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1.
Nutr Metab Cardiovasc Dis ; 29(6): 604-610, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30952572

RESUMO

AIM: To evaluate the possible association between dietary habits and progenitor cells using data obtained from a randomized crossover trial using two different diets, lacto-ovo-vegetarian (VD) and Mediterranean (MD), the CARDIVEG study. METHODS AND RESULTS: Eighty clinically healthy subjects with a low-to-moderate cardiovascular risk profile (61 F; 19 M; mean age: 50.7 ± 11.6 years) were randomly assigned to isocaloric VD and MD diets lasting three months each, and then crossed. The two diets showed no effects on endothelial progenitor cells and circulating endothelial cells but opposite effects on circulating progenitor cells. In fact, VD determined significant (p < 0.05) and negative changes on circulating progenitor cells, with an average geometric variation of -130 cells/106 events for CD34+/CD45-/dim, -80 cells/106 events for CD133+/CD45-/dim, and -84 cells/106 events for CD34+/CD133+/CD45-/dim while MD determined significant (p < 0.05) and positive changes for CD34+/CD45-/dim levels, with a geometric mean increase of +54 cells/106 events. No significant correlations were observed between changes in progenitor cells and changes in inflammatory parameters during the VD phase. On the other hand, during the MD phase negative correlations between changes of CD34+/CD45-/dim and interleukin-6 (R = -0.324; p = 0.004) as well as interleukin-8 (R = -0.228; p = 0.04) and monocyte chemotactic protein-1 (R = -0.277; p = 0.01), were observed. These correlations remained significant also after adjustment for confounding factors only for CD34+/CD45-/dim and interleukin-6 (ß = -0.282; p = 0.018) and monocyte chemotactic protein-1 (ß = -0.254; p = 0.031). CONCLUSIONS: MD, but not VD, reported a significant and positive effect on circulating progenitor cells in a group of subjects at low-to-moderate cardiovascular risk, probably acting through the modulation of inflammatory parameters.


Assuntos
Antígenos CD/sangue , Doenças Cardiovasculares/prevenção & controle , Dieta Mediterrânea , Dieta Vegetariana , Mediadores da Inflamação/sangue , Prevenção Primária/métodos , Células-Tronco/metabolismo , Antígeno AC133/sangue , Adulto , Idoso , Antígenos CD34/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/imunologia , Quimiocina CCL2/sangue , Estudos Cross-Over , Feminino , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Antígenos Comuns de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
2.
Pregnancy Hypertens ; 15: 146-153, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30825912

RESUMO

OBJECTIVES: Individuals delivered from preeclamptic pregnancies exhibit a long-term increased risk of developing cardiovascular and metabolic diseases, likely caused by aberrant fetal cell reprogramming incurred in utero. The present study investigated the functional impairment and epigenetic changes exhibited by endothelial progenitor cells derived from offspring born to preeclamptic pregnancies. STUDY DESIGN: The capacity of CD133+/C-kit+/Lin- (CKL-) human umbilical cord blood endothelial progenitor cells (EPCs) derived from gestationally matched normal and preeclamptic (n = 10 each) pregnancies to differentiate to form outgrowth endothelial cells (OECs) was assessed by observing both their morphology, and the number and size of generated OECs colonies. Likewise, OECs angiogenic function was evaluated via migration, adhesion, and tube-formation assays. EPCs from preeclampsia were cultured in normal-, and preeclampsia-derived serum-conditioned media to assess the effects of environmental factors on EPC differentiation potency and OEC angiogenic function, and finally, EPCs H3K4, H3K9, and H3K27 trimethylation levels were assayed. RESULTS: The preeclampsia-derived CKL- EPCs exhibited decreased H3K4 and H3K9 trimethylation levels, significantly delayed differentiation times, and a significant reduction in both their number of generated OECs colonies, and exhibited reduced OECs migration, adhesion, and tube formation activities compared to those achieved by the normal-derived EPCs. Interestingly, the reduced differentiation potency of the preeclampsia-derived EPCs was not rescued via exposure to normal serum. CONCLUSIONS: Exposure to preeclampsia significantly and irreversibly reduced CKL- EPC differentiation potency and OEC angiogenic function, likely reflecting incurred irreversible epigenetic changes.


