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1.
Plast Reconstr Surg ; 145(2): 433-443, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985637

RESUMO

BACKGROUND: This study explored the effect of a single local intraosseous application of a small dose of simvastatin on the wound healing process in type 1 diabetic rats and related mechanisms. METHODS: The authors chose the streptozotocin-induced type 1 diabetic rat to establish a full-thickness dermal wound using a 12-mm-diameter sterile disposable punch. The rats (n = 32) were divided randomly into four groups: (1) normal control rats, (2) type 1 diabetic rats with intraosseous injection of hydrogel vehicle, (3) type 1 diabetic rats with intraosseous injection of simvastatin (0.5 mg), and (4) type 1 diabetic rats with intragastric administration of simvastatin (20 mg/kg per day). Wound closure was followed by digital planimetry. Mobilization of endothelial progenitor cells into the circulatory system was studied using fluorescence-activated cell sorting. Neovascularization was analyzed with immunofluorescence histochemical staining. The relative levels of adiponectin and stromal cell-derived factor 1 (SDF-1) in serum, bone, and wound tissues were examined by enzyme-linked immunosorbent assay and Western blot. RESULTS: Diabetic rats exhibited impaired wound healing. Intraosseous administration of simvastatin accelerated wound healing beginning at day 4, and angiogenesis was more obvious than in the control group. Enzyme-linked immunosorbent assay revealed that adiponectin concentrations in the diabetic rats with intraosseous injection of hydrogel vehicle plus simvastatin 0.5-mg group were significantly higher compared with the diabetic rats with intraosseous injection of hydrogel vehicle group beginning at day 4. Intraosseous administration of simvastatin decreased the expression of adiponectin and SDF-1 in bone tissue but enhanced the expression of adiponectin in wounded skin. CONCLUSIONS: A single local intraosseous application of simvastatin promotes wound healing in type 1 diabetic rat. The underlying mechanisms may be attributed to the regulation of the adiponectin/SDF-1 pathway, which plays a pivotal role in endothelial progenitor cell mobilization and angiogenesis.


Assuntos
Indutores da Angiogênese/farmacocinética , Células Progenitoras Endoteliais/efeitos dos fármacos , Sinvastatina/farmacologia , Cicatrização/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Combinação de Medicamentos , Hidrogéis , Injeções , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Poloxâmero/administração & dosagem , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Pele/metabolismo
2.
Med Sci Monit ; 25: 7675-7683, 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31606730

RESUMO

BACKGROUND Endothelial progenitor cells (EPCs) play an important role in therapeutic angiogenesis. Besides, resveratrol (RSV) exerts many pharmacological functions in regulation of cell function. Furthermore, microRNAs (miRNAs) have been considered to be of great significance in biological process. In this study, we aimed to investigate the effect of RSV on EPCs and its potential mechanism that involved in recanalization of venous thrombosis. MATERIAL AND METHODS EPCs were treated with RSV, and angiogenic functions was evaluated by tube formation and migration assays. miR-542-3p expression level in EPCs was assessed and exogenously modified. Bioinformatic analysis was applied to detect the potential target of miR-542-3p. Effects of RSV treatment in vivo venous thrombosis rat model were evaluated. RESULTS RSV enhanced angiogenic function of EPCs and decreased expression of miR-542-3p. Dual luciferase reporter gene and western blot results confirmed angiopoietin-2 (ANGPT2) was a direct target of miR-542-3p. It was found that inhibition of miR-542-3p contributed to angiogenesis of EPCs and elevated ANGPT2 protein level. Finally, in a rat model of venous thrombosis, RSV-treated EPCs promoted recanalization of thrombi. CONCLUSIONS We demonstrated that RSV can contribute to progenitor cells angiogenesis via miR-542-3p by targeting ANGPT2, subsequently enhanced recanalization of thrombi.


