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1.
J Diabetes Res ; 2021: 6626627, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557552

RESUMO

BACKGROUND: Circulating endothelial progenitor cells (EPCs) play important roles in vascular repair. However, the mechanisms of high-glucose- (HG-) induced cord blood EPC senescence and the role of B2 receptor (B2R) remain unknown. METHODS: Cord blood samples from 26 patients with gestational diabetes mellitus (GDM) and samples from 26 healthy controls were collected. B2R expression on circulating CD34+ cells of cord blood mononuclear cells (CBMCs) was detected using flow cytometry. The plasma concentrations of 8-isoprostaglandin F2α (8-iso-PGF2α) and nitric oxide (NO) were measured. EPCs were treated with HG (40 mM) alone or with bradykinin (BK) (1 nM). The B2R and eNOS small interfering RNAs (siRNAs) and the PI3K antagonist LY294002 were added to block B2R, eNOS, and PI3K separately. To determine the number of senescent cells, senescence-associated ß-galactosidase (SA-ß-gal) staining was performed. The level of mitochondrial reactive oxygen species (ROS) in EPCs was assessed by Mito-Sox staining. Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assays. Mitochondrial DNA (mtDNA) copy number and the relative length of telomeres were detected by real time-PCR. The distribution of human telomerase reverse transcriptase (hTERT) in the nucleus, cytosol, and mitochondria of EPCs was detected by immunofluorescence. The expression of B2R, p16, p21, p53, P-Ser473AKT, T-AKT, eNOS, and hTERT was demonstrated by Western blot. RESULTS: B2R expression on circulating CD34+ cells of CBMCs was significantly reduced in patients with GDM compared to healthy controls. Furthermore, B2R expression on circulating CD34+ cells of CBMCs was inversely correlated with plasma 8-iso-PGF2α concentrations and positively correlated with plasma NO levels. BK treatment decreased EPC senescence and ROS generation. Furthermore, BK treatment of HG-exposed cells led to elevated P-Ser473AKT and eNOS protein expression compared with HG treatment alone. BK reduced hTERT translocation in HG-induced senescent EPCs. B2R siRNA, eNOS siRNA, and antagonist of the PI3K signalling pathway blocked the protective effects of BK. CONCLUSION: BK, acting through PI3K-AKT-eNOS signalling pathways, reduced hTERT translocation, increased the relative length of telomeres while reducing mtDNA copy number, and finally protected against EPC senescence induced by HG.


Assuntos
Bradicinina/farmacologia , Senescência Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Receptor B2 da Bradicinina/metabolismo , Estudos de Casos e Controles , Células Cultivadas , DNA Mitocondrial/genética , Diabetes Gestacional , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Células Progenitoras Endoteliais/citologia , Feminino , Sangue Fetal , Dosagem de Genes , Glucose/farmacologia , Humanos , Recém-Nascido , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Telomerase , Telômero
2.
Nanoscale ; 11(40): 18845-18853, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31595915

RESUMO

A multifunctional nanosensor of CPs@MnO2-AgNPs was constructed for sensitive and selective sensing of GSH and cancer theranostics in this work. The CPs@MnO2 nanocomposite was synthesized by capping MnO2 onto carbon nanoparticles through an in situ redox reaction under ultrasonication. AgNPs with fluorescence were obtained through a silver-mirror-like reaction using BSA as both a template and reductant and further anchored onto the surface of CPs@MnO2 through electrostatic interaction to construct the CPs@MnO2-AgNP nanocomposite. The fluorescence of AgNPs was effectively quenched by MnO2 through an inner filter effect and a static quenching effect and further recovered by GSH owing to the unique redox reaction between GSH and MnO2. Therefore, a novel fluorescent turn-on nanosensor was established for GSH sensing in vitro and in vivo. For GSH sensing, a satisfactory linear range of 0.8-80 µM with a detection limit of 0.55 µM was obtained under optimal conditions. Moreover, by integrating the GSH-responsive fluorescence imaging capacity, the photothermal activity of carbon nanoparticles and the anticancer effect of AgNPs, the CPs@MnO2-AgNP nanocomposite was successfully applied for cancer theranostics. The fluorescence recognition of cancer was achieved by overexpressing GSH in cancer, meanwhile the photothermal therapy from CPs and chemotherapy from AgNPs jointly produced an enhanced therapeutic effect. This redox-responsive nanocomposite of CPs@MnO2-AgNPs improves the MnO2 nanomaterial-based applications in GSH sensing and cancer theranostics.


