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1.
Commun Biol ; 2: 306, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428694

RESUMO

Adult stem-cells may serve as the cell-of-origin for cancer, yet their unbiased identification in single cell RNA sequencing data is challenging due to the high dropout rate. In the case of breast, the existence of a bipotent stem-like state is also controversial. Here we apply a marker-free algorithm to scRNA-Seq data from the human mammary epithelium, revealing a high-potency cell-state enriched for an independent mammary stem-cell expression module. We validate this stem-like state in independent scRNA-Seq data. Our algorithm further predicts that the stem-like state is bipotent, a prediction we are able to validate using FACS sorted bulk expression data. The bipotent stem-like state correlates with clinical outcome in basal breast cancer and is characterized by overexpression of YBX1 and ENO1, two modulators of basal breast cancer risk. This study illustrates the power of a marker-free computational framework to identify a novel bipotent stem-like state in the mammary epithelium.

2.
IEEE Trans Med Imaging ; 38(11): 2607-2619, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30908204

RESUMO

Over the past few years, dictionary learning (DL)-based methods have been successfully used in various image reconstruction problems. However, the traditional DL-based computed tomography (CT) reconstruction methods are patch-based and ignore the consistency of pixels in overlapped patches. In addition, the features learned by these methods always contain shifted versions of the same features. In recent years, convolutional sparse coding (CSC) has been developed to address these problems. In this paper, inspired by several successful applications of CSC in the field of signal processing, we explore the potential of CSC in sparse-view CT reconstruction. By directly working on the whole image, without the necessity of dividing the image into overlapped patches in DL-based methods, the proposed methods can maintain more details and avoid artifacts caused by patch aggregation. With predetermined filters, an alternating scheme is developed to optimize the objective function. Extensive experiments with simulated and real CT data were performed to validate the effectiveness of the proposed methods. The qualitative and quantitative results demonstrate that the proposed methods achieve better performance than the several existing state-of-the-art methods.

3.
Exp Ther Med ; 17(3): 1797-1801, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30867687

RESUMO

Long non-coding (lnc)RNA hypoxia inducible factor 1α-antisense RNA 1 (HIF1A-AS1) not only participates in different types of malignancies, but also serves pivotal roles in thoracic aortic aneurysms, which suggests its possible involvement in intracranial aneurysms. Therefore, the present study aimed to investigate its involvement in intracranial aneurysms. Expression levels of HIF1A-AS1 and transforming growth factor (TGF)-ß1 in the blood of patients with intracranial aneurysms and healthy controls were detected using reverse transcription-quantitative polymerase chain reaction. The diagnostic value of blood HIF1A-AS1 for intracranial aneurysms was analyzed using receiver operating characteristic curve analysis. A HIF1A-AS1 expression vector was constructed and transfected into human vascular smooth muscle cells (VSMCs) and the effects on cell proliferation and TGF-ß1 expression were explored using the Cell Counting kit-8 assay and western blot analysis, respectively. Upregulated HIF1A-AS1 expression levels in blood were observed in patients with intracranial aneurysms when compared with controls. Notably, upregulated HIF1A-AS1 expression effectively distinguished patients with intracranial aneurysms from healthy controls. Furthermore, HIF1A-AS1 and TGF-ß1 expression levels were positively correlated with intracranial aneurysms. HIF1A-AS1 overexpression also upregulated TGF-ß1 expression and inhibited VSMC proliferation. Although TGF-ß1 treatment had no significant effect on HIF1A-AS1 expression, TGF-ß inhibitor significantly reduced the effects of HIF1A-AS1 overexpression on cell proliferation. It was therefore concluded that HIF1A-AS1 may participate in intracranial aneurysms by regulating VSMC proliferation through the upregulation of TGF-ß1.

