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1.
Phytomedicine ; 79: 153350, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33002827

RESUMO

BACKGROUND: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. PURPOSE: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. METHODS: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. RESULTS: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10-7 M-10-5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. CONCLUSION: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Quempferóis/farmacologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas de Neoplasias/metabolismo , Orchidaceae/química , Molécula 1 de Interação Estromal/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Quempferóis/isolamento & purificação , Lipopolissacarídeos/farmacologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
2.
Crit Care Resusc ; 22(3): 257-265, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32900333

RESUMO

Albumin is the most abundant and perhaps most important protein in human blood. Research has identified many of albumin's possible roles in modulating acid-base balance, modifying inflammation, maintaining vascular endothelial integrity, and binding endogenous and exogenous compounds. Albumin plays a key role in the homeostasis of vascular endothelium, offering protection from inflammation and damage to the glycocalyx. Albumin binds a diverse range of compounds. It transports, delivers and clears drugs, plus it helps with uptake, storage and disposal of potentially harmful biological products. The biological effects of albumin in critical illness are incompletely understood, but may enhance its clinical role beyond use as an intravenous fluid. In this article, we summarise the evidence surrounding albumin's biological and physiological effects beyond its use for plasma volume expansion, and explore potential mechanistic effects of albumin as a disease modifier in patients with critical illness.


Assuntos
Albuminas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Glicocálix , Células Endoteliais/metabolismo , Homeostase , Humanos
3.
Medicine (Baltimore) ; 99(37): e22167, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925783

RESUMO

BACKGROUND: The prevalence of cardiac syndrome X (CSX) is considerable. Some patients show recurrent angina attacks and have a poor prognosis. However, the knowledge of CSX pathophysiological mechanism is still limited, and the treatment fails to achieve a satisfactory suppression of symptoms. Nicorandil has a beneficial effect on improving coronary microvascular dysfunction (CMD). This study aims to evaluate the clinical effects and safety of nicorandil on CSX patients. METHODS: The Cochrane Library, Pubmed, EMBASE, ClinicalTrials.gov and 4 Chinese databases were searched to identify relevant studies. The Cochrane "Risk of bias" tool was used to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.3 software. The Eggers test and meta-regression were performed by software Stata 14.0. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty four randomized controlled trials (RCTs) involving 2323 patients were included. Most of the included studies were classified as having an unclear risk of bias because of poor reported methodology. The main outcomes are angina symptoms improvement, resting electrocardiogram (ECG) improvement, treadmill test result, and endothelial function. Meta-analysis showed that nicorandil had some benefit on improving angina symptoms (RR 1.24, 95% CI 1.19 to 1.29, I = 20%, P < .00001), resting ECG (RR = 1.24, 95% IC: 1.15 to 1.33, I = 0%, P < .00001), and prolonged the time to 1 mm ST-segment depression in treadmill test result (WMD = 38.41, 95% IC: 18.46 to 58.36, I = 0%, P = .0002). Besides nicorandil could reduce the level of endothelin-1 (ET-1) (SMD = -2.22, 95% IC: -2.61 to -1.83, I = 77%, P < .00001) and increase the level of nitric oxide (NO) (WMD = 27.45, 95% IC: 125.65 to 29.24, I = 81%, P < .00001). No serious adverse drug event was reported. The Eggers test showed that significant statistical publication bias was detected (Eggers test P = .000). The quality of evidence ranged from very low to low. CONCLUSIONS: Nicorandil shows the potential of improving angina symptoms, ECG, and endothelial dysfunction in patients with CSX. However, there is insufficient evidence for the clinical benefits of nicorandil due to the very low-quality evidence.