Assuntos
Angiopoietina-2/metabolismo , Células Progenitoras Endoteliais/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Resveratrol/uso terapêutico , Trombose Venosa/tratamento farmacológico , Trombose Venosa/genética , Adulto , Animais , Sequência de Bases , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Humanos , Masculino , MicroRNAs/genética , Ratos Nus , Resveratrol/farmacologia , Trombose Venosa/patologia
3.
Biomed Pharmacother ; 118: 109296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545254

RESUMO

BACKGROUND: This study tested the hypothesis that intramuscular injections of erythropoietin (EPO) and endothelial progenitor cells (EPC) to critical limb ischemia (CLI; primary treatment site) could also improve heart function in rat after acute myocardial infarction (AMI; remote ischemic organ). METHOD: Adult-male SD rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI-AMI), group 3 [CLI-AMI + EPO (10 mg/kg)], group 4 [CLI-AMI + EPCs (1.2 × 106)] and group 5 (CLI-AMI + EPCs + EPO). RESULTS: By day 21 (end of study period), 2-D echo and Laser doppler showed that left-ventricular injection fraction (LVEF) and the ratio of ischemic to normal blood flow were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but not different in the latter two groups (all p < 0.0001). Flow cytometry and ELISA demonstrated that circulating angiogenesis factors were significantly progressively increased from groups 1 to 5 (all p < 0.001). The number of small vessels and protein (CD31/eNOS)/cellular (vWF) expressions reflecting integrity of endothelium exhibited an identical pattern to LVEF whereas protein (VEGF/SDF-1α)/cellular (VEGF) expressions were significantly progressively increased from groups 1 to 5 in quadriceps and heart tissues (all p < 0.0001). Protein expressions of apoptotic (Bax/caspase-3/PARP)/inflammatory (MMP-9) and microscopic findings of ischemic/fibrotic/collagen-deposition areas and DNA-damage marker (γ-H2AX+) were lowest in group 1 and significantly progressively decreased from groups 2 to 5 in quadriceps and heart tissues (all p < 0.0001). CONCLUSIONS: Direct injection of EPO-EPC into CLI effectively restored blood flow in the CLI area and also preserved remote heart function.


Assuntos
Células Progenitoras Endoteliais/transplante , Eritropoetina/farmacologia , Ventrículos do Coração/fisiopatologia , Isquemia/terapia , Infarto do Miocárdio/fisiopatologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Colágeno/metabolismo , Dano ao DNA , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Masculino , Miocárdio/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos
4.
Mar Drugs ; 17(7)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277207

RESUMO

The purpose of the present study is to improve the endothelial progenitor cells (EPC) activation, proliferation, and angiogenesis using enzyme-aided extraction of fucoidan by amyloglucosidase (EAEF-AMG). Enzyme-aided extraction of fucoidan by AMG (EAEF-AMG) significantly increased EPC proliferation by reducing the reactive oxygen species (ROS) and decreasing apoptosis. Notably, EAEF-AMG treated EPCs repressed the colocalization of TSC2/LAMP1 and promoted perinuclear localization of mTOR/LAMP1 and mTOR/Rheb. Moreover, EAEF-AMG enhanced EPC functionalities, including tube formation, cell migration, and wound healing via regulation of AKT/Rheb signaling. Our data provided cell priming protocols to enhance therapeutic applications of EPCs using bioactive compounds for the treatment of CVD.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Glucana 1,4-alfa-Glucosidase/metabolismo , Polissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Cicatrização/efeitos dos fármacos
5.
Molecules ; 24(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261859

RESUMO

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is recognized as a critical regulator in physiological and pathophysiological processes of atherosclerosis (AS). However, the underlying mechanism remains unclear. As the precursor cells of endothelial cells (ECs), endothelial progenitor cells (EPCs) can prevent AS development through repairing endothelial monolayer impaired by proatherogenic factors. The present study investigated the effects of S1P on the biological features of mouse bone marrow-derived EPCs and the underlying mechanism. The results showed that S1P improved cell viability, adhesion, and nitric oxide (NO) release of EPCs in a bell-shaped manner, and migration and tube formation dose-dependently. The aforementioned beneficial effects of S1P on EPCs could be inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor of LY294002 and nitric oxide synthase (NOS) inhibitor of N'-nitro-L-arginine-methyl ester hydrochloride (L-NAME). The inhibitor of LY294002 inhibited S1P-stimulated activation of phosphorylated protein kinase B (AKT) (p-AKT) and endothelial nitric oxide synthase (eNOS) (p-eNOS), and down-regulated the level of eNOS significantly. The results suggest that S1P improves the biological features of EPCs partially through PI3K/AKT/eNOS/NO signaling pathway.