4.
Methods Mol Biol ; 1935: 125-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30758824

RESUMO

The ability to measure molecular properties (e.g., mRNA expression) at the single-cell level is revolutionizing our understanding of cellular developmental processes and how these are altered in diseases like cancer. The need for computational methods aimed at extracting biological knowledge from such single-cell data has never been greater. Here, we present a detailed protocol for estimating differentiation potency of single cells, based on our Single-Cell ENTropy (SCENT) algorithm. The estimation of differentiation potency is based on an explicit biophysical model that integrates the RNA-Seq profile of a single cell with an interaction network to approximate potency as the entropy of a diffusion process on the network. We here focus on the implementation, providing a step-by-step introduction to the method and illustrating it on a real scRNA-Seq dataset profiling human embryonic stem cells and multipotent progenitors representing the 3 main germ layers. SCENT is aimed particularly at single-cell studies trying to identify novel stem-or-progenitor like phenotypes, and may be particularly valuable for the unbiased identification of cancer stem cells. SCENT is implemented in R, licensed under the GNU General Public Licence v3, and freely available from https://github.com/aet21/SCENT .


Assuntos
Diferenciação Celular/genética , Algoritmos , Biologia Computacional/métodos , Entropia , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Células-Tronco Embrionárias Humanas/fisiologia , Humanos , Células-Tronco Neoplásicas/fisiologia , RNA/genética , Análise de Célula Única/métodos , Software
5.
Brief Bioinform ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30289442

RESUMO

MOTIVATION: Estimating differentiation potency of single cells is a task of great biological and clinical significance, as it may allow identification of normal and cancer stem cell phenotypes. However, very few single-cell potency models have been proposed, and their robustness and reliability across independent studies have not yet been fully assessed. RESULTS: Using nine independent single-cell RNA-Seq experiments, we here compare four different single-cell potency models to each other, in their ability to discriminate cells that ought to differ in terms of differentiation potency. Two of the potency models approximate potency via network entropy measures that integrate the single-cell RNA-Seq profile of a cell with a protein interaction network. The comparison between the four models reveals that integration of RNA-Seq data with a protein interaction network dramatically improves the robustness and reliability of single-cell potency estimates. We demonstrate that underlying this robustness is a correlation relationship, according to which high differentiation potency is positively associated with overexpression of network hubs. We further show that overexpressed network hubs are strongly enriched for ribosomal mitochondrial proteins, suggesting that their mRNA levels may provide a universal marker of a cell's potency. Thus, this study provides novel systems-biological insight into cellular potency and may provide a foundation for improved models of differentiation potency with far-reaching implications for the discovery of novel stem cell or progenitor cell phenotypes.

6.
Int J Mol Med ; 42(2): 1199, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29749426

RESUMO

Subsequently to the publication of this article, the authors have realized that an address affiliation associated with certain of the authors had been omitted. The authors' affiliation information should have appeared as follows (the omitted address affiliation is featured in bold): Yi­Ying Yang1,2*, Xiu­Ting Sun1,2*, Zheng­Xun Li1,2, Wei­Yan Chen3, Xiang Wang4, Mei­Ling Liang5, Hui Shi1,2, Zhi­Sheng Yang1,2 and Wu­Tao Zeng1,2 1Department of Cardiology, The First Affiliated Hospital, Sun Yat­Sen University; 2Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong 510080; 3Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260; 4Department of Cardiology, Laiwu City People's Hospital, Laiwu, Shandong 27110; 5Department of Cardiology, Sun Yat­Sen Cardiovascular Hospital, Shenzhen, Guangdong 518020, P.R. China *Contributed equally. The authors regret this error in the affiliations, and apologize for any inconvenience caused. [the original article was published in the International Journal of Molecular Medicine 41: 1283­1292, 2018; DOI: 10.3892/ijmm.2017.3322].