Assuntos
Antígeno AC133/sangue , Células Progenitoras Endoteliais/citologia , Epigênese Genética , Pré-Eclâmpsia/sangue , Adulto , Análise de Variância , Estudos de Casos e Controles , Movimento Celular , Feminino , Sangue Fetal , Humanos , Pré-Eclâmpsia/fisiopatologia , Gravidez
3.
Biomed Pharmacother ; 108: 1328-1337, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372835

RESUMO

Metformin is commonly prescribed as a hypoglycemic agent following the onset of type 2 diabetes mellitus. This study aimed to investigate pro- and/or anti-angiogenic effects of Metformin on human bone marrow mesenchymal stem cells. Cells were incubated with different doses of Metformin including 0.5, 1, 10, 50, 100, 200 and 500 µM for 14 days. Cell viability and total fatty acids profile were examined by MTT and gas chromatography methods. Differentiation of cells to endothelial lineage was studied by monitoring the expression of VEGFR-2 and Tie-2 receptors and VE-cadherin via real-time PCR and western blotting. Angiogenic potential and migration of cells were assessed by tubulogenesis and Transwell migration assays. PCR array was performed to analyze mTOR signaling. CD133+ and VEGFR-2+ cells were detected in blood samples of non-diabetic control, diabetic subjects and diabetics received Metformin. Metformin dose-dependently reduced cell survival. Decreased content of palmitate and oleate coincided increased level of stearate, palmitoleate, and linoleate (p < 0.05). Metformin decreased the angiogenic potential of cells by decreasing VEGFR-2 and Tie-2 expression (p < 0.05). The protein level of VE-cadherin decreased in cells received Metformin. Compared to the control, Metformin blunted the expression of VEGF subtypes and directed cells to energy status by induction of PRKAA1, PRKAB2, and PRKAG1 genes (p < 0.05). Non-significant differences were observed regarding the number of CD133 and VEGFR-2 cells in blood samples (p > 0.05). These data support a notion that Metformin could blunt the angiogenic behavior of human mesenchymal stem cells by modulating mTOR signaling pathway.


Assuntos
Células-Tronco Mesenquimais/efeitos dos fármacos , Metformina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Antígeno AC133/sangue , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácidos Graxos/análise , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Serina-Treonina Quinases TOR/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
4.
Eur J Surg Oncol ; 44(4): 496-501, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29397265

RESUMO

INTRODUCTION: Neovascularisation is a critical step in the progression of malignant tumors. Circulating endothelial progenitor cells (cEPC) have been proposed as surrogate markers of vasculogenesis in malignancies. In this project, we studied the impact of tumor-specific therapy on cEPC and associated angiogenic factors in patients with soft tissue tumors. MATERIALS AND METHODS: Fifty-three patients with soft tissue tumors (25 soft tissue sarcomas, 19 GIST, 9 desmoids) and 15 healthy controls were included. Blood samples were obtained at two time points, before and 8 weeks after start of tumor-specific therapy. Peripheral blood mononuclear cells (PBMCs) were isolated. cEPCs were characterised as CD34+, CD133+, CD45dim, CD31+ and vascular endothelial growth factor 2 (VEGFR-2) positive cells. Serum concentrations of VEGF-A and angiopoetin-2 were determined by enzyme-linked immunosorbent assay. RESULTS: VEGF-A and Ang-2 concentrations were significantly higher in tumor patients than in healthy controls in both samples (p < .01). Sarcoma patients with progressive disease developed a significant increase in cEPC levels between the two blood samples compared to those with stable disease (p = .002). GIST patients with progressive tumor or metastatic disease showed significant increase in VEGF-A values (p = .01). DISCUSSION: The pre-treatment values of the angiogenic markers did not correlate with the clinical course of the disease. However, cEPCs levels were significantly higher in sarcoma patients with progressive disease compared to those with stable disease and should be further evaluated as early markers of disease progression in sarcoma patients. VEGF-A and angiopoetin-2 clearly play a role as mediators of the vasculogenesis contributing to tumor progression.


Assuntos
Biomarcadores Tumorais/sangue , Células Progenitoras Endoteliais/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neoplasias de Tecidos Moles/sangue , Neoplasias de Tecidos Moles/patologia , Antígeno AC133/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiopoietina-2/sangue , Antígenos CD34/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Antígenos Comuns de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/sangue , Prognóstico , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
5.
Neurol Sci ; 39(3): 437-443, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29147957

