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1.
Pak J Med Sci ; 40(3Part-II): 534-543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38356845

RESUMO

Background & Objective: Previous studies have suggested that the modified Glasgow Prognostic Score (mGPS) could be a potential biomarker for lung cancer (LC). However, the association between mGPS and overall survival (OS) or progression-free survival (PFS) in lung cancer patients remains unclear. The purpose of our study was to investigate possible correlation between mGPS and OS or PFS in LC patients. Methods: An extensive search of PubMed, Cochrane Library, EMbase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Trip Database, Worldwide Science, and Google Scholar databases was done for relevant articles, published prior to May 30, 2021, that report correlation between mGPS and OS or PFS in LC patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used as the main parameters for evaluation. Results: A total of 28 studies involving 9,748 lung cancer patients were analysed. The pooled analysis revealed that elevated mGPS (≥ 0) was associated with poor OS (HR=1.54; 95% CI, 1.32-1.77) and PFS (HR=1.49; 95% CI, 1.17-1.82). Furthermore, a significant correlation between mGPS (1 or 2) and OS was observed. However, no significant correlation was found between mGPS (1 or 2) and PFS. Subgroup analysis based on ethnicity demonstrated that mGPS ≥ 0 was associated with worse OS compared to mGPS=0 in both Asian (HR=1.46; 95% CI, 1.04-1.89; p<0.05) and Caucasian (HR=1.64; 95% CI, 1.35-1.94; p<0.05) cohorts of LC patients. Conclusions: Our results demonstrate that positive mGPS is associated with poor survival results. Therefore, mGPS may be used as a biomarker for predicting prognosis in LC patients.

2.
Eur J Cardiothorac Surg ; 64(5)2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37699000

RESUMO

OBJECTIVES: Early-stage lung adenocarcinoma (ADC) has a great heterogeneity in prognosis that is difficult to evaluate effectively. Thus, we developed and validated an effective nomogram prognostic model based on the clinical and laboratory characteristics of stage I-IIA ADC. METHODS: We included 1585 patients with pathologically diagnosed stage I-IIA ADC who underwent surgery at Shanghai Pulmonary Hospital. The nomogram was constructed based on the peripheral blood test and coagulation test indicators and evaluated using Calibration plots, concordance index, decision curve analysis and the X-tile software. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method and the Cox proportional hazard regression model. The primary end point of this study was RFS. RESULTS: Thrombin time and 4 clinical indicators for RFS were integrated into nomograms. A favourable agreement between the nomogram prediction and validation was observed in the calibration curves for RFS probabilities. The concordance index of the nomogram to predict RFS was 0.736 (95% confidence interval, 0.717-0.755). Moreover, significant differences were shown between the high-risk and low-risk groups in RFS and OS (P < 0.001) after effective cut-off values of risk points were found based on the nomogram. CONCLUSIONS: We established and validated a prognostic nomogram including thrombin time to predict RFS and OS of stage I-IIA ADC patients. This nomogram provided an effective prediction ability for the prognosis of stage I-IIA ADC patients.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Nomogramas , Prognóstico , China , Adenocarcinoma de Pulmão/patologia , Estadiamento de Neoplasias
3.
Pathol Res Pract ; 249: 154759, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37586214

RESUMO

BACKGROUND: Lung cancer is the most common cancer in the world. High Mobility Group AT-Hook 1 (HMGA1) is found to be associated with the glycolytic pathway in a variety of cancers, and abnormal glycolysis function is one of the important characteristics of cancer cells. Therefore, this paper discusses the effect of HMGA1 on glycolysis of lung adenocarcinoma (LUAD) cells METHODS: The mRNA expression data were downloaded from TCGA-LUAD database. Groups were set according to the median expression of HMGA1, followed by GSEA enrichment analysis. The upstream transcriptional regulators of HMGA1 were predicted by bioinformatics. The correlation between HMGA1 and Transcription Factor AP-2 Alpha (TFAP2A) and their expression in LUAD tissues were analyzed as well. mRNA expression levels of HMGA1 and TFAP2A were detected by qRT-PCR. The binding of HMGA1 and TFAP2A was demonstrated by ChIP and dual luciferase reporter assays. Cell function experiments were utilized to assay proliferation, apoptosis, glycolysis ability of LUAD cells, and glycolysis-related protein expression in each treatment group. RESULTS: HMGA1 was highly expressed in LUAD patients' tissues and enriched in the glycolytic pathway. Additionally, silencing HMGA1 markedly hampered cell proliferation and glycolysis, and promoted cell apoptosis. The upstream transcriptional regulator TFAP2A was predicted to be highly expressed in LUAD. ChIP and dual luciferase reporter assays confirmed the targeted relationship between HMGA1 and TFAP2A. Cell rescue assay confirmed that TFAP2A promoted glycolysis and LUAD progression by activating HMGA1. CONCLUSION: TFAP2A promotes glycolysis, proliferation and hampers apoptosis of LUAD cells by stimulating HMGA1. Hence, TFAP2A/HMGA1 may be a feasible therapeutic target for LUAD. AVAILABILITY OF DATA AND MATERIALS: All the data within this manuscript could be gotten from corresponding author at reasonable request.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Proteína HMGA1a/genética , Fator de Transcrição AP-2/genética , Fatores de Transcrição , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Proliferação de Células/genética , Glicólise , RNA Mensageiro
4.
Int J Mol Sci ; 23(23)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36499045