7.
Medicine (Baltimore) ; 97(6): e9765, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29419669

RESUMO

The purpose of this study was to examine the association between serum uric acid (sUA) and the incidence of hypertension in nonmetabolic syndrome (non-MetS) subjects.This was a prospective observational study including 23,525 subjects who had been followed up for at least 5 years. A logistic regression model was used to assess independent risk factors associated with hypertension. An area under the receiver operating characteristic curve (auROC) was generated, and a nomogram was developed to assess diagnostic ability of sUA and the sUA-based score.We enrolled 11,642 subjects, and 763 (6.55%) were diagnosed with hypertension at the 5-year follow-up. Subjects were classified into 4 groups based on the sUA quarter. Using Q1 as the reference group, Q2, Q3, and Q4 were found to show a higher risk for the development of hypertension with odds ratio of 1.51 (1.15, 1.98), 1.72 (1.30, 2.27), and 2.27 (1.68, 3.06), respectively (P < .001) after adjusting for other known confounding variables. Interaction analysis showed that there was no significant difference between subgroups stratified on the basis of sex, age, body mass index, fasting plasma glucose, and high-density lipoprotein cholesterol except triglycerides (P = .006). The auROCs for sUA and the sUA-based score were 0.627 (0.607, 0.647) and 0.760 (0.742, 0.777), respectively. A nomogram comprising independent risk factors was developed to predict the 5-year risk of hypertension for each subject.High sUA was significantly associated with the incidence of hypertension in non-MetS subjects adjusting for confounders.


Assuntos
Hipertensão , Hiperuricemia , Ácido Úrico , Adulto , China/epidemiologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Fatores de Risco , Ácido Úrico/análise , Ácido Úrico/sangue
8.
Int J Mol Med ; 41(3): 1283-1292, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29286068

RESUMO

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of AngⅠ and AngⅡ, possesses physiological and pharmacological properties, including anti­inflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3K̸Akt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3K̸Akt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 µmol/l (µM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3K̸Akt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co-treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3K̸Akt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3K̸Akt signaling pathway.


Assuntos
Angiotensina I/farmacologia , Cardiotônicos/farmacologia , Hiperglicemia/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Glucose/toxicidade , Inflamação/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
9.
Mol Med Rep ; 17(1): 1461-1468, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29257199

RESUMO

The transplantation of mesenchymal stem cells (MSCs) has been a reported method for alleviating atherosclerosis (AS). Because the availability of bone marrow­derived MSCs (BM­MSCs) is limited, the authors used this study to explore the use of a new type of MSC, human induced pluripotent stem cell­derived MSCs (iPSC­MSCs), to evaluate whether these cells could alleviate AS. iPSC­MSCs were intravenously administered to ApoE knock out mice fed on a high­fat diet (HFD) for 12 weeks. It was reported that systematically administering iPSC­MSCs clearly reduced the size of plaques. In addition, the numbers of macrophages and lipids in plaques were lower in the HFD + iPSC­MSCs group than in the HFD group. Furthermore, iPSC­MSCs attenuated AS­associated inflammation by decreasing the levels of inflammatory cytokines, such as tumor necrosis factor­α and interleukin­6, in serum. In addition, the expression of Notch1 was higher in the HFD group, and injecting iPSC­MSCs reversed this effect. In conclusion, the current study provides the first evidence indicating that iPSC­MSCs may be a new optional MSC­based strategy for treating AS.


Assuntos
Aterosclerose/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Aterosclerose/sangue , Aterosclerose/complicações , Aterosclerose/imunologia , Células Cultivadas , Citocinas/sangue , Citocinas/imunologia , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Inflamação/sangue , Inflamação/complicações , Inflamação/imunologia , Inflamação/terapia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos C57BL
10.
Molecules ; 24(1)2018 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-30597974

RESUMO

The ultrasonic-assisted extraction process and antioxidant activity of flavonoids from Sophora flavescens were investigated in this study. In order to optimize the extraction of flavonoids from Sophora flavescens, the influence of extraction time, methanol concentration, ultrasonic temperature, and solvent-to-material ratio was analyzed. Results showed that the extraction yields reached a maximum with the extraction time of 30 min, methanol concentration of 80%, temperature of 80 °C, and solvent-to-material ratio of 26 mL/g. The flavonoids were determined by HPLC, and the mean yields of trifolirhizin, formononetin, isoxanthohumol, maackiain, and kurarinone under the optimal conditions were 2.570, 0.213, 0.534, 0.797, and 3.091 mg/g, respectively. The evaluation of vitro antioxidant activity exhibited Sophora flavescens flavonoids had a strong 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radical-scavenging ability with IC50 of 0.984 and 1.084 mg/g, respectively. These results indicate that ultrasonic-assisted extraction is an efficient approach for the selective extraction of flavonoids, and response surface methodology further optimized the extraction.