RESUMO

Endothelial progenitor cells (EPCs) have important effect in tissue repair in ischemic organs. The present study was conducted to demonstrate the mobilization of EPCs and its possible mechanism after acute ischemic stroke (AIS). A total of 148 individuals were examined, including 106 patients with ischemic stroke and 42 healthy controls. Seventy-one patients with imaging-confirmed AIS were examined at days 1, 7, 14, and 21 after stroke onset. Circulating EPCs were quantified by flow cytometry using CD133 and KDR surface markers. Serum stromal cell-derived factor-1 (SDF-1) concentrations were determined by enzyme-linked immunosorbent assay. Patients with AIS had significantly lower EPC level than that in the controls (0.022 ± 0.013 vs 0.051 ± 0.020; p < 0.01). This difference did not remain significant after adjusting for risk factors at multivariate analysis. Blood pressure, triglyceride, low-density lipoprotein (LDL), and fasting blood sugar were inversely correlated with EPC levels (p < 0.01). Systolic blood pressure and LDL remained independent predictors of baseline EPC levels. The number of circulating EPCs increased on day 7 after AIS, reached a peak on day 14, and decreased on day 21. The concentration of SDF-1 had similar changes. The increment of EPCs was correlated with the infarct volume (r = 0.708; p = 0.006) and SDF-1 concentration on day 14 (r = 0.714; p < 0.001). Baseline EPC level in patients with AIS reflects the cumulative vascular endothelial damage. EPCs could be mobilized into peripheral circulation in response to stroke stress. This mobilization was associated with the increased expression of SDF-1.


Assuntos
Isquemia Encefálica/sangue , Células Progenitoras Endoteliais/fisiologia , Acidente Vascular Cerebral/sangue , Antígeno AC133/sangue , Idoso , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Isquemia Encefálica/diagnóstico por imagem , Quimiocina CXCL12/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
6.
Cancer Med ; 6(12): 2850-2857, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29105339

RESUMO

In the previous study, we had showed the expression of CD133+ CD54+ CD44+ cellular subpopulation of circulating tumor cells (CTCs) was significantly associated with liver metastasis of colorectal cancer (CRC). This study aimed to explore whether this subpopulation of CTCs have a prognostic value in CRC patients. Flow cytometry was used to detect the expression of cellular subpopulations of CTCs with CD133, CD54, and CD44 in 152 CRC patients, between December 2013 and October 2014. The impact of clinicopathological factors and the expression of cellular subpopulations of CTCs on overall survival were then analyzed. CRC patients with liver metastases who underwent resection of the primary tumor accompanied by surgical treatment for metastasis had a better survival than other patients (P < 0.001). The liver metastatic CRC patients with high expression of CD133+ CD54+ (P < 0.001), CD133- CD54+ (P = 0.004), and CD133+ CD44+ CD54+ (P = 0.003) cellular subpopulations of CTCs had a worse survival than those patients with low expression. Multivariable survival analyses identified carcinoembryonic antigen levels (hazard ratio [HR] = 3.056; 95% confidence interval [CI] = 1.354-6.897; P = 0.007), treatment strategy (HR = 0.212; 95% CI = 0.056-0.808; P = 0.023), and CD133+ CD44+ CD54+ cellular subpopulation of CTCs (HR = 6.459; 95% CI = 1.461-28.558; P = 0.014) as independent prognostic factors for CRC patients with liver metastasis. CD133+ CD44+ CD54+ cellular subpopulation of CTCs has a prognostic value in CRC patients with liver metastasis, especially in the survival of CRC patients with liver metastasis who did not undergo surgical treatment for metastasis.


Assuntos
Antígeno AC133/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/patologia , Receptores de Hialuronatos/sangue , Molécula 1 de Adesão Intercelular/sangue , Neoplasias Hepáticas/secundário , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Ablação por Cateter , Quimioembolização Terapêutica , Distribuição de Qui-Quadrado , Colectomia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Hepatectomia , Humanos , Imunofenotipagem/métodos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Células Neoplásicas Circulantes/imunologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
7.
Cardiovasc Res ; 113(13): 1560-1573, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016733

RESUMO

Aims: The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression. Methods and results: When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT. Conclusion: EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.


Assuntos
Pressão Arterial , Linhagem da Célula , Transdiferenciação Celular , Células Progenitoras Endoteliais/patologia , Células-Tronco Hematopoéticas/patologia , Hipertensão Pulmonar/patologia , Artéria Pulmonar/patologia , Antígeno AC133/sangue , Animais , Antígenos CD34/metabolismo , Estudos de Casos e Controles , Subunidade alfa 2 de Fator de Ligação ao Core/sangue , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/transplante , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos Transgênicos , Fenótipo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia
8.
J Am Heart Assoc ; 6(11)2017 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-29080864