RESUMO

FASN plays a critical role in lipid metabolism, which is involved in regulating ovarian follicular development. However, the molecular mechanisms of how FASN regulate the function of ovarian follicular cells still remain elusive. In this study, by overexpression or interference of FASN in pre-hierarchical follicle granulosa cells (phGCs) and hierarchical follicle granulosa cells (hGCs), we analyzed their effects on the granulosa cell transcriptome and metabolome profiles using RNA-Seq and LC-MS/MS, respectively. The results showed that overexpression of FASN promoted proinflammatory factors expression by activating TLR3/IRF7 and TLR3/NF-κB pathways in phGCs, but only by activating TLR3/IRF7 pathways in hGCs. Then, necroptosis and apoptosis were triggered through the JAK/STAT1 pathway (induced by inflammatory factors) and BAK/caspase-7 pathway, respectively. The combined analysis of the metabolome and transcriptome revealed that FASN affected the demand of GCs for 5-hydroxytryptamine (5-HT) by activating the neuroactive ligand-receptor interaction pathway in two categorized GCs and only altering the metabolic pathway of tryptophan in phGCs, and ultimately participated in regulating the physiological function of geese GCs. Taken together, this study showed that the mechanisms of FASN regulating the physiological function of geese phGCs and hGCs were similar, but they also had some different characteristics.


Assuntos
Gansos , Espectrometria de Massas em Tandem , Animais , Feminino , Gansos/genética , Gansos/metabolismo , Cromatografia Líquida , Células Cultivadas , Células da Granulosa/metabolismo , Transcriptoma
5.
Sheng Wu Gong Cheng Xue Bao ; 38(8): 2713-2724, 2022 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-36002405

RESUMO

Gene editing technology has been a hotspot in the field of biotechnology. CRISPR/Cas systems are efficient gene editing tools because of its specificity, simplicity and flexibility, these features enabled the rapid application of CRISPR/Cas systems in a variety of organisms. Moreover, the combination of transcriptional activator with dead Cas protein can achieve specific regulation of gene expression at the transcription level, which has made important contributions to the development of biotechnology in medical and agriculture. Overexpression of foreign genes is a common method to verify gene function and regulation. However, due to the limitation of vector capacity, it is difficult to achieve overexpression of multiple genes. CRISPR/Cas9 activation system can regulate the expression of multiple genes under the guidance of different guide RNAs to verify gene functions at the regulatory level. This review summarizes the composition of the CRISPR/Cas9 activation system and different activation strategies, and summarizes solutions for excessive activation. It may facilitate the application of CRISPR/Cas9 activation system in genetic improvement of cotton and herbicide resistance research.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Biotecnologia , Sistemas CRISPR-Cas/genética , Fenótipo , RNA Guia de Cinetoplastídeos/genética , RNA Guia de Cinetoplastídeos/metabolismo
6.
Artif Organs ; 45(8): 866-880, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33432632