Assuntos
Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Sophora/química , Análise de Variância , Antioxidantes/química , Fracionamento Químico/métodos , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Estrutura Molecular , Extratos Vegetais/química , Temperatura Ambiente , Fatores de Tempo , Ondas Ultrassônicas
11.
Oncol Lett ; 14(5): 5711-5718, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29113199

RESUMO

The present study aimed to investigate the potential role of microRNA (miR)-214 in targeting the phosphatase and tensin homolog (PTEN)-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ovarian cancer (OC). The target gene of miR-214 was determined by luciferase reporter gene assay and was indicated to be PTEN. Human SK-OV-3 cells were transfected with a miR-214 inhibitor and a miR-214 mimic, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect relative expression of miR-214. The MTT assay was performed to detect cell viability following transfection. Cell cycle and apoptosis were assessed by staining with propidium iodide (PI) and double staining with Annexin V/PI, respectively. The expression levels of PTEN and PI3K/Akt signaling pathway-associated proteins were detected by western blot analysis. The expression of miR-214 in tumor tissues and normal tissues was detected by RT-qPCR, and PTEN expression was detected by immunohistochemistry. SK-OV-3 cells transfected with a miR-214 inhibitor showed significantly inhibited cell viability and proliferation, and markedly increased apoptotic rate. SK-OV-3 cells transfected with miR-214 mimic showed significantly increased viability and proliferation, and markedly decreased apoptotic rate. The cells transfected with a miR-214 inhibitor exhibited significantly upregulated PTEN expression and significantly downregulated phosphatidylinositol (3,4,5)-trisphosphate (PIP3), phosphorylated (p)-Akt and p-glycogen synthase kinase (GSK)-3ß expression. The cells transfected with miR-214 mimic exhibited significantly downregulated PTEN expression and significantly upregulated PIP3, p-Akt and p-GSK-3ß expressions. The OC tissues exhibited an increased expression of miR-214 and a reduced positive rate of PTEN expression compared with adjacent normal tissues. miR-214 may activate the PI3K/Akt signaling pathway by downregulating the targeted PTEN, which may promote OC cell proliferation and inhibit apoptosis.

12.
J Hum Genet ; 62(12): 1065-1071, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28878336

RESUMO

We investigated the relationship between gonadotropin-releasing hormone receptor (GnRHR) gene polymorphisms and outcome of patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). PCOS patients undergoing IVF-ET were selected, and infertile patients due to dysfunctional oviducts served as controls. GnRHR gene polymorphisms were detected using the polymerase chain reaction-restriction fragment length polymorphism assay. Gene-gene interaction and linkage disequilibrium tests were performed using the SHEsis software. Logistic regression analysis was performed to evaluate factors affecting outcome of patients undergoing IVF-ET. The PCOS group showed more patients with CC+CT genotypes rs12644822, rs3756159 and rs13138607 than the control group, and CC+CT genotypes and C alleles from three positions enhanced risk of PCOS. Patients with CC+CT genotypes from three positions exhibited increased serum luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), testosterone (T) and follicles than those with TT genotypes. The haplotype analysis indicated that CCC, CCT and TCC haplotypes increased the risk of PCOS, while TCT, TTC and TTT haplotypes lowered the risk. After IVF-ET treatment, patients with CC+CT genotypes of three positions in the GnRHR gene had a lower pregnancy rate than patients with TT genotypes. Logistic regression analysis indicated that CC+CT genotypes rs12644822, rs3756159 and rs13138607 were risk factor for patients undergoing IVF-ET. In conclusion, these findings demonstrate that CC+CT genotypes rs12644822C>T, rs3756159C>T and rs13138607C>T in the GnRHR gene may contribute to a decreased pregnancy rate for PCOS patients after IVF-ET.


Assuntos
Síndrome do Ovário Policístico/genética , Polimorfismo Genético/genética , Receptores LHRH/genética , Adulto , Transferência Embrionária , Feminino , Fertilização In Vitro , Genótipo , Haplótipos , Humanos , Gravidez , Taxa de Gravidez , Adulto Jovem
13.
Eur J Clin Pharmacol ; 72(11): 1327-1334, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27488389

RESUMO

PURPOSE: The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. RESULTS: A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. CONCLUSIONS: For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.