Assuntos
Células Progenitoras Endoteliais/citologia , Lisofosfolipídeos/farmacologia , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromonas/farmacologia , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Morfolinas/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/farmacologia
6.
J Orthop Surg Res ; 14(1): 226, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324193

RESUMO

BACKGROUND: Avascular necrosis of the femoral head (ANFH) is a severe complication after high-dose glucocorticoid (GC) administration. The pathogenesis of GC-induced ANFH remains unclear. Though the important role of endothelial progenitor cells (EPCs) in the progression of GC-induced ANFH has been noticed, the effects of GCs on EPCs and the underlying mechanism still need further study. METHODS: Circulating EPCs were obtained from the peripheral blood of ANFH patients and healthy controls by Ficoll-density gradient centrifugation. CD133+CD34+ cells with DiI-Ac-LDL uptake and FITC-UEA-1 binding were considered as EPCs. Number and functions of EPCs were analyzed by flow cytometry, chemotaxis assay, and tube formation assay. EPCs from healthy controls were also treated by different concentrations of methylprednisolone and prednisolone in vitro, and cell growth and angiogenic function were evaluated. Expression of CXCR7 and its downstream Akt/GSK-3ß/Fyn pathway were also analyzed by western blots after cells treated by methylprednisolone in vitro. RESULTS: The number and functions of EPCs in patients with GC-induced ANFH were significantly decreased. In vitro study showed for the first time that except extremely high concentrations, low to medium concentrations of GCs did not have significant effects on EPCs' growth. Methylprednisolone and prednisolone both inhibited angiogenesis of EPCs even at low concentrations. Mechanism studies found CXCR7 was downregulated in EPCs after methylprednisolone treatment in vitro. Expression and phosphorylation of Akt and GSK-3ß were also decreased with an upregulation of Fyn expression after steroid treatment. CONCLUSIONS: Our study showed that GC-induced ANFH patients have reduced the number and impaired functions of circulating EPCs. GCs did not show a significant effect on the growth of EPCs in vitro except extremely high concentrations of GCs. However, GCs significantly impaired EPC angiogenic function in vitro, even at low concentrations. Our study also suggested that downregulation of CXCR7 and its downstream Akt/GSK-3ß/Fyn pathway in EPCs might be a novel mechanism of how GCs suppress EPCs' angiogenesis.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Necrose da Cabeça do Fêmur/sangue , Necrose da Cabeça do Fêmur/induzido quimicamente , Glucocorticoides/efeitos adversos , Adulto , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Necrose da Cabeça do Fêmur/diagnóstico , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
7.
J Steroid Biochem Mol Biol ; 193: 105425, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302220

RESUMO

Vitamin D (vit-D) supplementation can improve endothelial cell function in type 2 diabetes mellitus patients with vit-D insufficiency or deficiency. In the present study, we aimed to compare the expression profiles of circRNAs, lncRNAs, miRNAs, and mRNAs between 1,25-(OH)2D3-treated endothelial progenitor cells (EPCs) and control cells, and to further construct the 1,25-(OH)2D3-regulated ceRNA networks in EPCs. RNA sequencing was performed on the 1,25-(OH)2D3-treated EPCs and control cells derived from the bone marrow (BM). Bioinformatics analyses were performed to identify differentially expressed (DE) microRNAs (miRNAs), circular RNAs (circRNAs), mRNAs, and long non-coding RNAs (lncRNAs). Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predict the function of genes. Competing endogenous RNA (ceRNA) networks were constructed with Cytoscape software. 1,25-(OH)2D3 application induced changes in the expression profiles of 1791 mRNAs, 2726 lncRNAs, 205 circRNAs, and 45 miRNAs in EPCs treated with high levels of glucose. These DE RNAs were associated with MMP and GTPase activities, specific signaling pathways, and components of actin, extracellular matrix, or adherens junction. DE circRNAs, which functioned independently of their linear host genes, interacted with miRNAs to serve as miRNA sponges in complex ceRNA networks. The data indicated that circRNAs and lncRNAs comprised ceRNAs to sponge effects of miRNAs on the expressions of mRNAs following 1,25-(OH)2D3 application in EPCs. 1,25-(OH)2D3 improved the function of EPCs via associated ceRNA interaction networks in diabetes patients.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , RNA/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Células Progenitoras Endoteliais/metabolismo , Ontologia Genética , Masculino , Ratos Sprague-Dawley , Análise de Sequência de RNA
8.
Diabetes Metab Syndr ; 13(2): 1123-1129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336454

