta, mesenteric and coronary microvessels, increased SGLT1 and 2 protein levels in the aorta. All Ang II-induced cardiac and vascular responses were reduced by the empagliflozin treatment. Thus, the SGLT2i effectively attenuated the deleterious impact of Ang II-induced hypertension on target organs including cardiac diastolic dysfunction and remodeling, and endothelial cell activation and pro-atherosclerotic, pro-fibrotic and pro-remodeling responses in macro and microvessels despite persistent hypertension.


Assuntos
Hipertensão , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Masculino , Ratos , Angiotensina II/farmacologia , Compostos Benzidrílicos , Pressão Sanguínea , Colágeno , Células Endoteliais/metabolismo , Fibrose , Glucosídeos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Ratos Wistar , Transportador 1 de Glucose-Sódio , Transportador 2 de Glucose-Sódio , Molécula 1 de Adesão de Célula Vascular/metabolismo
11.
Medicina (Kaunas) ; 58(7)2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35888632

RESUMO

(1) Background and Objectives: Venous thromboembolism (VTE) is strongly associated with cancer, and may be the first event revealing occult neoplasia. Nonetheless, the reasonable extent of the etiological assessment after an unprovoked VTE event remains debated. The main objective of this study was to evaluate the incidence of occult neoplasia one year after an episode of VTE, in consecutively hospitalized patients for VTE from the REMOTEV registry. The secondary objectives were to assess the performance of the various tests used for occult cancer screening in a real-life setting and analyze the risk factors associated with the discovery of cancer and the 1-year prognosis. (2) Methods: REMOTEV is a prospective, non-interventional cohort study of patients with acute VTE. Patients included in the registry from 23 October 2013 to 28 July 2018 were analyzed after a follow-up of 12 months. Cancer detection was performed according to local practices and consisted of a limited strategy to which an abdominal ultrasound was added. In the presence of suggestive clinical manifestations, further examinations were performed on an individual basis. (3) Results: A total of 993 patients were included in the study. At 1 year, the incidence of newly diagnosed cancer was low (5.3%). Half of the detected cancers were metastatic at discovery (51%) and had a poor global prognosis (32% of mortality at 1 year). Admission pulmonary CT scans as well as (thoracic)-abdomino-pelvic CT scans (when performed) were responsible for the majority of detected cancers. Age over 65 years and the concomitant presence of an unusual site and lower-limb deep vein thrombosis were the only factors associated with occult neoplasia in this cohort. After 1-year FU, mortality was higher in cancer patients (HR 6.0 (CI 95% 3.5−10.3, p < 0.0001)), and cancer evolution was the leading cause of death in the cancer group. (4) Conclusions: In REMOTEV, VTE-revealed occult cancer prevalence was low, but similar to recent reports and associated with higher age, multiple thrombotic sites and worse prognosis.


Assuntos
Neoplasias , Tromboembolia Venosa , Idoso , Estudos de Coortes , Detecção Precoce de Câncer , Humanos , Neoplasias/complicações , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
12.
Environ Int ; 164: 107248, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35461096

RESUMO

Global plastic use has increased rapidly, and environmental pollution associated with nanoplastics (NPs) has been a growing concern recently. However, the impact and biological mechanism of NPs on the cardiovascular system are not well characterized. This study aimed to assess the possibility that NPs exposure promotes premature endothelial cell (EC) senescence in porcine coronary artery ECs and, if so, to elucidate the underlying mechanism. Treatment of ECs with NPs promoted the acquisition of senescence markers, senescence-associated ß-galactosidase activity, and p53, p21, and p16 protein expression, resulting in the inhibition of proliferation. In addition, NPs impaired endothelium-dependent vasorelaxation associated with decreased endothelial nitric oxide synthase (eNOS) expression. NPs enhanced reactive oxygen species formation in ECs, and increased oxidative stress levels were associated with the induction of NADPH oxidases expression, followed by the subsequent downregulation of Sirt1 expression. The characteristics of EC senescence and dysfunction caused by NPs are prevented by an antioxidant (N-acetylcysteine), an NADPH oxidase inhibitor (apocynin), and a Sirt1 activator (resveratrol). These findings indicate that NPs induced premature EC senescence, at least in part, through the redox-sensitive eNOS/Sirt1 signaling pathway. This study suggested the effects and underlying mechanism of NPs on the cardiovascular system, which may provide pharmacological targets to prevent NPs-associated cardiovascular diseases.