Assuntos
Anticoagulantes/administração & dosagem , Grupo com Ancestrais do Continente Asiático/genética , Sistema Enzimático do Citocromo P-450/genética , Modelos Biológicos , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Varfarina/uso terapêutico , Adulto Jovem
14.
Genet Test Mol Biomarkers ; 20(7): 367-72, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27227456

RESUMO

AIMS: To explore the associations between two endoplasmic reticulum (ER) stress proteins, protein disulfide isomerase (PDI), binding immunoglobulin protein (BIP), and the development and progression of pressure ulcers (PUs) in spinal cord injury (SCI) paraplegia patients. METHODS: ELISA kits were used to measure the levels of serum PDI and BIP in 67 SCI paraplegia patients with PUs and 61 SCI paraplegia patients without PUs. The associations between PDI and BIP, PU formation, PU staging, and pressure ulcer scale for healing (PUSH) score were analyzed. RESULTS: The patients in the PU group had higher levels of PDI and BIP than those in the non-PU group (both p < 0.05). Furthermore, the levels of PDI were positively correlated with those of BIP (r = 0.707, p < 0.0001). There were significant differences in the PDI and BIP levels among the different stages of PU (all p < 0.05). As the PU stages progressed, the levels of PDI and BIP first increased, then decreased, and finally peaked at stage III of the PUs. The PUSH scores significantly declined 7 days after debridement for the PU stage II (p < 0.01) but showed no significant difference between stages III and IV at 7 days after debridement (p > 0.05). The PUSH scores also decreased at 28 days after debridement for stages II, III, and IV (all p < 0.01). Higher PUSH scores indicated a longer time of debridement accompanied by a longer wound surface healing time (p < 0.05). CONCLUSION: ER stress proteins may be involved in the process of PU formation and healing; moreover, the levels of PDI and BIP were also associated with the severity of the PUs. Finally, we found that the PUSH scores can be used as a reference to evaluate PU severity and healing.


Assuntos
Linfocinas/metabolismo , Lesão por Pressão/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Traumatismos da Medula Espinal/patologia , Adulto , Idoso , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfocinas/sangue , Masculino , Pessoa de Meia-Idade , Paraplegia/enzimologia , Paraplegia/metabolismo , Lesão por Pressão/sangue , Lesão por Pressão/enzimologia , Isomerases de Dissulfetos de Proteínas/sangue , Fatores de Risco , Traumatismos da Medula Espinal/enzimologia
15.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 25(10): 604-7, 2013 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-24119697

RESUMO

OBJECTIVE: To investigate the regulatory effect of microRNA-141 (miR-141) on expression of high mobility group protein B1(HMGB1) in human monocytes THP-1 cell line. METHODS: THP-1 cells were transfected with miR-141 mimic or inhibitor (100 nmol/L) for 48 hours with lipofectamine RNAi MAX. The levels of miR-141 and HMGB1 mRNA in the THP-1 cells were detected by real-time fluorescence quantitation reverse transcription-polymerase chain reaction (RT-PCR), and HMGB1 protein was determined with Western blotting. RESULTS: The levels of miR-141 could be up regulated (35.33±7.24 vs. 1.21±0.20, t=-8.408, P=0.010) or down regulated (0.55±0.12 vs 1.09±0.05, t=7.473, P=0.002) after being transfected with 100 nmol/L miR-141 mimic or inhibitor for 48 hours by lipofectamine RNAi MAX in THP-1, and the level of HMGB1 mRNA and protein decreased (mRNA: 0.43±0.06 vs. 0.97±0.08, t=9.760, P=0.001; protein: 0.63±0.12 vs. 1.00±0.11, t=2.991, P=0.040) or increased (mRNA: 2.13±0.11 vs. 1.16±0.13, t=-9.977, P=0.001; protein: 1.78±0.04 vs. 0.96±0.09, t=-13.778, P=0.000) simultaneously compared with the control group. CONCLUSIONS: miR-141 is involved in regulation of inflammation through HMGB1 gene and protein pathway, suggesting that miR-141 plays an important role in regulating immune cells during the inflammatory response.