Assuntos
Angina Microvascular/tratamento farmacológico , Nicorandil/uso terapêutico , Vasodilatadores/uso terapêutico , Eletrocardiografia , Endotelina-1/sangue , Endotélio Vascular/efeitos dos fármacos , Teste de Esforço , Humanos , Óxido Nítrico/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Life Sci ; 259: 118383, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896555

RESUMO

AIMS: Previous studies have shown that the widespread use of estrogen preparations can cause adverse outcomes such as thrombosis and cardiovascular disease. Autophagy is a biochemical process necessary to maintain cell homeostasis. The present study investigated whether E-2 mediates autophagy-induced endothelial cell dysfunction. The role of aspirin in this process was then studied. MAIN METHODS: Western blot, fluorescence microscopy, electron transmission microscopy, plasma construction and transfection, vasoreactivity study in wire myograph are all used in this study. KEY FINDINGS: We found that E-2 activated the PI3K/mTOR signaling pathway and inhibited the formation of the Atg14L-Beclin1-Vps34-Vps15 complex, thereby inhibiting autophagy. Aspirin promoted Beclin1 phosphorylation in autophagy initiation complexes and enhanced autophagy. Furthermore, E-2 treatment of HAECs resulted in endothelial dysfunction by inhibiting autophagy and leading to accumulation of α-smooth muscle actin (α-SMA). E-2 inhibited the activation of eNOS and reduced the expression of eNOS protein. In the mouse aortic vascular function test, E-2 disrupted endothelium-dependent vasodilation. An α-SMA-shRNA lentivirus eliminated the disruption to endothelium-dependent vasodilation by E-2. Aspirin inhibited α-SMA accumulation by enhancing autophagy, reversed endothelial functional impairment caused by E-2, and promoted endothelium-dependent vasodilation. SIGNIFICANCE: This study provides new evidence that E-2 inhibits autophagy and induces abnormal accumulation of α-SMA, resulting in endothelial cell dysfunction and affecting vasodilation. Aspirin can effectively restore the endothelial cell function disrupted E-2.


Assuntos
Actinas/metabolismo , Aspirina/farmacologia , Autofagia/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estradiol/metabolismo , Proteína VPS15 de Distribuição Vacuolar/metabolismo , Animais , Western Blotting , Células Cultivadas , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Fosforilação/efeitos dos fármacos
5.
Biomolecules ; 10(8)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796765

RESUMO

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a "treatment on a named-patient basis" approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0-16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/complicações , Endotélio Vascular/efeitos dos fármacos , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Sepse/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Infecções por Coronavirus/patologia , Estado Terminal , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Sepse/etiologia
6.
High Blood Press Cardiovasc Prev ; 27(5): 363-371, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740853

RESUMO

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs-also known as "epi-drugs"-is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting.


Assuntos
Doenças Cardiovasculares/genética , Endotélio Vascular/metabolismo , Epigênese Genética , Síndrome Metabólica/genética , Animais , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Epigênese Genética/efeitos dos fármacos , Interação Gene-Ambiente , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Fatores de Risco , Transdução de Sinais
7.
PLoS One ; 15(8): e0234492, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790760

RESUMO

Endothelial injury is a common manifestation in IgA nephropathy (IgAN). After the previous identification of the upregulated soluble fms-like tyrosine kinase-1 (sFlt-1) correlated with endothelial injury in IgAN, in the present study, we further explored the role of sFlt-1 in endothelial injury in IgAN. We enrolled 72 patients with IgAN and detected the sFlt-1 levels. The polymeric IgA1 (pIgA1) complexes were isolated from the pooled plasma samples of another 10 patients with IgAN. Apoptosis proteins were detected in cultured human umbilical vein endothelial cells (HUVECs) with the stimulation of recombinant sFlt-1 or the caspase-9 inhibitor Z-LEHD-FMK. We identified there were positive correlations between sFlt-1 and IgA-IgG complex as well as vWF levels in patients with IgAN. The sFlt-1 levels in HUVECs were significantly upregulated by pIgA1 complex derived from IgAN patients in a concentration-dependent manner. The proliferation ability of HUVECs was damaged when stimulated with sFlt-1 protein in a time- and dose- dependent manner. And the apoptosis rate was up-regulated significantly as the stimulation concentrations of sFlt-1 increased. We found sFlt-1 challenge could significantly increase the expression of vWF. In addition, sFlt-1 increased the levels of caspase-9, caspase-3, Bax and mitochondrial membrane potential; facilitated the release of cytochrome C from mitochondria to cytoplasma. In contrast, Z-LEHD-FMK attenuated high sFlt-1-induced HUVECs apoptosis. In conclusion, our study demonstrated that sFlt-1 expression was up-regulated by the challenge of pIgA1 complex derived from patients with IgAN. Furthermore, increased sFlt-1 facilitated human umbilical vein endothelial cells apoptosis via the mitochondrial-dependent pathway.