RESUMO

Neurological dysfunction commonly occurs after cardiac surgery with deep hypothermic circulatory arrest (DHCA). The mechanisms underlying DHCA-associated brain injury remain poorly understood. This study determined the changes in expression profiles of circular RNAs (circRNAs) in the hippocampus in rats that underwent DHCA, with an attempt to explore the potential role of circRNAs in the brain injury associated with DHCA. Adult male Sprague Dawley rats were subjected to cardiopulmonary bypass with DHCA. Brain injury was evaluated by neurological severity scores and histological as well as transmission electron microscope examinations. The expression profiles of circRNAs in the hippocampal tissues were screened by microarray. Quantitative real-time PCR (RT-qPCR) was used to validate the reliability of the microarray results. Bioinformatic algorithms were applied to construct a competing endogenous RNA (ceRNA) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the potential biological roles of the circRNAs. Out of 14 145 circRNAs screened, 56 were differentially expressed in the hippocampus between the DHCA and sham-operated rats, including 30 upregulated and 26 downregulated circRNAs. The expression changes of six selected circRNAs (upregulated: rno_circRNA_011190, rno_circRNA_012988, rno_circRNA_000544; downregulated: rno_circRNA_010393, rno_circRNA_012043, rno_circRNA_015149) were further confirmed by RT-qPCR. Bioinformatics analysis showed the enrichment of these confirmed circRNAs and their potential target mRNAs in several KEGG pathways including histidine metabolism, adipocytokine signaling, and cAMP signaling. By revealing the change expression profiles of circRNAs in the brain after DHCA, this study indicates possible involvements of these dysregulated circRNAs in brain injury and suggests a potential of targeting circRNAs for prevention and treatment of neurological dysfunction associated with DHCA.


Assuntos
Parada Circulatória Induzida por Hipotermia Profunda , Hipocampo/metabolismo , RNA Circular/metabolismo , Algoritmos , Animais , Biologia Computacional/métodos , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
7.
J Trace Elem Med Biol ; 62: 126612, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32673943

RESUMO

BACKGROUND: Dietary factors including trace elements contribute to the development of disorders including coronary artery diseases. Whether there are differences in concentrations of trace elements between on-pump and off-pump coronary artery bypass grafting (CABG) surgery remains unclear. The aim of this study was to investigate the differences in the plasma level of four trace elements Cu, Fe, Zn, magnesium (Mg), and calcium (Ca) during and after CABG between on-pump and off-pump procedure and the correlation between these trace elements and the development of postoperative AF. METHODS: Fifty-three CABG patients using on-pump or off-pump methods were enrolled. The blood sample was taken before skin incision (T1), 4 h after skin incision (T2), postoperative day1 (T3), and day3 (T4) respectively. Plasma concentrations of Mg, Ca, Fe, Zn, and Cu were determined. RESULTS: The plasma Mg concentration reached the highest level at T3 (0.94 ± 0.03 vs. 1.20 ± 0.03 mmol/L,P < 0.001) and completely recovered at T4 whereas Zn (11.28 ± 0.23 vs. 6.80 ± 0.20 mmol/L, P < 0.001) and Fe (10.97 ± 0.51 vs. 2.22 ± 0.1 µmol/L, P < 0.001) was lowest at T3 and partially recovered at T4. Cu was lowest at T2 (12.10 ± 0.33 vs. 9.62 ± 0.25 µmol/L, P < 0.001) then increased until T4. There were significant differences in Mg and Fe (P < 0.05), as well as Cu (P < 0.01) between on-pump and off-pump groups. No significant differences were detected between postoperative atrial fibrillation and sinus rhythm groups. CONCLUSIONS: In CABG, Cu and Zn are significantly reduced and Cu is recovered at postoperative Day 1 but Zn takes longer to recover. Addition of Mg and Ca during CABG are sufficient to maintain the plasma concentration. However, supplementation of Cu and Zn during and after CABG may be necessary. Further, the correlation between these trace elements and postoperative AF is to be further determined.


Assuntos
Cálcio/sangue , Cobre/sangue , Ponte de Artéria Coronária , Ferro/sangue , Magnésio/sangue , Oligoelementos/sangue , Zinco/sangue , Idoso , Feminino , Humanos , Masculino , Pele/metabolismo
8.
Front Physiol ; 11: 600, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676035