RESUMO

Endothelial progenitor cells are recognized as the potential targets for the revascularization and angiogenesis because of their ability to get themselves transformed into mature endothelial cells. Underlying pathophysiology in diabetes mellitus leads to decrease in circulatory endothelial progenitor cells, resulting in diabetic macro-vascular and micro-vascular complications. Peroxisome Proliferator Activated Receptor (PPAR) gamma analogues serves as an effective therapy for controlling blood sugar levels and preventing its complications. Reports of clinical trials and meta-analysis of clinical trial suggests the beneficial aspects of PPAR gamma therapy in increasing the number and function of circulating endothelial progenitor cells. This review highlights the pleotropic effect of PPAR gamma analogs, apart from their antidiabetic action via reduction of oxidative stress, increasing expression of eNOS, reducing level of miR 22, miR 222 levels and positive modulation of rapamycin/Protein kinase B/phosphoinoside3-kinase pathways, preventing the early apoptosis, enhanced mobility proliferation and transformation into mature endothelial cells. PPAR gamma therapy in diabetes regulates endothelial progenitor cells, reduces complications of diabetes like retinopathy, nephropathy, neuropathy, cardiomyopathy, deep vein thrombosis, and maintains the healthy vasculature.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , PPAR gama/agonistas , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos
9.
Med Sci Monit ; 25: 5572-5579, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31350844

RESUMO

BACKGROUND The aim of this study was to investigate the effect of using osteoprotegerin (OPG) to treat bone defects mediated by endothelial progenitor cell (EPC) recruitment and migration through the CXCR4 signaling pathway. MATERIAL AND METHODS The EPCs extracted from human peripheral blood were cultured in vitro and the expression of CXCR4 and its downstream p-AKT was monitored by the Western blot analysis after OPG treatment. Using the scratch wound healing test and Transwell assay, we assessed the variables influencing the effect of OPG on EPCs after pre-treatment with CXCR4 blocker (AMD3100) and PI3K blocker (Ly294002). After 4 weeks, the bone defect repair condition was estimated via micro-CT and staining with HE and Masson trichrome. Then, immunofluorescence staining was performed to assess angiogenesis in bone defects, while the expression of EPC marker and vascular endothelial growth factor receptor 2 (VEGFR2) was detected by immunohistochemical staining. RESULTS The EPCs treated with OPG had increased levels of CXCR4 and p-AKT. Moreover, the difference in EPC levels among groups in the scratch wound healing experiment and migration experiment indicated that the OPG treatment promoted cell migration and AMD3100 and LY294002 inhibited the function of OPG. In addition, OPG promoted angiogenesis and repair of bone defect in rats, and these effects were abolished by AMD3100 and LY294002 administration. CONCLUSIONS OPG enhanced the proliferation and migration of EPCs through the CXCR4 pathway and promoted angiogenesis and bone formation at bone defect sites.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Osteoprotegerina/farmacologia , Receptores CXCR4/metabolismo , Indutores da Angiogênese/metabolismo , Animais , Regeneração Óssea/genética , Regeneração Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/metabolismo , Células Progenitoras Endoteliais/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Neovascularização Patológica/metabolismo , Osteoprotegerina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Respir Res ; 20(1): 131, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242908

RESUMO

BACKGROUND: Patients with acute lung injury (ALI) have increased levels of pro-inflammatory mediators, which impair endothelial progenitor cell (EPC) function. Increasing the number of EPC and alleviating EPC dysfunction induced by pro-inflammatory mediators play important roles in suppressing ALI development. Because the high density lipoprotein reverse-D-4F (Rev-D4F) improves EPC function, we hypothesized that it might repair lipopolysaccharide (LPS)-induced lung damage by improving EPC numbers and function in an LPS-induced ALI mouse model. METHODS: LPS was used to induce ALI in mice, and then the mice received intraperitoneal injections of Rev-D4F. Immunohistochemical staining, flow cytometry, MTT, transwell, and western blotting were used to assess the effect of Rev-D4F on repairment of lung impairment, and improvement of EPC numbers and function, as well as the signaling pathways involved. RESULTS: Rev-D4F inhibits LPS-induced pulmonary edema and decreases plasma levels of the pro-inflammatory mediators TNF-α and ET-1 in ALI mice. Rev-D4F inhibited infiltration of red and white blood cells into the interstitial space, reduced lung injury-induced inflammation, and restored injured pulmonary capillary endothelial cells. In addition, Rev-D4F increased numbers of circulating EPC, stimulated EPC differentiation, and improved EPC function impaired by LPS. Rev-D4F also acted via a PI3-kinase-dependent mechanism to restore levels of phospho-AKT, eNOS, and phospho-eNOS suppressed by LPS. CONCLUSIONS: These findings indicate that Rev-D4F has an important vasculoprotective role in ALI by improving the EPC numbers and functions, and Rev-D4F reverses LPS-induced EPC dysfuncion partially through PI3K/AKT/eNOS signaling pathway.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Peptídeos/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Animais , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia
11.
Intern Med ; 58(19): 2773-2781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243210