Assuntos
Poliestirenos , Sirtuína 1 , Animais , Células Cultivadas , Senescência Celular/fisiologia , Endotélio/metabolismo , Microplásticos , NADPH Oxidases/metabolismo , NADPH Oxidases/farmacologia , Estresse Oxidativo , Poliestirenos/metabolismo , Poliestirenos/farmacologia , Sirtuína 1/metabolismo , Sirtuína 1/farmacologia , Suínos
13.
Anticancer Agents Med Chem ; 22(9): 1793-1801, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34488604

RESUMO

BACKGROUND: Conyza bonariensis is known to have anti-cancer properties. OBJECTIVE: The current study investigated the in vitro pro-apoptotic properties of Conyza bonariensis (C. bonariensis) towards human lymphoblastic leukemia Jurkat cells. METHODS: Ariel parts of C. bonariensis were macerated in a non-polar (n-Hexane) solvent. MTS cell viability assay was employed to determine the cytotoxic activity of the extract towards human leukemia Jurket cells and normal Peripheral Blood Mononuclear Cells (PBMCs). The phytochemical composition of the extract was screened using HPLC method. Flow cytometric studies (FACS) were conducted to explore the pro-apoptotic potential of the extract. Western blot studies were employed to identify the molecular targets involved in the induction of apoptosis. RESULTS: The n-hexane extract showed selective cytotoxic activity towards Jurkat cells. FACS analysis indicated that the extract induced early and late apoptosis in Jurkat cells. Western blot studies revealed that the extract downregulated the expression of DNMT1, SIRT1, and UHRF1 with a simultaneous up-regulation of p73 and caspases-3 proteins expression. HPLC characterization of the extract revealed the presence of phenolic compounds. CONCLUSION: Overall, these findings demonstrate that the anti-cancer effects of a Conyza bonariensis extract towards human lymphoblastic leukemia Jurkat cells are due to the modulation of the activity of multiple oncogenic and tumor suppressor proteins. Phenolic contents of the extract are proposed to be responsible for these activities.


Assuntos
Antineoplásicos , Conyza , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/farmacologia , Apoptose , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/farmacologia , Conyza/química , Conyza/metabolismo , Humanos , Células Jurkat , Leucócitos Mononucleares , Fenóis/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Ubiquitina-Proteína Ligases
15.
Ann Intensive Care ; 11(1): 166, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851467

RESUMO

Among the long-term consequences of sepsis (also termed "post-sepsis syndrome") the increased risk of unexplained cardiovascular complications, such as myocardial infarction, acute heart failure or stroke, is one of the emerging specific health concerns. The vascular accelerated ageing also named premature senescence is a potential mechanism contributing to atherothrombosis, consequently leading to cardiovascular events. Indeed, vascular senescence-associated major adverse cardiovascular events (MACE) are a potential feature in sepsis survivors and of the elderly at cardiovascular risk. In these patients, accelerated vascular senescence could be one of the potential facilitating mechanisms. This review will focus on premature senescence in sepsis regardless of age. It will highlight and refine the potential relationships between sepsis and accelerated vascular senescence. In particular, key cellular mechanisms contributing to cardiovascular events in post-sepsis syndrome will be highlighted, and potential therapeutic strategies to reduce the cardiovascular risk will be further discussed.