RESUMO

Lipid metabolism participates in regulating the functions of granulosa cells (GCs), which is important for follicular development. In this experiment, goose GCs from pre-hierarchical follicles and hierarchical follicles were selected to be the model for studying the putative regulatory role of lipid metabolism in apoptosis and steroidogenesis, through overexpression and interference with fatty acid synthase (FASN). When FASN was overexpressed, the lipid accumulation was increased in hierarchical GCs (hGCs) and it was increased in the two categorized GCs when FASN was interfered. In addition, the apoptosis of the two categorized GCs was increased when FASN was overexpressed, and their progesterone production was decreased when FASN was interfered. The results of qRT-PCR showed that, when FASN was overexpressed, the expression level of CYP11A1 was decreased in pre-hierarchical GCs (phGCs), while the expression levels of SCD1, DGAT2, APOB, and StAR were increased in hGCs. When FASN was interfered, the expression levels of CPT-1, DGAT2, and StAR were decreased whereas the expression level of CYP11A1 was increased in phGCs, and the expression levels of CPT-1, SCD1, and StAR were decreased in hGCs. These results not only identify the different effects of manipulated FASN expression on lipid metabolism of goose phGCs and hGCs but also demonstrate that FASN-mediated lipid metabolism plays an important role in regulating apoptosis and steroidogenesis of in vitro cultured goose GCs.

9.
Lung Cancer ; 142: 59-62, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114282

RESUMO

OBJECTIVES: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. MATERIALS AND METHODS: With advances in detection methods, more and more uncommon ALK fusion partners have been identified. Herein we present a novel SOS1-ALK fusion and the efficacy of crizotinib in an advanced NSCLC patient harboring this type of fusion. RESULTS: A 52-year-old Chinese man had left upper lobe primary NSCLC and synchronous multiple lung metastases (cT2N3M1, stage IV). The ultrasound-guided fine-needle aspiration cytology of palpable left supraclavicular lymph nodes and the results of immunohistochemistry staining supported the diagnosis of metastatic lung adenocarcinoma. Using a next-generation sequencing assay (NGS), we showed that the tumor had a SOS1-ALK fusion which the breakpoints was (S2, A20) rather than other actionable mutations. Therefore, the patient received first-line crizotinib and experienced a remarkable tumor response and has tolerated crizotinib well until this writing. CONCLUSION: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Proteína SOS1/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/secundário , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
10.
PLoS One ; 11(6): e0157085, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27257686

RESUMO

Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid accumulation and inflammatory response via downregulation of LPL gene expression, suggesting a potential strategy to the diagnosis and treatment of atherosclerosis.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Inflamação/metabolismo , Lipase Lipoproteica/farmacocinética , MicroRNAs/metabolismo , Animais , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/genética , Linhagem Celular , Quimiocina CCL2/sangue , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação/sangue , Inflamação/genética , Interleucina-1beta/sangue , Interleucina-6/sangue , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipase Lipoproteica/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real , Receptores Depuradores/metabolismo , Fator de Necrose Tumoral alfa/sangue
11.
Atherosclerosis ; 250: 122-32, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27205869

RESUMO

BACKGROUND AND AIMS: Several studies suggest that cardiomyocyte-enriched miR-186 is involved in cardiac injury and myocardial infarction, and also plays an important role in atherosclerotic diseases, but the underlying mechanism is unknown. Cystathionine-γ-lyase (CSE) is the predominant enzyme to produce H2S in the cardiovascular system. Here, miR-186 was identified to bind to the 3'UTR of CSE. In this study, we aimed at exploring whether miR-186 affects lipid accumulation and secretion of pro-inflammatory cytokines by targeting CSE and its underlying mechanism in human THP-1 macrophages and peripheral blood monocyte-derived macrophages (PBMDM). PBMDM just as a control group for the comparison with the THP-1 macrophages. METHODS: MiR-186 target genes, CSE 3'UTR sequence and free energy were predicted and analyzed by bioinformatics analyses and dual-luciferase reporter assays. The expression of CSE mRNA and protein were measured by real-time quantitative PCR and western blot analyses. The lipid accumulation in THP-1 macrophages was detected by high performance liquid chromatography (HPLC). The effects of miR-186 on secretion of IL-6, IL-1ß and TNF-α were examined by ELISA. Endogenous H2S was detected by spectrophotometry. Using small interfering RNA (siRNA) approach to decrease the expression of CSE protein and mRNA. RESULTS: We found that miR-186 directly inhibited CSE protein and mRNA expression through targeting CSE 3'UTR by bioinformatics analyses and dual-luciferase reporter assays. HPLC assays showed that miR-186 increased the lipid accumulation in human THP-1 macrophages. We also showed that miR-186 enhanced secretion of pro-inflammatory cytokines in human THP-1 macrophages. Using siRNA approach, we found that CSE siRNA could inhibit the miR-186 inhibitor-induced decrease in the expression of LPL protein and mRNA in human THP-1 macrophages, which was accompanied a decrease in the level of H2S. CONCLUSIONS: MicroRNA-186 promotes macrophage lipid accumulation and pro-inflammatory cytokine secretion by targeting cystathionine γ-lyase in THP-1 macrophages.