RESUMO

BACKGROUND: Transradial catheterization is associated with radial artery injury and vasomotor dysfunction and represents an accessible model of acute vascular injury in humans. We characterized vascular injury and functional recovery to understand the role of circulating endothelial progenitor cells in vascular repair. METHODS AND RESULTS: In 50 patients (aged 64±10 years, 70% male) undergoing transradial cardiac catheterization, radial artery injury was assessed by optical coherence tomography and examination of explanted vascular sheaths. Flow- and nitrate-mediated dilatation of the radial artery was assessed in both arms at baseline, at 24 hours, and at 1, 4, and 12 weeks. Circulating endothelial progenitor cell populations were quantified using flow cytometry. Late endothelial outgrowth colonies were isolated and examined in vitro. Optical coherence tomography identified macroscopic injury in 12 of 50 patients (24%), but endothelial cells (1.9±1.2×104 cells) were isolated from all arterial sheaths examined. Compared with the noncatheterized radial artery, flow-mediated vasodilatation was impaired in the catheterized artery at 24 hours (9.9±4.6% versus 4.1±3.1%, P<0.0001) and recovered by 12 weeks (8.1±4.9% versus 10.1±4.9%, P=0.09). Although the number of CD133+ cells increased 24 hours after catheterization (P=0.02), the numbers of CD34+ cells and endothelial outgrowth colonies were unchanged. Migration of endothelial cells derived from endothelial outgrowth colonies correlated with arterial function before catheterization but was not related to recovery of function following injury. CONCLUSIONS: Transradial cardiac catheterization causes endothelial denudation, vascular injury, and vasomotor dysfunction that recover over 12 weeks. Recovery of vascular function does not appear to be dependent on the mobilization or function of endothelial progenitor cells. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147119.


Assuntos
Cateterismo Cardíaco/efeitos adversos , Cateterismo Periférico/efeitos adversos , Movimento Celular , Proliferação de Células , Células Progenitoras Endoteliais/patologia , Artéria Radial/patologia , Lesões do Sistema Vascular/patologia , Antígeno AC133/sangue , Idoso , Antígenos CD34/sangue , Cateterismo Cardíaco/métodos , Cateterismo Periférico/métodos , Separação Celular/métodos , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Punções , Artéria Radial/lesões , Artéria Radial/metabolismo , Artéria Radial/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Tomografia de Coerência Óptica , Ultrassonografia , Lesões do Sistema Vascular/sangue , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/fisiopatologia , Vasodilatação
9.
BMC Nephrol ; 18(1): 250, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747175

RESUMO

BACKGROUND: Hemodialysis (HD) patients have increased risk of cardiovascular disease (CVD). Impaired stem cell health and adipocytokine metabolism may play important roles in the complex pathophysiological mechanisms of CVD in this patient population. We aimed to investigate the relationships between CD133+ cell counts, adipocytokines and parameters of endothelial dysfunction and atherosclerosis in HD patients. METHODS: In 58 chronic HD patients (male/female:28/30, mean age:58 ± 14 years), serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin and resistin were measured by ELISA. Left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), flow-mediated dilatation (FMD) of the brachial artery were measured. CD133+ cells were counted by flow cytometry (BD FACSCalibur-BD Bioscience,CA). RESULTS: CD133+ cell counts were inversely associated with FMD (r = -0.39, p = 0.007) and positively correlated with serum resistin (r = 0.45, p < 0.001) and serum TNF-α (r = 0.31, p = 0.02). Serum leptin levels were higher in high CD133 group compared to low CD133 group [32.37(12.74-72.29) vs 15.50(5.38-37.12)ng/mL, p = 0.03]. Serum leptin levels were correlated with TNF-α(r = 0.35, p = 0.009). Serum adiponectin levels were negatively correlated with serum leptin (r = -0.28, p = 0.03). Serum resistin levels were associated with TNF-α (r = 0.54, p < 0.001) and leptin (r = 0.29, p = 0.03). Serum IL-6 levels were significantly associated with LVMI (r = 0.31, p = 0.03). Serum IL-6 levels were significantly higher in patients with carotid plaque compared to patients without plaque [12.75(9.91-28.68) vs 8.27(5.97-14.04) pg/mL, p = 0.02]. In multiple linear regression analysis to determine the factors predicting LogFMD; dialysis vintage, LVMI and LogCD133+ cell counts were included as independent variables(R = 0.57, adjusted R-square = 0.27, p = 0.001). CD133+ cell count and LVMI were found to significantly predict FMD (p = 0.03 and p = 0.04 respectively). CONCLUSION: CD133+ cells were associated with inflammation and endothelial dysfunction in HD patients. Serum leptin, resistin and TNF-α levels were positively related to CD133+ cell count. Impaired regulation of undifferentiated stem cells and adipocytokines might contribute to endothelial dysfunction in HD patients.