RESUMO

Objective Circulating endothelial progenitor cells (EPCs) are regulated by stromal cell-derived factor-1alpha (SDF-1α) and are reduced in type 2 diabetes mellitus (DM). SDF-1α is a substrate of dipeptidyl-peptidase-4 (DPP-4), so we investigated whether or not DPP-4-inhibitors modulate EPC levels in type 2 DM patients with coronary artery disease (CAD). Methods Thirty patients with CAD and type 2 DM treated using an ordinary regimen were enrolled. EPC and SDF-1α levels were compared between those receiving additional 24-week treatment with a DPP-4-inhibitor (n=11) and no additional treatment (n=19). We determined the HbA1c, 1.5-Anhydro-D-glucitol (1,5-AG), coronary flow reserve (CFR), brain natriuretic peptide (BNP), E/e', and circulating EPC proportion and SDF-1α levels at baseline and the end of follow-up. The CFR was assessed using a dual-sensor-equipped guidewire. The primary endpoints were changes in the EPC count, SDF-1α levels, and CFR from baseline to the end of follow-up. The secondary endpoints were changes in the HbA1c and 1,5-AG, which are useful clinical markers of postprandial hyperglycemia, as well as the BNP and E/e'. Results After the 6-month follow-up, compared with ordinary regimen subjects, the patients receiving a DPP-4-inhibitor showed no significant increase in the EPC proportion (-0.01±0.50 vs. 0.02±0.77%, p=0.87), SDF-1α level (-600.4±653.6 vs. -283.2±543.1 pg/mL, p=0.18), or CFR (0.0±0.2 vs. 0.1±0.6, p=0.20), whereas both the 1.5-AG level (2.4±4.6 vs. -0.7±2.5 µg/dL, p=0.07) and HbA1c (-0.8±1.8 vs. 0.0±0.7%, p=0.02) were improved. There were no significant differences between the two groups in changes in the BNP and E/e'. Conclusion DPP-4 inhibition with sitagliptin did not increase or decrease the EPC proportion, SDF-1α level, or CFR, although the glycemic control was improved.


Assuntos
Quimiocina CXCL12/sangue , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Fosfato de Sitagliptina/uso terapêutico , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/sangue , Dipeptidil Peptidase 4/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Fatores de Tempo
12.
Oxid Med Cell Longev ; 2019: 6492029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223423

RESUMO

Cardiovascular diseases (CVDs) are a major cause of death worldwide. Due to the prevalence of many side effects and incomplete recovery from pharmacotherapies, stem cell therapy is being targeted for the treatment of CVDs. Among the different types of stem cells, endothelial progenitor cells (EPCs) have great potential. However, cellular replicative senescence decreases the proliferation, migration, and overall function of EPCs. Sirtuin 1 (SIRT1) has been mainly studied in the mammalian aging process. MHY2233 is a potent synthetic SIRT1 activator and a novel antiaging compound. We found that MHY2233 increased the expression of SIRT1, and its deacetylase activity thereby decreased expression of the cellular senescence biomarkers, p53, p16, and p21. In addition, MHY2233 decreased senescence-associated beta-galactosidase- (SA-ß-gal-) positive cells and senescence-associated secretory phenotypes (SASPs), such as the secretion of interleukin- (IL-) 6, IL-8, IL-1α, and IL-1ß. MHY2233 treatment protected senescent EPCs from oxidative stress by decreasing cellular reactive oxygen species (ROS) levels, thus enhancing cell survival and function. The angiogenesis, proliferation, and migration of senescent EPCs were enhanced by MHY2233 treatment. Thus, MHY2233 reduces replicative and oxidative stress-induced senescence in EPCs. Therefore, this novel antiaging compound MHY2233 might be considered a potent therapeutic agent for the treatment of age-associated CVDs.