Assuntos
Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Citocinas/metabolismo , Lipídeos/química , MicroRNAs/fisiologia , Regiões 3' não Traduzidas , Alelos , Células HEK293 , Humanos , Sulfeto de Hidrogênio/química , Inflamação , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Lipase Lipoproteica/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Células THP-1
12.
Atherosclerosis ; 248: 149-59, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27017521

RESUMO

RATIONALE: Previous studies have shown that apolipoprotein-1 (apoA-1) binding protein (AIBP) is highly associated with the regulation of apoA-1 metabolism, suggesting its role in the treatment of atherosclerosis. However, how AIBP regulates foam cell formation remains largely unexplored. OBJECTIVE: To investigate the mechanisms underlying AIBP inhibition of foam cell formation from macrophages. METHODS AND RESULTS: THP-1-derived macrophages were incubated without or with apoA-1 and AIBP, followed by assessing the formation of foam cells and the potential mechanisms. Our results showed that AIBP and apoA-1 enhanced cholesterol efflux, altered the levels of cellular free cholesterol and cholesterol ester and prevented lipid accumulation so as to reduce the formation of foam cells. Meanwhile, lack of AIBP 115-123 amino acids resulted in the loss of AIBP binding to apoA-1. Moreover, our chemiluminescent analysis showed that AIBP promoted biotin-labeled apoA-1 binding to macrophages. Besides with AIBP, more apoA-1 bound to ABCA1, a key transporter responsible for cholesterol efflux to apoA-1, as indicated by our co-immunoprecipitation assay. Our results also showed that AIBP did not regulate ABCA1 mRNA expression, but stabilized its protein from CSN2-mediated degradation. CONCLUSIONS: AIBP promotes apoA-1 binding to ABCA1 on the cell membrane of macrophages and prevents ABCA1 protein from CSN2-mediated degradation so as to prevent foam cell formation. AIBP 115-123 amino acids is at least partially responsible for its binding to apoA-1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Aterosclerose/metabolismo , Transporte Biológico , Biotina/química , Complexo do Signalossomo COP9 , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Células Espumosas/citologia , Humanos , Macrófagos/metabolismo , Camundongos , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/metabolismo , Ubiquitinação
13.
Biochem Biophys Res Commun ; 470(1): 107-116, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26772887

RESUMO

This study was designed to evaluate whether CSE/H2S system, which is regulated by miR-216a, regulated ABCA1-mediated cholesterol efflux and cholesterol contents in THP-1 macrophages-derived foam cells. Our qPCR and western blotting results showed that CSE/H2S significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via PI3K/AKT pathway in foam cells derived from human THP-1 macrophages. The miR-216a directly targeted 3' untranslated region of CSE. It significantly reduced CSE and ABCA1 expression, and also decreased the phosphorylation of PI3K and AKT. Additionally, cholesterol efflux decreased, and cholesterol levels increased in THP-1 macrophage-derived foam cells in response to treatment with miR-216a. Our study demonstrates that CSE/H2S system is regulated by miR-216a, and regulates ABCA1-mediated cholesterol efflux and cholesterol levels through the PI3K/AKT pathway.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Linhagem Celular , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
14.
Biochem Biophys Res Commun ; 472(3): 410-7, 2016 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-26546816

RESUMO

Angiopoietin-like 4 (Angptl4), a secreted protein, is an important regulator to irreversibly inhibit lipoprotein lipase (LPL) activity. Macrophage LPL contributes to foam cell formation via a so-called"molecular bridge" between lipoproteins and receptors on cell surface. It has been reported that macrophage ANGPTL4 suppresses LPL activity, foam cell formation and inflammatory gene expression to reduce atherosclerosis development. Recently, some studies demonstrated that microRNA-134 is upregulated in atherosclerotic macrophages. Here we demonstrate that miR-134 directly binds to 3'UTR of ANGPTL4 mRNA to suppression the expression of ANGPTL4. To investigate the potential roles of macrophage miR-134, THP-1 macrophages were transfected with miR-134 mimics or inhibitors. Our results showed that LPL activity and protein were dramatically increased. We also found that miR-134 activated LPL-mediated lipid accumulation. Collectively, our findings indicate that miR-134 may regulate lipid accumulation and proinfiammatory cytokine secretion in macrophages by targeting the ANGPTL4 gene. Our results have also suggested a promising and potential therapeutic target for atherosclerosis.