Assuntos
Antígeno AC133/sangue , Adipocinas/sangue , Endotélio Vascular/metabolismo , Diálise Renal/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/tendências
10.
Arq Bras Cardiol ; 108(3): 212-216, 2017 Mar.
Artigo em Português, Inglês | MEDLINE | ID: mdl-28443964

RESUMO

BACKGROUND: The effects of chronic exposure to exercise training on vascular biomarkers have been poorly explored. OBJECTIVE: Our study aimed to compare the amounts of endothelial progenitor cells (EPCs), and endothelial (EMP) and platelet (PMP) microparticles between professional runners and healthy controls. METHODS: Twenty-five half-marathon runners and 24 age- and gender-matched healthy controls were included in the study. EPCs (CD34+/KDR+, CD133+/KDR+, and CD34+/CD133+), EMP (CD51+) and PMP (CD42+/CD31+) were quantified by flow-cytometry. All blood samples were obtained after 12 h of fasting and the athletes were encouraged to perform their routine exercises on the day before. RESULTS: As compared with controls, the CD34+/KDR+ EPCs (p=0.038) and CD133+/KDR+ EPCs (p=0.018) were increased, whereas CD34+/CD133+ EPCs were not different (p=0.51) in athletes. In addition, there was no difference in MPs levels between the groups. CONCLUSION: Chronic exposure to exercise in professional runners was associated with higher percentage of EPCs. Taking into account the similar number of MPs in athletes and controls, the study suggests a favorable effect of exercise on these vascular biomarkers.


Assuntos
Atletas , Plaquetas/fisiologia , Micropartículas Derivadas de Células/fisiologia , Células Progenitoras Endoteliais/fisiologia , Corrida/fisiologia , Antígeno AC133/sangue , Antígenos CD34/sangue , Biomarcadores/sangue , Teste de Esforço , Feminino , Citometria de Fluxo , Humanos , Masculino , Valores de Referência , Espirometria , Estatísticas não Paramétricas , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
11.
Atherosclerosis ; 261: 117-123, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28298252

RESUMO

BACKGROUND AND AIMS: Reduced levels of circulating stem cells (CSCs) predict cardiovascular events and death, but the factors underlying variability of CSCs in healthy adults are mostly unknown. Previous studies detected associations of CSCs with glucose tolerance or insulin resistance, while the role of fatty acids has been overlooked. We herein aimed to describe in better detail the metabolic abnormalities associated with a reduced CSC level. METHODS: This was a cross-sectional study on 94 healthy male and female individuals with normal glucose tolerance, aged 18-65 years. All participants underwent an oral glucose tolerance test (OGTT) with blood samples collected at 0, 10, 20, 30, 60, 90 and 120 min. Mathematical models were applied to plasma glucose, insulin, C-peptide and non-esterified fatty acids (NEFA) concentrations. CSCs were defined as CD34+ or CD133+. RESULTS: Participants (mean ± SEM age 43.8 ± 0.7; 41% males) were divided according to CSC levels below (low) or above (high) the median value and metabolic parameters were compared. There was no significant baseline difference between groups except for higher concentrations of fasting NEFA in subjects with low CSCs. Upon OGTT, individuals with low CSCs had higher area under curve (AUC) of NEFA (p < 0.001) and no significant differences in glucose, insulin and C-peptide. Several insulin sensitivity and beta cell function indexes were not significantly different, except for a decrease in the disposition index (DI) in subjects with low CSCs. CSCs were associated with excess NEFA levels independently from age and DI. CONCLUSIONS: We show for the first time that, in healthy adults with normal glucose tolerance, low CSCs are strongly associated with excess NEFA exposure. The pathophysiological consequence of this association needs to be interpreted in view of the prognostic role of CSCs. Future studies should explore whether excess NEFA and low CSCs and are causally interconnected.


Assuntos
Glicemia/metabolismo , Jejum/sangue , Ácidos Graxos não Esterificados/administração & dosagem , Células-Tronco/metabolismo , Antígeno AC133/sangue , Adolescente , Adulto , Idoso , Antígenos CD34/sangue , Biomarcadores/sangue , Peptídeo C/sangue , Estudos Transversais , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/farmacocinética , Feminino , Teste de Tolerância a Glucose , Voluntários Saudáveis , Homeostase , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fenótipo , Adulto Jovem
12.
Stem Cell Rev Rep ; 13(2): 244-257, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28054239