Assuntos
Benzoxazóis/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Sirtuína 1/metabolismo , Senescência Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Sangue Fetal/citologia , Sangue Fetal/diagnóstico por imagem , Sangue Fetal/metabolismo , Humanos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos
13.
Radiat Res ; 192(1): 53-62, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31081743

RESUMO

Acute high-dose radiation injury damages the bone marrow hematopoietic stem and progenitor cell compartment. This damage compromises the functional ability of the bone marrow to produce mature blood cells and results in an increased risk of death due to hematopoietic complications. Past work has shown that the bone marrow endothelium provides critical cues, which promote hematopoietic stem cell regeneration after injury. Additionally, transfusion of endothelial cells after radiation injury has been shown to promote recovery of both the bone marrow vasculature and hematopoietic systems. In this work, we examined the regenerative capacity of intravenous infusion of umbilical cord-blood derived endothelial progenitor cells (EPCs) since this is a cell source which is easy to obtain, expand and cryopreserve. We show that pre-treatment with the Wnt-antagonist Dickkopf1 (Dkk1) augments EPC regenerative function in an allogeneic mouse transplant model. Here, hematopoietic recovery was assessed in Balb/c mice after 5 Gy total-body irradiation and transplantation with C57/BL6-derived EPCs either with or without Dkk1 pre-treatment. The Dkk1-treated EPC group had significantly faster recovery of peripheral white blood cells, total bone marrow cellularity, bone marrow progenitors and BM endothelial cells compared to EPC treatment alone or saline controls. Importantly, after an LD50/30 dose of 8 Gy in the Balb/c mouse, Dkk1-treated EPCs were able to rescue 100% of irradiated mice versus 80% in the EPC control group and only 33% in the saline-treated group. To understand how Dkk1 induces regenerative function in the EPCs, we screened for pro-regenerative factors secreted by the EPC in response to Dkk1. Dkk1-treated EPCs were observed to secrete high levels of the anti-fibrotic protein follistatin as well as several proteins known to promote regeneration including EGF, VEGF and G-CSF. This work demonstrates the potential for Dkk1-treated EPCs as a rescue therapeutic for victims of acute radiation injury.


Assuntos
Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Animais , Células Progenitoras Endoteliais/efeitos da radiação , Feminino , Hematopoese/efeitos da radiação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Regeneração/efeitos dos fármacos , Regeneração/efeitos da radiação
14.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 101-106, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078159

RESUMO

Endothelial progenitor cells (EPCs) improve neovascularization and endothelium regeneration. Transplantation with EPCs is a therapeutic strategy for the treatment of ischemic diseases. However, the transplanted EPCs are susceptible to adverse environments such as hypoxia, inflammation and oxidative stress. Oxidative stress-induced apoptosis of transplanted EPCs greatly reduces their therapeutic efficacy. Lipopolysaccharide (LPS) is a highly immunogenic antigen. Recent findings suggest that low dose of LPS pretreatment has protective effect against apoptosis. In this study, the role of LPS in apoptosis of EPCs was investigated. Pretreatment with 1µg/ml LPS prevented oxidative stress-induced EPCs apoptosis and ROS generation, which effects were abolished by TAK-242, a specific TLR4 antagonist. Further investigation of the mechanisms demonstrated that the activation was mediated by TLR4, and that PI3K/Akt/ NF-κB p65 signaling pathway may play a critical role in the process.


Assuntos
Apoptose/efeitos dos fármacos , Células Progenitoras Endoteliais/patologia , Lipopolissacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Células Progenitoras Endoteliais/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
15.
Phytomedicine ; 61: 152850, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035054

RESUMO

BACKGROUD: Endothelial progenitor cells (EPCs) have been characterized as one of the key effectors of endothelial healing. The effect of Danhong injection (DHI), the most widely prescribed Chinese medicine for coronary heart disease (CHD), on EPCs mobilization remains unclear. PURPOSE: We aimed to assess the effect of DHI on EPCs mobilization to repair percutaneous coronary intervention (PCI) induced vascular injury, and to investigate the characteristics and potential mechanism of DHI on EPCs mobilization. METHOD: Forty-two patients with CHD underwent PCI and received stent implantation were enrolled in a Phase II clinical trials. All patients received routine western medical treatment after PCI, patients of DHI group received DHI in addition. The levels of CECs, cytokines (vWF, IL-6, CRP) and EPCs were analyzed at baseline, post-PCI and after treatment. To investigate the characteristics of DHI on EPCs mobilization, 12 healthy volunteers received intravenous infusion of DHI once and the other 12 received for 7 days. EPCs enumeration were done at a series of time points. At last we tested the effect of DHI and three chemical constituents of DHI (danshensu; lithospermic acid, LA; salvianolic acid D, SaD) on EPCs level and expression of Akt, eNOS and MMP-9 in bone marrow cells of myocardial infarction (MI) mice. RESULTS: In the DHI group the angina symptoms were improved, the levels of cytokines and CECs were reduced; while EPCs population was increased after treatment. In the phase I clinical trials, EPCs counts reached a plateau phase in 9 h and maintained for more than 10 h after a single dose. After continuous administration, EPCs levels plateaued on the 3rd or 4th day, and maintain till 1 day after the withdrawal, then its levels gradually declined. DHI treatment induced a timely dependent mobilization of EPCs. DHI promoted EPCs mobilization via upregulating the expression of Akt, eNOS and MMP-9 in BM. LA and SaD have played a valuable role in EPCs mobilization. CONCLUSION: These initial results demonstrated that DHI is effective in alleviating endothelial injury and promoting endothelial repair through enhancing EPCs mobilization and revealed the effect feature and possible mechanisms of DHI in mobilizing EPCs.