Assuntos
Endotélio Vascular/fisiopatologia , Glomerulonefrite por IGA/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Caspase 9/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Oligopeptídeos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
8.
Med Hypotheses ; 143: 110142, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759013

RESUMO

BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Ácido Fólico/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/complicações , Administração por Inalação , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Humanos , Hipertensão Pulmonar/complicações , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , Camundongos , Óxido Nítrico/administração & dosagem , Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Taquifilaxia
9.
Med Hypotheses ; 143: 110150, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763660

RESUMO

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Estrogênios/fisiologia , Hemostáticos/uso terapêutico , Mucosite/tratamento farmacológico , Pandemias , Fitoestrógenos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Pneumonia Viral/complicações , Receptor PAR-1/antagonistas & inibidores , Administração Tópica , Distribuição por Idade , Anti-Inflamatórios/administração & dosagem , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Reposicionamento de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Estrogênios/agonistas , Hemostáticos/administração & dosagem , Humanos , Mucosite/etiologia , Fitoestrógenos/administração & dosagem , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Receptor PAR-1/fisiologia , Estomatite/tratamento farmacológico , Estomatite/etiologia , Trombofilia/sangue , Trombofilia/etiologia
10.
Toxicol Lett ; 333: 80-89, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738273

RESUMO

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin-angiotensin system and COX2 pathway activation.


Assuntos
Cloreto de Cádmio/toxicidade , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hipertensão/induzido quimicamente , NADPH Oxidases/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Cádmio/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Poluentes Ambientais/sangue , Hipertensão/enzimologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Injeções Intraperitoneais , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos
11.
Toxicol Lett ; 333: 97-104, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763312

RESUMO

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Rim/efeitos dos fármacos , Pantoprazol/toxicidade , Inibidores da Bomba de Prótons/toxicidade , Administração Oral , Animais , Aorta Torácica/imunologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Rim/imunologia , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nitratos/metabolismo , Nitritos/metabolismo , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
12.
Toxicol Lett ; 334: 110-116, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707277

RESUMO

Endothelial cell migration is a critical process in the maintenance of healthy blood vessels. Impaired endothelial migration is reportedly associated with the development of cardiovascular diseases. Here, we report on the development of a 96-well in vitro endothelial migration assay for the purpose of comparative toxicological assessment of a novel THP relative to cigarette smoke, to be able to rapidly inform regulatory decision making. Uniform scratches were induced in confluent human umbilical vein endothelial cells using the 96-pin wound maker and exposed to 3R4F cigarette or THP aqueous extracts (AqE). Endothelial migration was recorded over 24 h, and the rate of wound closure calculated using mean relative wound density rather than migration rate as previously reported. This self-normalising parameter accounts for starting wound size, by comparing the density of the scratch to the outer region at each time-point. Furthermore, wound width acceptance criteria was defined to further increase the sensitivity of the assay. 3R4F and THP AqE samples were tested at comparable nicotine concentrations. 3R4F showed significant cytotoxicity and inhibition of wound healing whereas THP AqE did not show any response in either endpoint. This 96-well endothelial migration assay was suitably sensitive to distinguish combustible cigarette and THP test articles.


Assuntos
Movimento Celular/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Nicotina/toxicidade , Material Particulado/toxicidade , Produtos do Tabaco/toxicidade , Tabaco/toxicidade , Aerossóis , Ensaios de Migração Celular , Endotélio Vascular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Células Endoteliais da Veia Umbilical Humana , Humanos
13.
Am J Respir Cell Mol Biol ; 63(4): 519-530, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32628869