Assuntos
Angiopoietinas/imunologia , Inflamação/imunologia , Metabolismo dos Lipídeos/imunologia , Lipase Lipoproteica/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Proteína 4 Semelhante a Angiopoietina , Linhagem Celular , Ativação Enzimática , Humanos , Macrófagos/enzimologia , Transdução de Sinais/imunologia
15.
Biochem Biophys Res Commun ; 472(3): 418-24, 2016 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-26654953

RESUMO

RATIONALE: Excessive cholesterol accumulation in macrophages is a major factor of foam cell formation and development of atherosclerosis. Previous studies suggested that miR-486 plays an important role in cardiovascular diseases, but the underlying mechanism is still unknown. OBJECTIVE: The purpose of this study is to determine whether miR-486 regulates ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, and also explore the underlying mechanism. METHODS AND RESULTS: Based on bioinformatics analysis and luciferase reporter assay, we transfected miR-486 mimic and miR-486 inhibitor into THP-1 macrophage-derived foam cells, and found that miR-486 directly bound to histone acetyltransferase-1 (HAT1) 3'UTR, and downregulated its mRNA and protein expression. In addition, our studies through transfection with wildtype HAT1 or shHAT1 (short hairpin HAT1) revealed that HAT1 could promote the expression of ABCA1 at both mRNA and protein levels. At the same time, the acetylation levels of the lysines 5 and 12 of histone H4 were upregulated after overexpression with HAT1. Meanwhile, the results of liquid scintillation counter and high performance liquid chromatography (HPLC) showed that miR-486 promoted cholesterol accumulation in THP-1 macrophages. CONCLUSION: These data indicated that miR-486 aggravate the cholesterol accumulation in THP-1 cells by targeting HAT1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Histona Acetiltransferases/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Linhagem Celular , Regulação para Baixo/fisiologia , Humanos
16.
PLoS One ; 10(9): e0138788, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26397958

RESUMO

Recent studies have suggested that miR-590 may play critical roles in cardiovascular disease. This study was designed to determine the effects of miR-590 on lipoprotein lipase (LPL) expression and development of atherosclerosis in apolipoprotein E knockout (apoE-/-) mice and explore the potential mechanisms. En face analysis of the whole aorta revealed that miR-590 significantly decreased aortic atherosclerotic plaque size and lipid content in apoE-/- mice. Double immunofluorescence staining in cross-sections of the proximal aorta showed that miR-590 agomir reduced CD68 and LPL expression in macrophages in atherosclerotic lesions. MiR-590 agomir down-regulated LPL mRNA and protein expression as analyzed by RT-qPCR and western blotting analyses, respectively. Consistently, miR-590 decreased the expression of CD36 and scavenger receptor A1 (SRA1) mRNA and protein. High-performance liquid chromatography (HPLC)analysis confirmed that treatment with miR-590 agomir reduced lipid levels either in plasma orinabdominal cavity macrophages of apoE-/- mice. ELISA analysis showed that miR-590 agomir decreased plasma levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-1ß (IL-1ß)and interleukin-6 (IL-6). In contrast, treatment with miR-590 antagomir prevented or reversed these effects. Taken together, these results reveal a novel mechanism of miR-590 effects, and may provide new insights into the development of strategies for attenuating lipid accumulation and pro-inflammatory cytokine secretion.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/enzimologia , Lipase Lipoproteica/genética , MicroRNAs/genética , Animais , Aorta/enzimologia , Aorta/patologia , Antígenos CD36/metabolismo , Citocinas/sangue , Repressão Enzimática , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Macrófagos Peritoneais/enzimologia , Masculino , Camundongos Knockout , MicroRNAs/metabolismo , Interferência de RNA
17.
Clin Chim Acta ; 450: 127-34, 2015 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-26265233