RESUMO

Adult stem cells have beneficial effects when exposed to damaged tissue due, at least in part, to their paracrine activity, which includes soluble factors and extracellular vesicles (EVs). Given the multiplicity of signals carried by these vesicles through the horizontal transfer of functional molecules, human mesenchymal stem cell (hMSCs) and CD133+ cell-derived EVs have been tested in various disease models and shown to recover damaged tissues. In this study, we profiled the protein content of EVs derived from expanded human CD133+ cells and bone marrow-derived hMSCs with the intention of better understanding the functions performed by these vesicles/cells and delineating the most appropriate use of each EV in future therapeutic procedures. Using LC-MS/MS analysis, we identified 623 proteins for expanded CD133+-EVs and 797 proteins for hMSCs-EVs. Although the EVs from both origins were qualitatively similar, when protein abundance was considered, hMSCs-EVs and CD133+-EVs were different. Gene Ontology (GO) enrichment analysis in CD133+-EVs revealed proteins involved in a variety of angiogenesis-related functions as well proteins related to the cytoskeleton and highly implicated in cell motility and cellular activation. In contrast, when overrepresented proteins in hMSCs-EVs were analyzed, a GO cluster of immune response-related genes involved with immune response-regulating factors acting on phagocytosis and innate immunity was identified. Together our data demonstrate that from the point of view of protein content, expanded CD133+-EVs and hMSCs-EVs are in part similar but also sufficiently different to reflect the main beneficial paracrine effects widely reported in pre-clinical studies using expanded CD133+ cells and/or hBM-MSCs.


Assuntos
Vesículas Extracelulares/metabolismo , Sangue Fetal/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteoma/metabolismo , Medicina Regenerativa/métodos , Antígeno AC133/sangue , Apoptose , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proliferação de Células , Células Cultivadas , Cromatografia Líquida , Exossomos/metabolismo , Exossomos/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Sangue Fetal/citologia , Humanos , Células-Tronco Mesenquimais/citologia , Microscopia Eletrônica de Transmissão , Necrose , Proteômica/métodos , Espectrometria de Massas em Tandem
13.
Diabetes Care ; 40(1): 125-131, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27815289

RESUMO

OBJECTIVE: Cardiovascular risk varies substantially in the population with diabetes, and biomarkers can improve risk stratification. Circulating stem cells predict future cardiovascular events and death, but data for the population with diabetes are scant. In this study we evaluated the ability of circulating stem cell levels to predict future cardiovascular outcomes and improve risk discrimination in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A cohort of 187 patients with type 2 diabetes was monitored for a median of 6.1 years. The primary outcome was time to a first cardiovascular event, defined as 3-point major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) plus hospitalization for cardiovascular causes. At baseline, we measured six stem/progenitor cell phenotypes in peripheral blood based on expression of CD34, CD133, and KDR. RESULTS: The primary outcome occurred in 48 patients (4.5/100 patient-years). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Higher rates of cardiovascular events occurred in patients with below median levels of CD34+ and CD34+CD133+. In Cox proportional hazards regression analyses, a reduced CD34+ (hazard ratio 2.21 [95% CI 1.14-4.29]) and CD34+CD133+ (2.98 [1.46-6.08]) cell count independently predicted future events. Addition of the CD34+ cell count to the reference model or the UK Prospective Diabetes Study risk engine improved C statistics, continuous net reclassification improvement, and/or integrated discrimination index. CONCLUSIONS: In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts adverse cardiovascular outcomes up to 6 years later and improves risk stratification.


Assuntos
Antígeno AC133/sangue , Antígenos CD34/sangue , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/sangue , Células-Tronco/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Contagem de Células , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão , Fatores de Risco
14.
Clin Cancer Res ; 23(11): 2681-2690, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27789528

RESUMO

Purpose: Circulating tumor cells (CTCs) have been identified in the blood of patients with pancreatic adenocarcinoma (PDAC), but little is known about the exact phenotype of these cells. We assessed expression of aldehyde dehydrogenase (ALDH), CD133, and CD44 as markers of CTCs with a tumor-initiating cell (TIC) phenotype in patients with PDAC and the relationship of this expression to patient outcomes.Experimental Design: Peripheral blood from 60 consecutive patients with PDAC undergoing surgical resection was obtained and processed using the Isolation by Size of Epithelial Tumor (ISET) method. Immunofluorescence was used to identify CTCs expressing cytokeratin, CD133, CD44, and ALDH.Results: Forty-seven patients (78%) had epithelial CTCs staining positive for pan-cytokeratin and at least one TIC marker. Forty-six patients (77%) had epithelial CTCs that labeled with antibodies to cytokeratin and ALDH. By separate analysis, 34 (57%) had cytokeratin-positive, CD133-positive, and CD44-positive (triple-positive) CTCs, whereas 40 (67%) had cytokeratin-positive, CD133-positive, CD44-negative CTCs. The remaining 13 patients did not have CTCs, as defined by cytokeratin expression. ALDH-positive CTCs and triple-positive CTCs were significantly associated with worse survival by univariate analysis, even when accounting for other significant prognostic factors (all, P ≤ 0.01). ALDH-positive CTCs, triple-positive CTCs, and dual cytokeratin- and CD133-positive CTCs were independent predictors of tumor recurrence by logistic regression analysis and associated with decreased disease-free survival (all, P ≤ 0.03).Conclusions: CTCs labeling with one or more markers of TICs are found in a majority of patients with PDAC and are independently predictive of decreased disease-free and overall survival. Clin Cancer Res; 23(11); 2681-90. ©2016 AACR.