RESUMO

KD025 is a ROCK2 inhibitor currently being tested in clinical trials for the treatment of fibrotic lung diseases. The therapeutic effects of KD025 are partly due to its inhibition of profibrotic pathways and fat metabolism. However, whether KD025 affects pulmonary microvascular endothelial cell (PMVEC) function is unknown, despite evidence that alveolar-capillary membrane disruption constitutes major causes of death in fibrotic lung diseases. We hypothesized that KD025 regulates PMVEC metabolism, pH, migration, and survival, a series of interrelated functional characteristics that determine pulmonary barrier integrity. We used PMVECs isolated from Sprague Dawley rats. KD025 dose-dependently decreased lactate production and glucose consumption. The inhibitory effect of KD025 was more potent compared with other metabolic modifiers, including 2-deoxy-glucose, extracellular acidosis, dichloroacetate, and remogliflozin. Interestingly, KD025 increased oxidative phosphorylation, whereas 2-deoxy-glucose did not. KD025 also decreased intracellular pH and induced a compensatory increase in anion exchanger 2. KD025 inhibited PMVEC migration, but fasudil (nonspecific ROCK inhibitor) did not. We tested endothelial permeability in vivo using Evans Blue dye in the bleomycin pulmonary fibrosis model. Baseline permeability was decreased in KD025-treated animals independent of bleomycin treatment. Under hypoxia, KD025 increased PMVEC necrosis as indicated by increased lactate dehydrogenase release and propidium iodide uptake and decreased ATP; it did not affect Annexin V binding. ROCK2 knockdown had no effect on PMVEC metabolism, pH, and migration, but it increased nonapoptotic caspase-3 activity. Together, we report that KD025 promotes oxidative phosphorylation; decreases glycolysis, intracellular pH, and migration; and strengthens pulmonary barrier integrity in a ROCK2-independent manner.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Pulmão/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Anexina A5/metabolismo , Movimento Celular/efeitos dos fármacos , Desoxiglucose/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glicólise/efeitos dos fármacos , Concentração de Íons de Hidrogênio , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Masculino , Fosforilação Oxidativa/efeitos dos fármacos , Propídio/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/metabolismo
14.
Medicine (Baltimore) ; 99(27): e20783, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629660

RESUMO

BACKGROUND: To systematically review the effects of Danhong injection on endothelial function and inflammatory factors after the percutaneous coronary intervention (PCI) for coronary heart disease (CHD) and to provide a basis for further research. METHODS: Through computer retrieval, including PubMed, Embase, the Cochrane Library, CNKI, Wan Fang Data, VIP, SinoMed were retrieved on a computer. Randomized controlled trials (RCTs) on the effects of Danhong injection on endothelial function and inflammatory factors after PCI for CHD were collected in strict accordance with the pre-established inclusion and exclusion criteria. Chinese and English literatures in published from the establishment of each database to December 1, 2019, were retrieved by combining subject headings and free terms. Literatures were screened out by 2 researchers independently, and the risk of bias was assessed by 2 independent researchers by using the assessment tool for risk of bias as described Cochrane systematic reviewer's manual 5.1.0. Statistical analysis was performed by using Stata 14.0 software. RESULTS: By collecting the existing evidence, this study would determine the effects of Danhong injection on endothelial function and inflammatory factors after PCI for CHD by meta-analysis. CONCLUSION: Through this study, we will draw a definite conclusion on whether Danhong injection has significant effects on endothelial function and inflammatory factors after PCI for CHD. This conclusion will provide practical and scientific guidance for the use of Danhong injection after PCI for CHD. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020165568.


Assuntos
Doença das Coronárias/cirurgia , Medicamentos de Ervas Chinesas/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Intervenção Coronária Percutânea/métodos , Terapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Endotélio Vascular/lesões , Humanos , Inflamação/etiologia , Injeções , Intervenção Coronária Percutânea/efeitos adversos
15.
Ther Adv Cardiovasc Dis ; 14: 1753944720934937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32611276

RESUMO

Ivabradine is a pure heart-rate lowering drug that is nowadays used, accordingly to the last ESC Guidelines, to reduce mortality and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction and in symptomatic patiens with inappropriate sinus tachycardia. Moreover, interesting effect of ivabradine on endothelial and myocardial function and on oxidative stress and inflamation pathways are progressively emerging. The aim of this paper is to highlight newer evidences about ivabradine effect (and consequently possible future application of the drug) in pathological settings different from guidelines-based clinical practice.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Ivabradina/uso terapêutico , Animais , Função Atrial/efeitos dos fármacos , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Ivabradina/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
16.
Life Sci ; 258: 118106, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682916

RESUMO

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.