RESUMO

Trefoil factor family (TFF), composed of TFF1, TFF2, and TFF3, is a cluster of secreted peptides characterized by trefoil domain (s) and C-terminal dimerization domain. TFF1, a gastric tumor suppressor, is a single trefoil peptide originally detected in breast cancer cell lines but expressed mainly in the stomach; TFF2, a candidate of gastric cancer suppressor with two trefoil domains, is abundant in the stomach and duodenal Brunner's glands; and TFF3 is another single trefoil peptide expressed throughout the intestine which can promote the development of gastric carcinoma. According to multiple studies, TFFs play a regulatory function in the mammals' digestive system, namely in mucosal protection and epithelial cell reconstruction, tumor suppression or promotion, signal transduction and the regulation of proliferation and apoptosis. Action mechanisms of TFFs remain unresolved, but the recent demonstration of a GKN (gastrokine) 2-TFF1 heterodimer implicates structural and functional interplay with gastrokines. This review aims to encapsulate the structural and biological characteristics of TFF.


Assuntos
Peptídeos/metabolismo , Neoplasias Gástricas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos/química , Peptídeos/genética , Transporte Proteico , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Fator Trefoil-2
18.
Biochem Biophys Res Commun ; 452(4): 881-7, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25194807

RESUMO

The purpose of this study is to determine whether IL-27 regulates macrophage ABCA1 expression, foam cell formation, and also explore the underlying mechanisms. Here, we revealed that IL-27 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux and increasing ABCA1 expression at both protein and mRNA levels. Our study further demonstrated that IL-27 increased ABCA1 level via activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of Janus kinase 2, (JAK2)/STAT3 suppressed the stimulatory effects of IL-27 on ABCA1 expression. The present study concluded that IL-27 reduces lipid accumulation of foam cell by upregulating ABCA1 expression via JAK2/STAT3. Therefore, targeting IL-27 may offer a promising strategy to treat atherosclerotic vascular disease.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Células Espumosas/fisiologia , Interleucina-27/farmacologia , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fator de Transcrição STAT3/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Espumosas/citologia , Células Espumosas/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
19.
Cardiol Young ; 18(6): 608-14, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18812012

RESUMO

OBJECTIVES: The strategies of repair of tetralogy of Fallot change with the age of patients. In children older than 4 years and adults, the optimal strategy may be to use different method of reconstruction of the right ventricular outflow tract from those followed in younger children, so as to avoid, or reduce, the pulmonary insufficiency that is increasingly known to compromise right ventricular function. METHODS: From April, 2001, through May, 2008, we undertook complete repair in 312 patients, 180 male and 132 female, with a mean age of 11.3 years +/-0.4 years, and a range from 4 to 48 years, with typical clinical and morphological features of tetralogy of Fallot, including 42 patients with the ventriculo-arterial connection of double outlet right ventricle. The operation was performed under moderate hypothermia using blood cardioplegia. The ventricular septal defect was closed with a Dacron patch. When it was considered necessary to resect the musculature within the right ventricular outflow tract, or perform pulmonary valvotomy, we sought to preserve the function of the pulmonary valve by protecting as far as possible the native leaflets, or creating a folded monocusp of autologous pericardium. RESULTS: The repair was achieved completely through right atrium in 192, through the right ventricular outflow tract in 83, and through the right atrium, the outflow tract, and the pulmonary trunk in 36 patients. A transjunctional patch was inserted in 169 patients, non-valved in all but 9. There were no differences regarding the periods of aortic cross-clamping or cardiopulmonary bypass. Of the patients, 5 died (1.6%), with no influence noted for the transjunctional patch. Of those having a non-valved patch inserted, three-tenths had pulmonary regurgitation of various degree, while those having a valved patch had minimal pulmonary insufficiency and good right ventricular function postoperatively, this being maintained after follow-up of 8 to 24-months. CONCLUSIONS: Based on our experience, we suggest that the current strategy of repair of tetralogy of Fallot in older children and adults should be based on minimizing the insertion of transjunctional patches, this being indicated only in those with very small ventriculo-pulmonary junctions. If such a patch is necessary, then steps should be taken to preserve the function of the pulmonary valve.


Assuntos
Procedimentos Cirúrgicos Cardiovasculares/métodos , Pericárdio/transplante , Valva Pulmonar/cirurgia , Tetralogia de Fallot/cirurgia , Adolescente , Adulto , Fatores Etários , Ponte Cardiopulmonar , Procedimentos Cirúrgicos Cardiovasculares/efeitos adversos , Procedimentos Cirúrgicos Cardiovasculares/mortalidade , Criança , Pré-Escolar , China , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenotereftalatos , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/fisiopatologia , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Direita/fisiologia , Adulto Jovem
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