Assuntos
Proteína HMGB1/metabolismo , MicroRNAs/metabolismo , Monócitos/metabolismo , Linhagem Celular , Humanos , Monócitos/citologia , Transfecção
16.
Bioorg Med Chem Lett ; 23(13): 3793-7, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23726343

RESUMO

A new series of estrogen-derived metal complexes were synthesized and characterized. The functionalized estrogen receptor ligands were prepared by a four-step synthetic strategy, and then three transition metal Pd, Ni, Zn were introduced readily to give the title metal complexes, in which the squaramide was introduced as ion acceptor for the first time in the development of estrogen-derived metal complexes for estrogen receptor. Upon binding to estrogen receptors, all of the estrogen conjugates exhibited acceptable binding affinity (up to 4.04% relative to estradiol), and in transcription assays, all the compounds are agonists on ERα. Molecular modeling studies suggest a structural basis for the agonist activity of these compounds.


Assuntos
Desenho de Drogas , Estrogênios/química , Compostos Organometálicos/farmacologia , Receptores Estrogênicos/agonistas , Esteroides/química , Elementos de Transição/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade
17.
J Cardiovasc Pharmacol ; 62(3): 312-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23719092

RESUMO

MicroRNA (miR)-26 was found to be downregulated in cardiac diseases. In this study, the critical role of miR-26 in myocardial hypertrophy in both in vivo and in vitro was investigated. Sixteen male Wistar rats that underwent sham or transverse abdominal aortic constriction (TAAC) surgery were divided into control or TAAC group. Cardiomyocytes were isolated from neonatal Sprague-Dawley rats. Our study demonstrated that miR-26a/b was downregulated in both TAAC rat model and cardiomyocytes. The results of luciferase assays also suggested that glycogen synthase kinase 3ß (GSK3ß) may be a direct target of miR-26. The overexpression of miR-26 attenuated GSK3ß expression and inhibited myocardial hypertrophy. The downregulation of miR-26 reversed these effects. Furthermore, silence of GSK3ß gene phenocopied the anti-hypertrophy effects of miR-26, whereas overexpression of this protein attenuated the effects of miR-26. Taken together, these data suggest that miR-26 regulates pathological structural changes in the rat heart, which may be associated with suppression of the GSK3ß signaling pathway, and implicate the potential application of miR-26 in diagnosis and therapy of cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/terapia , Células Cultivadas , Terapia Genética , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Regulação para Cima
18.
Yao Xue Xue Bao ; 47(9): 1153-8, 2012 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-23227544

RESUMO

To observe the effect and mechanism of Yiqi Tongluo Jiedu capsule aganist cerebral ischemia reperfusion injury, the SD rats were randomly divided into following groups: sham-operated group, model group, the group of low, medium and high dose of Yiqi Tongluo Jiedu capsule, and nimodipine group. Using focal middle cerebral artery embolization (MCAO) model, following items were observed: symptoms of neurological deficit score; infarct volume; activity of SOD, content of MDA and NO, activity of NOS of ischemic brain tissue; Bcl-2 and Bax protein expression; content of IL-1beta, IL-6 and TNFalpha in serum; IL-1beta mRNA expression of ischemic brain tissue. Results showed that Yiqi Tongluo Jiedu capsule could significantly reduce the symptoms of neurological deficits, promote the recovery symptoms of neurological deficits; narrow infarct volume of brain tissue obviously, reduce the percentage of infarct volume; raise activity of SOD, reduce content of MDA and NO, reduce activity of NOS; increase Bcl-2 protein, reduce Bax expression; reduce content of IL-1beta, IL-6 and TNFa in serum; reduce IL-1beta mRNA expression of ischemic brain tissue. Yiqi Tongluo Jiedu capsule has significant protective effects against ischemic brain injury, it has significant anti-apoptotic, antioxidant and anti-inflammatory effects.