Assuntos
Antígeno AC133/sangue , Adenocarcinoma/sangue , Aldeído Desidrogenase/sangue , Carcinoma Ductal Pancreático/sangue , Receptores de Hialuronatos/sangue , Queratinas/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico
15.
Stem Cell Rev Rep ; 13(2): 217-225, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27914035

RESUMO

In this paper we examined whether stem cells and factors responsible for their movement may serve as new biological markers of anxiety disorders. The study was carried out on a group of 30 patients diagnosed with panic disorder (examined before and after treatment), compared to 30 healthy individuals forming the control group. We examined the number of circulating HSCs (hematopoetic stem cells) (Lin-/CD45 +/CD34 +) and HSCs (Lin-/CD45 +/AC133 +), the number of circulating VSELs (very small embryonic-like stem cells) (Lin-/CD45-/CD34 +) and VSELs (Lin-/CD45-/AC133 +), as well as the concentration of complement components: C3a, C5a and C5b-9, SDF-1 (stromal derived factor) and S1P (sphingosine-1-phosphate). Significantly lower levels of HSCs (Lin-/CD45 +/AC133 +) have been demonstrated in the patient group compared to the control group both before and after treatment. The level of VSELs (Lin-/CD45-/CD133 +) was significantly lower in the patient group before treatment as compared to the patient group after treatment.The levels of factors responsible for stem cell movement were significantly lower in the patient group compared to the control group before and after treatment. It was concluded that the study of stem cells and factors associated with their movement can be useful in the diagnostics of panic disorder, as well as differentiating between psychotic and anxiety disorders.


Assuntos
Movimento Celular , Mobilização de Células-Tronco Hematopoéticas , Transtorno de Pânico/sangue , Células-Tronco de Sangue Periférico/metabolismo , Antígeno AC133/sangue , Adulto , Antígenos CD34/sangue , Transtornos de Ansiedade/sangue , Transtornos de Ansiedade/patologia , Contagem de Células , Quimiocina CXCL12/sangue , Proteínas do Sistema Complemento/metabolismo , Feminino , Citometria de Fluxo , Humanos , Antígenos Comuns de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/patologia , Células-Tronco de Sangue Periférico/patologia , Transtornos Psicóticos/sangue , Transtornos Psicóticos/patologia , Adulto Jovem
16.
Life Sci ; 157: 108-115, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27287679

RESUMO

AIMS: Brain damage at birth can cause lifelong neurodevelopmental deficits. Recently, stem cell therapies have been used in several fields of medicine. We previously reported that CD133(+) cells, endothelial progenitor cells derived from human umbilical cord blood, induce nerve extension in an ex vivo hypoxic-ischemic encephalopathy model. Here, we used an in vivo model to examine the effect of CD133(+) cells in neonatal hypoxic-ischemic encephalopathy. MAIN METHODS: Hypoxic-ischemic brain lesions were induced in neonatal severe combined immunodeficiency mice using the Rice-Vannucci method. CD133(+) cells were administered by intraperitoneal injection 24h after injury. KEY FINDINGS: Immunohistochemical analysis revealed that intraperitoneally transplanted CD133(+) cells migrate towards the brain 48h after injection. Moreover, in CD133(+) cell-treated animals, motor function improved and the brain was protected from the hypoxic-ischemic insult compared with untreated animals. SIGNIFICANCE: Our results suggest that CD133(+) cells derived from human umbilical cord blood have therapeutic potential in neonatal hypoxic-ischemic encephalopathy.


Assuntos
Antígeno AC133/sangue , Modelos Animais de Doenças , Sangue Fetal/citologia , Hipóxia-Isquemia Encefálica/sangue , Animais , Movimento Celular , Humanos , Hipóxia-Isquemia Encefálica/fisiopatologia , Camundongos , Atividade Motora
17.
Int Urol Nephrol ; 48(6): 891-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27068816