Assuntos
Fármacos Cardiovasculares/farmacologia , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/cirurgia , Medicamentos de Ervas Chinesas/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Endotélio Vascular/lesões , Idoso , Animais , Fármacos Cardiovasculares/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Células Progenitoras Endoteliais/fisiologia , Feminino , Humanos , Injeções , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Intervenção Coronária Percutânea/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/etiologia
16.
PLoS One ; 14(3): e0205477, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889182

RESUMO

Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Isquemia/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Obesidade/tratamento farmacológico , Regeneração/efeitos dos fármacos , Triazóis/farmacologia , Adulto , Animais , Dieta/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Voluntários Saudáveis , Humanos , Isquemia/etiologia , Isquemia/patologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/metabolismo , Adulto Jovem
17.
J Vasc Res ; 56(1): 17-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30879014

RESUMO

Vitamin D has an important protective effect on chronic inflammatory disease. Angiotensin II (AngII) triggers vascular damage and plays a key role in vascular diseases via several mechanisms, including inflammation. Conversely, vitamin D has been shown to have an important protective effect on chronic inflammation. There is evidence showing that vitamin D can reverse the effects of AngII, but the molecular mechanisms by which this occurs are not known. Our results demonstrate that vitamin D improved the viability, migration ability, and tube formation of AngII-pretreated endothelial progenitor cells (EPCs) and inhibited the apoptosis of EPCs induced by AngII. Vitamin D also reversed reactive oxygen species production, vascular inflammatory cytokine generation, and nuclear factor kappa-B activation in EPCs induced by AngII. Furthermore, EPC pretreatment with GW9662 (the antagonist for PPAR-γ) or siHO-1 decreased the protective effect of vitamin D on AngII-induced EPC injury. Overall, our data indicate that vitamin D ameliorated AngII-induced abnormal EPC injury by decreasing oxidative stress and inflammatory cytokine levels. These findings also suggest that vitamin D protected EPCs from AngII-induced vascular injury via the activation of the PPAR-γ/HO-1 signaling pathway.


Assuntos
Angiotensina II/toxicidade , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , PPAR gama/metabolismo , Vitamina D/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Citoproteção , Células Progenitoras Endoteliais/enzimologia , Células Progenitoras Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
18.
Int J Mol Med ; 43(5): 2187-2198, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896786

RESUMO

Metformin serves an important role in improving the functions of endothelial progenitor cells (EPCs). MicroRNAs (miRNAs), small non­coding RNAs, have been investigated as significant regulators of EPC vascular functions. The present study investigated the molecular crosstalk between metformin and miRNA­130a (miR­130a) in the functions of EPCs exposed to palmitic acid (PA). Isolated EPCs were treated with metformin, PA, and metformin + PA, respectively. Cell Counting Kit­8, Transwell and Matrigel assays were performed to detect the proliferation, migration and tube formation ability of EPCs following different treatments. The expression of miR­130a, phosphatase and tensin homolog (PTEN) and phosphorylated­AKT was analyzed by reverse transcription­quantitative polymerase chain reaction and western blotting. The specific mechanism underlying the function of metformin in EPCs was further elucidated by transfecting miR­130a mimics and inhibitor to overexpress and inhibit the expression of miR­130a in EPCs, respectively. EPCs exhibited impaired functions of proliferation (P<0.01 compared with the control), migration (P<0.01 compared with the control) and tube formation (P<0.01 compared with the control) following treatment with PA, and the expression levels of miR­130a and PTEN were decreased and increased, respectively. However, the presence of metformin, or the overexpression of miR­130a using miR­130a mimic alleviated the impairment of angiogenesis and proliferation, decreased the expression of PTEN and activated the phosphoinositide­3 kinase/AKT pathway in EPCs exposed to PA. By contrast, downregulating the expression of miR­130a with a miR­130a inhibitor reversed the metformin­mediated protection. These results demonstrate the beneficial effect of miR­130a/PTEN on EPC functions, which can be regulated by metformin. The effects of metformin on improving PA­induced EPC dysfunction are mediated by miR­130a and PTEN, which may assist in the prevention and/or treatment of diabetic vascular disease.