Assuntos
Glutationa/metabolismo , Compostos de Manganês , Nanopartículas Metálicas , Nanocompostos , Neoplasias , Imagem Óptica , Óxidos , Prata , Nanomedicina Teranóstica , Linhagem Celular Tumoral , Humanos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Nanocompostos/química , Nanocompostos/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Óxidos/química , Óxidos/farmacologia , Prata/química , Prata/farmacologia
3.
Analyst ; 144(6): 1988-1994, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30698591

RESUMO

A MnO2 nanoparticle (MnO2 NP)-mediated fluorescent turn-on probe for sensitively and selectively detecting glutathione (GSH) and recognizing cancer cells was established in this work. MnO2 NPs were synthesized simply and quickly through an in situ redox reaction by mixing bovine serum albumin (BSA) and KMnO4, in which BSA served the dual roles of template and reductant. It was found that the MnO2 NPs served as an effective energy acceptor and quenched the fluorescence intensity of carbon dots (CDs), owing to the fluorescence resonance energy transfer (FRET) process. Further, the addition of GSH triggered the decomposition of MnO2, breaking the FRET between MnO2 NPs and CDs and thus restoring the fluorescence intensity of CDs. Based on this mechanism, quantitative determination of GSH was performed. Under optimal conditions, a satisfactory linear range of 0.05-90 µM and limit of detection of 39 nM were obtained, and GSH content in human serum samples was detected. Moreover, taking advantage of the higher levels of GSH in cancer cells than in normal cells, the MnO2 NP-CD probe was applied to distinguish SMMC-7721 cancer cells from L02 normal cells. The FRET was interrupted by GSH in cancer cells, and strong fluorescence was observed. This work provides a facile approach for synthesizing MnO2 NPs, and this rapid, low-cost method with no need for reductants makes synthesis green and convenient. The MnO2 NP-mediated fluorescent turn-on response to GSH could improve the MnO2 nanomaterial-based biochemical analysis applications.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Fluorescência , Glutationa/sangue , Neoplasias Hepáticas/diagnóstico , Compostos de Manganês/química , Nanopartículas/química , Óxidos/química , Soroalbumina Bovina/química , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Bovinos , Proliferação de Células , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes , Humanos , Limite de Detecção , Neoplasias Hepáticas/metabolismo , Nanocompostos/química , Pontos Quânticos , Células Tumorais Cultivadas
4.
Hum Gene Ther ; 30(3): 339-351, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30205711

RESUMO

Kallistatin (KS) has been recognized as a plasma protein with anti-inflammatory functions. Macrophages are the primary inflammatory cells in atherosclerotic plaques. However, it is unknown whether KS plays a role in macrophage development and the pathogenesis of atherosclerosis. This study investigated the role of KS in macrophage development, a key pathological process in atherosclerosis. An atherosclerosis model was established in ApoE-/- mice via partial left carotid artery (PLCA) ligation. An adenovirus vector (Ad. HKS) containing the human KS gene was delivered via the tail vein before PLCA ligation. The mice were divided into two groups: the PLCA + Ad. HKS and PLCA + adenovirus vector (Ad. Null) groups and followed for 2 and 4 weeks. Human KS was expressed in the mice after KS gene delivery. In addition, KS significantly inhibited plaque formation and reduced inflammation in the plaques and liver 4 weeks after gene delivery. Moreover, KS gene delivery significantly increased the expression of interleukin-10 and Arginase 1, which are M2 macrophage markers, and reduced the expression of inducible nitric oxide synthase and monocyte chemotactic protein 1, which are M1 macrophage markers. Furthermore, in cultured RAW 264.7 macrophages, KS significantly stimulated M2 marker expression and differentiation and decreased M1 marker expression, as determined by flow cytometry and real-time polymerase chain reaction. These effects were blocked by Krüppel-like factor 4 small-interfering RNA oligonucleotides. These findings demonstrate that KS inhibits atherosclerotic plaque formation and regulates M1/M2 macrophage polarization via Krüppel-like factor 4 activation.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Serpinas/genética , Adenoviridae/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Expressão Gênica , Vetores Genéticos/genética , Humanos , Fator 4 Semelhante a Kruppel , Metabolismo dos Lipídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas Recombinantes/farmacologia , Serpinas/farmacologia
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