Assuntos
Encéfalo , Medicamentos de Ervas Chinesas/farmacologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cápsulas , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Infarto da Artéria Cerebral Média/patologia , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Plantas Medicinais/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/sangue , Proteína X Associada a bcl-2/metabolismo
19.
Cardiovasc Ther ; 30(3): 152-61, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21167013

RESUMO

AIMS: We evaluated effects of the nonpeptide angiotensin (ANG)-(1-7) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-ß1)/tumor necrosis factor-alpha (TNF-α) expression in myocardial infarction rat models. METHODS AND RESULTS: Sprague-Dawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala(7) ]-ANG-(1-7), a selective antagonist for the ANG-(1-7)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 ± 7.3% vs. 18.4 ± 3.3%, P < 0.05) and left ventricular ejection fraction (LVEF) (44.8 ± 7.6% vs. 32.7 ± 6.5%, P < 0.05) when compared to the control group, but no effects on the left ventricular end-diastolic and end-systolic diameters (LVDd and LVDs, respectively) were observed. In addition, we found that the myocyte diameter (18 ± 2 µm vs. 22 ± 4 µm, P < 0.05), infarct size (42.6 ± 3.6% vs. 50.9 ± 4.4%, P < 0.001) and collagen volume fraction (CVF) (16.4 ± 2.2% vs. 25.3 ± 3.2%, P < 0.001) were significantly reduced in the AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P < 0.001) and collagen III (P < 0.001) and inhibited the overexpression of TGF-ß1 (P < 0.05) and TNF-α (P < 0.05) compared to the control group. CONCLUSION: AVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-ß1/TNF-α overexpression and the action on the specific receptor Mas of ANG-(1-7).


Assuntos
Cardiotônicos/farmacologia , Imidazóis/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/patologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Colágeno/genética , Colágeno/metabolismo , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Zhonghua Xin Xue Guan Bing Za Zhi ; 38(6): 531-8, 2010 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-21033136

RESUMO

OBJECTIVE: To explore the effects of Angiotensin (ANG)-(1-7) on postangioplasty fibrotic remodeling and the involvement of TGF-beta/Smad signaling pathway in this process. METHODS: Thirty two healthy New Zealand white rabbits were randomly divided into 4 groups: sham group, control group, ANG-(1-7) group and ANG-(1-7) + A-779 group. Rabbits underwent angioplasty in the abdominal aorta or sham surgery. Subsequently, an osmotic minipump was implanted for saline, ANG-(1-7) (576 microg x kg(-1) x d(-1)) or ANG-(1-7) + A-779 (576 microg x kg(-1) x d(-1)) delivery. Before and after 4 weeks treatment, the levels of ANG II in plasma were measured by ELISA. At week 4, angiography and histomorphometric analysis were performed, mRNA levels of collagen I and III were assayed by RT-PCR and protein levels of TGF-beta1 and Smad2 in local vessel were assayed by Western blot. RESULTS: Following 4 weeks treatment, ANG-(1-7) and ANG-(1-7) + A-779 group displayed a significant elevation in lumen diameter [(4.11 +/- 0.10) mm and (3.34 +/- 0.11) mm vs. (2.88 +/- 0.08) mm, P < 0.05, respectively] and reduction in neointimal thickness [(208 +/- 17) microm and (407 +/- 25) microm vs. (448 +/- 15) microm, P < 0.05, respectively], neointimal area [(0.27 +/- 0.09) mm2 and (0.38 +/- 0.01) mm2 vs. (0.41 +/- 0.02) mm2, P < 0.05, respectively] and restenosis rate [(28.1 +/- 2.7)% and (36.8 +/- 2.2)% vs. (40.1 +/- 2.7)%, P < 0.05, respectively] compared with control group. Collagen I, III mRNA and TGF-beta1, Smad2 protein levels were significantly elevated in control group, ANG-(1-7) group and ANG-(1-7) +A-779 group compared to sham group (P < 0.01 or P < 0.05) and reduced in ANG-(1-7) group compared to control group (all P < 0.05). Co-treatment with A-779 reversed the inhibitory action of ANG-(1-7). Plasma levels of ANG II postangioplasty were similar in control and ANG-(1-7) group and both were significantly higher than preoperation levels. CONCLUSION: ANG-(1-7) attenuates postangioplasty collagen synthesis in rabbits possibly through down-regulating the expression of TGF-beta1 and inhibiting the activation of Smad2 pathway.


Assuntos
Angiotensina I/farmacologia , Aorta Abdominal/efeitos dos fármacos , Fibrose/metabolismo , Músculo Liso Vascular/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Coelhos , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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