Assuntos
Autofagia/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Quercetina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
17.
Arterioscler Thromb Vasc Biol ; 40(9): 2244-2264, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640900

RESUMO

OBJECTIVE: Nanog is expressed in adult endothelial cells (ECs) at a low-level, however, its functional significance is not known. The goal of our study was to elucidate the role of Nanog in adult ECs using a genetically engineered mouse model system. Approach and Results: Biochemical analyses showed that Nanog is expressed in both adult human and mouse tissues. Primary ECs isolated from adult mice showed detectable levels of Nanog, Tert (telomerase reverse transcriptase), and eNos (endothelial nitric oxide synthase). Wnt3a (Wnt family member 3A) increased the expression of Nanog and hTERT (human telomerase reverse transcriptase) in ECs and increased telomerase activity in these cells. In a chromatin immunoprecipitation experiment, Nanog directly bound to the hTERT and eNOS promoter/enhancer DNA elements, thereby regulating their transcription. Administration of low-dose tamoxifen to ROSAmT/mG::Nanogfl/+::Cdh5CreERT2 mice induced deletion of a single Nanog allele, simultaneously labeling ECs with green fluorescent protein and resulting in decreased Tert and eNos levels. Histological and morphometric analyses of heart tissue sections prepared from these mice revealed cell death, microvascular rarefaction, and increased fibrosis in cardiac vessels. Accordingly, EC-specific Nanog-haploinsufficiency resulted in impaired EC homeostasis and angiogenesis. Conversely, re-expression of cDNA encoding the hTERT in Nanog-depleted ECs, in part, restored the effect of loss of Nanog. CONCLUSIONS: We showed that low-level Nanog expression is required for normal EC homeostasis and angiogenesis in adulthood.


Assuntos
Proliferação de Células , Senescência Celular , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Proteína Homeobox Nanog/metabolismo , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Homeobox Nanog/deficiência , Proteína Homeobox Nanog/genética , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Telomerase/genética , Telomerase/metabolismo , Ativação Transcricional , Via de Sinalização Wnt , Proteína Wnt3A/farmacologia
18.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
19.
Am J Physiol Heart Circ Physiol ; 319(2): H456-H467, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706261

RESUMO

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.


Assuntos
Antioxidantes/uso terapêutico , Artéria Braquial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Claudicação Intermitente/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Artéria Poplítea/efeitos dos fármacos , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/metabolismo , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/metabolismo , Artéria Braquial/fisiopatologia , Estudos Cross-Over , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Contração Muscular/efeitos dos fármacos , Nebraska , Compostos Organofosforados/metabolismo , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/metabolismo , Artéria Poplítea/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Ubiquinona/metabolismo , Ubiquinona/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Caminhada
20.
Int J Hematol ; 112(4): 584-591, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32557125

RESUMO

A 66-year-old man with hypertension was diagnosed with chronic myelogenous leukemia in 1996. Treatment was started with hydroxycarbamide and imatinib 400 mg in 1996 + 6, which was increased to 600 mg. Although he achieved a complete cytogenic response in 1996 + 9, he could not continue imatinib because of edema; the regimen was changed to nilotinib 800 mg in 1996 + 13. After he achieved a molecular response better than 4.5 in 1996 + 19, he was referred to our hospital. His urinalysis had shown urine protein since 1996 + 13, and his creatinine level increased in 1996 + 16. Renal biopsy, performed in 1996 + 20, revealed abdominal distention and massive ascites. After the nilotinib dosage was reduced to 400 mg, liver biopsy, also performed in 1996 + 20, revealed hypertrophy of renal small blood vessels and endothelial cells of the hepatic artery and loss of endothelial cells of the renal glomeruli, portal vein, and hepatic sinusoids. Both renal and liver biopsies revealed marked pathological vascular damage. The patient took oral imatinib for approximately 3.5 years and nilotinib for 11 years. Pathological findings indicated a tendency for thrombosis, which could induce vascular occlusive disease. Accumulation of cases, such as the present case, is needed to further analyze the pathophysiological processes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/efeitos adversos , Idoso , Substituição de Medicamentos , Humanos , Hidroxiureia/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Rim/irrigação sanguínea , Rim/patologia , Fígado/irrigação sanguínea , Fígado/patologia , Masculino , Pirimidinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
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