Assuntos
Células Progenitoras Endoteliais/patologia , Metformina/farmacologia , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Ácido Palmítico/toxicidade , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citoproteção/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Masculino , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley
19.
Acta Diabetol ; 56(7): 785-795, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30859314

RESUMO

AIMS: Circulating endothelial progenitor cells (EPCs) play a key role in maintaining endothelial function. Dysfunction of EPCs is associated with the cardiovascular complication of diabetes. The purpose of this study is to investigate the direct effects of hyperinsulinemia on EPCs and the underlying mechanisms. METHODS: EPCs isolated from healthy adults were cultured with various concentrations of insulin (control group, without insulin; physiological insulin group, 10 nM insulin and hyperinsulinemia group, 100 nM insulin) with or without phosphatidylinositol-3-kinase (PI3-K) inhibitor (LY294002, 5 µM), endothelial nitric oxide synthase (eNOS) inhibitor (L-NG-nitro-arginine methyl ester (L-NAME), 100 µM), sodium nitroprusside (SNP, 25 µM), p38 mitogen-activated protein kinase(MAPK) inhibitor (SB203580, 5 µM) or extracellular signal-regulated kinases (ERK) 1/2 inhibitor (PD98059, 10 µM). Proliferation, tube formation, and apoptosis of EPCs were determined. Expressions of eNOS, PI3-K, protein kinase B (Akt), p38 MAPK, and ERK 1/2 were assessed. RESULTS: Hyperinsulinemia caused a significant decrease in proliferation and tube formation abilities than control group. Hyperinsulinemia increased apoptosis rate of EPCs than control group. Furthermore, hyperinsulinemia downregulated phosphorylation of eNOS, PI3-K and Akt, and upregulated phosphorylation of p38 MAPK and ERK. SNP could restore impaired tube formation induced by hyperinsulinemia. P38 MAPK inhibitor but not ERK inhibitor could decrease apoptosis induced by hyperinsulinemia. CONCLUSION: Hyperinsulinemia impaired EPCs' tube formation ability by downregulation of PI-3K/Akt/eNOS pathway. Hyperinsulinemia induced apoptosis of EPCs via upregulation of p38 MAPK.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/fisiologia , Hiperinsulinismo/fisiopatologia , Insulina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Adulto , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Progenitoras Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/patologia , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos
20.
Nanomedicine ; 18: 135-145, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30849548

RESUMO

We report here the preparation, physico-chemical characterization, and biological evaluation of a new liposome formulation as a tool for tumor angiogenesis inhibition. Liposomes are loaded with sunitinib, a tyrosine kinase inhibitor, and decorated with cyclo-aminoprolineRGD units (cAmpRGD), efficient and selective ligands for integrin αVß3. The RGD units play multiple roles since they target the nanovehicles at the integrin αVß3-overexpressing cells (e.g. activated endothelial cells), favor their active cell internalization, providing drug accumulation in the cytoplasm, and likely take part in the angiogenesis inhibition by interfering in the αVß3-VEGFR2 cross-talk. Both in vitro and in vivo studies show a better efficacy of this integrated antiangiogenic tool with respect to the free sunitinib and untargeted sunitinib-loaded liposomes. This system could allow a lower administration of the drug and, by increasing the vector specificity, reduce side-effects in a prolonged antiangiogenic therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/química , Prolina/análogos & derivados , Sunitinibe/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Animais , Adesão Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Humanos , Recém-Nascido , Lipídeos/química , Lipossomos , Camundongos , Nanopartículas/química , Neovascularização Patológica/tratamento farmacológico , Oligopeptídeos/síntese química , Fosfolipídeos/síntese química , Fosfolipídeos/química , Fosforilação/efeitos dos fármacos , Prolina/síntese química , Prolina/química , Sunitinibe/química , Sunitinibe/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vitronectina/metabolismo
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