16.
Vascul Pharmacol ; 141: 106922, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34592427

RESUMO

BACKGROUND: Major adverse cardiovascular events among sepsis survivors is an emerging health issue. Because endothelial senescence leads to vascular dysfunction and atherothrombosis, sepsis could be associated to vascular stress-induced premature senescence and thus with long-term cardiovascular events. MATERIALS & METHODS: Adult Wistar male rats were submitted to cecal ligation and puncture, or a SHAM operation. Markers of inflammation, oxidative stress and endothelial senescence were assessed at 3, 7 and 90 days (D), and vascular reactivity was assessed in conductance and resistance vessels at D90. Expression of proteins involved in senescence and inflammation was assessed by Western blot analysis and confocal microscopy, oxidative stress by dihydroethidium probing. RESULTS: Pro-inflammatory endothelial ICAM-1 and VCAM-1 were up-regulated by three-fold in CLP vs. SHAM at D7 and remained elevated at D90. Oxidative stress followed a similar pattern but was detected in the whole vascular wall. Sepsis accelerated premature senescence in aorta vascular tissue as shown by the significant up-regulation of p53 and down-stream p21 and p16 senescent markers at D7, values peaking at D90 whereas the absence of significant variation in activated caspase-3 confirmed p53 as a prime inducer of senescence. In addition, p53 was mainly expressed in the endothelium. Sepsis-induced long-term vascular dysfunction was confirmed in aorta and main mesenteric artery, with a major alteration of the endothelial-dependent nitric oxide pathway. CONCLUSIONS: Septic shock-induced long-term vascular dysfunction is associated with endothelial and vascular senescence. Our model could prove useful for investigating senotherapies aiming at reducing long-term cardiovascular consequences of septic shock.


Assuntos
Sepse , Choque Séptico , Animais , Aorta/metabolismo , Senescência Celular , Masculino , Ratos , Ratos Wistar , Sepse/complicações
17.
ERJ Open Res ; 7(2)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34159187

RESUMO

Procoagulant microparticles are associated with the extent of lung injuries in #COVID19 and pulmonary thrombosis https://bit.ly/3eX2LPc.

18.
Transplant Proc ; 53(5): 1736-1743, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33934912

RESUMO

BACKGROUND: Ischemia-driven islet isolation procedure is one of the limiting causes of pancreatic islet transplantation. Ischemia-reperfusion process is associated with endothelium dysfunction and the release of pro-senescent microvesicles. We investigated whether pro-senescent endothelial microvesicles prompt islet senescence and dysfunction in vitro. MATERIAL AND METHODS: Pancreatic islets were isolated from male young rats. Replicative endothelial senescence was induced by serial passaging of primary porcine coronary artery endothelial cells, and microvesicles were isolated either from young passage 1 (P1) or senescent passage 3 (P3) endothelial cells. Islet viability was assessed by fluorescence microscopy, apoptosis by flow cytometry, and Western blot. Function was assessed by insulin secretion and islet senescence markers p53, p21, and p16 by Western blot. Microvesicles were stained by the PKH26 lipid fluorescent probe and their islet integration assessed by microscopy and flow cytometry. RESULTS: Regardless of the passage, half microvesicles were integrated in target islets after 24 hours incubation. Insulin secretion significantly decreased after treatment by senescent microvesicles (P3: 1.7 ± 0.2 vs untreated islet: 2.7 ± 0.2, P < .05) without altering the islet viability (89.47% ± 1.69 vs 93.15% ± 0.97) and with no significant apoptosis. Senescent microvesicles significantly doubled the expression of p53, p21, and p16 (P < .05), whereas young microvesicles had no significant effect. CONCLUSION: Pro-senescent endothelial microvesicles specifically accelerate the senescence of islets and alter their function. These data suggest that islet isolation contributes to endothelial driven islet senescence.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Senescência Celular , Ilhotas Pancreáticas/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular , Micropartículas Derivadas de Células/fisiologia , Células Cultivadas , Senescência Celular/genética , Vasos Coronários/citologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Suínos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
Nanomedicine ; 34: 102379, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33713860

RESUMO

Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang II-induced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPA:DHA6:1) were more effective than native EPA:DHA 6:1 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-ß-galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.


Assuntos
Senescência Celular , Portadores de Fármacos , Endotélio Vascular/citologia , Corantes Fluorescentes/química , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Autoanticorpos/imunologia , Proliferação de Células , Endotélio Vascular/metabolismo , Medicina de Precisão , Suínos , Molécula 1 de Adesão de Célula Vascular/imunologia
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