RESUMO

AIMS: Arteriovenous fistula (AVF) failure is one of the most important clinical problems in end-stage renal disease. Endothelial progenitor cells (EPCs) have a role on vascular angiogenesis and endothelialization. We aimed to investigate the association markers of EPCs on AVF maturation by measuring the surface expressions of CD34, CD309 and CD133 on the monocytes. METHODS: This prospective observational study was conducted in 54 voluntary patients with end-stage renal disease who were admitted for their first renal replacement therapy and were available for AVF creation. Venography was performed in all patients before AVF creation. Six patients were excluded due to inadequate veins after venographic imaging, and also seven patients were excluded due to postoperative thrombosis. The blood samples were analyzed a day before the fistula operation, and the expressions of CD34, CD133 and CD309 on the surface of monocytes were measured. RESULTS: Patients were divided into two groups after the evaluation of AVF maturation, as the mature group and the failure group. The CD309 expression level on the monocytes was 338.00 (35.00-479.00) in the mature group; however, it was 36.00 (5.50-237.00) (p 0.031) in the failure group. Multiple logistic regression analyses showed that both BMI and the mean fluorescence intensity level of CD309 expression on monocytes independently predicted AVF maturation. CONCLUSIONS: The presence of DM and increased BMI negatively correlated with AVF maturation. High intensity of CD309 expression on monocytes was observed in patients with successful AVF maturation.


Assuntos
Derivação Arteriovenosa Cirúrgica , Células Progenitoras Endoteliais/fisiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Monócitos/fisiologia , Diálise Renal , Antígeno AC133/sangue , Idoso , Antígenos CD34/sangue , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
18.
Tumour Biol ; 37(9): 11799-11804, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27034262

RESUMO

Cancer stem cells are responsible for the development, metastasis, recurrence, and drug resistance of cancer. More and more studies exhibited that the circulating CD133+ cells is a marker for the prognosis of various malignancies. Programmed cell death protein 5 (PDCD5) can promote apoptosis in different tumor cell types in response to various stimuli. However, the impact of PDCD5 on circulating CD133+ cells of gastric cancer patients remains unclear. In this study, we detected serum PDCD5 level in blood samples of the patients with gastric cancer by using ELISA. MTT assay, sphere assay, and wound healing assay were used to test the anti-tumor effects of rhPDCD5 on CD133+ cells in vitro. Lower serum levels of PDCD5 protein were identified in the gastric cancer patients that with CD133+ fraction more than 1.6 %. No difference between healthy controls and the gastric cancer patients that with CD133+ fraction less than 1.6 %. Serum PDCD5 was correlated with the favorable prognosis of patients with gastric cancer. In the last, we confirmed that rhPDCD5 could induce apoptosis, and inhibit the proliferation, colony formation, and mobility of CD133+ cells in vitro by suppressing MEK/ERK pathway. Serum PDCD5 could be considered as a potential drug for the gastric cancer patients with circulating CD133+ cells.


Assuntos
Antígeno AC133/sangue , Proteínas Reguladoras de Apoptose/sangue , Proteínas de Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , Neoplasias Gástricas/sangue , Idoso , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/farmacologia , Western Blotting , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/farmacologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Proteínas Recombinantes/farmacologia , Neoplasias Gástricas/patologia
19.
J Neurol Sci ; 362: 91-9, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944125

RESUMO

BACKGROUND AND PURPOSE: Statins are active in reducing plasma lipids, suppressing inflammation and promoting angiogenesis. Because angiogenesis is critical for the absorbance of subdural hematoma (SDH), we hypothesize that atorvastatin promotes angiogenesis to enhance hematoma absorption. METHODS: SDH was induced in adult Wistar rats and treated with 3mg/kg, 8mg/kg of atorvastatin, or vehicle saline daily for 7days. The treated rats were examined for the level of CD34+/CD133+ endothelial progenitor cells (EPCs) in the circulation by flow cytometry, hematoma volumes by magnetic resonance imaging (MRI), and changes in cognitive functions. We also examined angiogenesis in the hematoma wall by transmission electronic microscopy and immunohistochemistry for the expression of vascular endothelial growth factor (VEGF), matrix metalloprotease 9 (MMP 9) and angiopoietin. RESULTS: SDH volume was significantly reduced and neurological deficits improved in rats receiving the low dose atorvastatin compared to those receiving either the high dose of atorvastatin or saline. Consistent with these outcome measures, the low dose atorvastatin increased the expression of angiopoient-1 and VEGF and reduced MMP9 expression in the connective tissue of the SDH wall, resulting in an increased vascular density and enhanced vascular maturation. CONCLUSIONS: The low-dose atorvastatin is effective in reducing SDH and improving neurological deficits in a rat model, primarily by promoting angiogenesis and vascular maturation.


Assuntos
Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Hematoma Subdural/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Antígeno AC133/sangue , Análise de Variância , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Animais , Antígenos CD34/sangue , Atorvastatina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/ultraestrutura , Regulação da Expressão Gênica/efeitos dos fármacos , Hematoma Subdural/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Microscopia Eletrônica de Transmissão , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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