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1.
Cell Death Dis ; 11(6): 429, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513989

RESUMO

Although most patients with COVID-19 pneumonia have a good prognosis, some patients develop to severe or critical illness, and the mortality of critical cases is up to 61.5%. However, specific molecular information about immune response in critical patients with COVID-19 is poorly understood. A total of 54 patients were enrolled and divided into three groups, among which 34 were common, 14 were severe, and 6 were critical. The constitution of peripheral blood mononuclear cells (PBMC) in patients was analyzed by CyTOF. The profile of cytokines was examined in plasma of patients using luminex. The IL-2 signaling pathway was investigated in the PBMC of patients by qRT-PCR. The count and percentage of lymphocytes were significantly decreased in critical patients compared to common and severe patients with COVID-19 pneumonia. The count of T cells, B cells, and NK cells was remarkably decreased in critical patients compared to normal controls. The percentage of CD8+ T cells was significantly lower in critical patients than that in common and severe patients with COVID-19 pneumonia. The expression of IL-2R, JAK1, and STAT5 decreased in PBMC of common, severe, and critical patients, but IL-2 level was elevated in severe patients and decreased in critical patients with COVID-19 pneumonia. The decrease of CD8+ T cells in critical patients with COVID-19 pneumonia may be related to the IL-2 signaling pathway. The inhibition of IL-2/IL-2R gives rise to CD8+ T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia.


Assuntos
Betacoronavirus , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/sangue , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/sangue , Janus Quinase 1/metabolismo , Pneumonia Viral/sangue , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia
3.
Clin Infect Dis ; 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32307550

RESUMO

BACKGROUND: WHO characterizes novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pandemic. Here, we investigated the clinical, cytokine levels, T cell proportion and related gene expression occurring in COVID-19 patients on admission and after intial treatment. METHODS: 11 patients diagnosed as COVID-19 with similar initial treatment regimen were enrolled in the hospital. Plasma cytokines, CyTOF and microfluidic qPCR for gene expression were conducted. RESULTS: 5 mild and 6 severe patients were included. Cough and fever were the top symptoms in the 11 COVID-2019 cases. The elder age, more neutrophils numbers and higher C-reactive protein level were found in severe cases. IL-10 level was significantly varied with disease progression and treatment. The decreased T cell proportions were observed in COVID-19 patients especially in severe cases, and all elevated to normal in mild patiens after initial treatment but only CD4+T cells return to normal in severe cases. The number of DEGs increased with the disease progress, and decreased after initial treatment. All down-regulated DEGs in severe cases mainly involved in Th17 cell differentiation, cytokine-mediated signaling pathway and T cell activation. After initial treatmen in severe cases, MAP2K7 and SOS1 were upregulated relative to that on admission. CONCLUSIONS: Our findings show a decreased T cell proportion with down-regulated gene expression related to T cell activation and differentiation were occurred in COVID-19 severe patients, which may help to provide effective treatment strategies for COVID-19 .

4.
J Endocrinol ; 246(1): 13-27, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32302972

RESUMO

Chronic exposure of pancreatic ß-cells to saturated fatty acid (palmitic or stearic acid) is a leading cause of impaired insulin secretion. However, the molecular mechanisms underlying stearic-acid-induced ß-cell dysfunction remain poorly understood. Emerging evidence indicates that miRNAs are involved in various biological functions. The aim of this study was to explore the differential expression of miRNAs and mRNAs, specifically in stearic-acid-treated- relative to palmitic-acid-treated ß-cells, and to establish their co-expression networks. ß-TC-6 cells were treated with stearic acid, palmitic acid or normal medium for 24 h. Differentially expressed miRNAs and mRNAs were identified by high-throughput sequencing and bioinformatic analysis. Co-expression network, gene ontology (GO) and pathway analyses were then conducted. Changes in the expression of selected miRNAs and mRNAs were verified in ß-TC-6 cells and mouse islets. Sequencing analysis detected 656 known and 1729 novel miRNAs. miRNA-mRNA network and Venn-diagram analysis yielded two differentially expressed miRNAs and 63 mRNAs exclusively in the stearic-acid group. miR-374c-5p was up-regulated by a 1.801 log2(fold-change) and miR-297b-5p was down-regulated by a -4.669 log2(fold-change). We found that miR-297b-5p and miR-374c-5p were involved in stearic-acid-induced lipotoxicity to ß-TC-6 cells. Moreover, the effects of miR-297b-5p and miR-374c-5p on the alterations of candidate mRNAs expressions were verified. This study indicates that expression changes of specific miRNAs and mRNAs may contribute to stearic-acid-induced ß-cell dysfunction, which provides a preliminary basis for further functional and molecular mechanism studies of stearic-acid-induced ß-cell dysfunction in the development of type 2 diabetes.

5.
Aging (Albany NY) ; 12(1): 945-964, 2020 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927529

RESUMO

Analyses of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) implicated in myocardial infarction (MI) have increased our understanding of gene regulatory mechanisms in MI. However, it is not known how their expression fluctuates over the different stages of MI progression. In this study, we used time-series gene expression data to examine global lncRNA and miRNA expression patterns during the acute phase of MI and at three different time points thereafter. We observed that the largest expression peak for mRNAs, lncRNAs, and miRNAs occurred during the acute phase of MI and involved mainly protein-coding, rather than non-coding RNAs. Functional analysis indicated that the lncRNAs and miRNAs most sensitive to MI and most unstable during MI progression were usually related to fewer biological functions. Additionally, we developed a novel computational method for identifying dysregulated competing endogenous lncRNA-miRNA-mRNA triplets (LmiRM-CTs) during MI onset and progression. As a result, a new panel of candidate diagnostic biomarkers defined by seven lncRNAs was suggested to have high classification performance for patients with or without MI, and a new panel of prognostic biomarkers defined by two lncRNAs evidenced high discriminatory capability for MI patients who developed heart failure from those who did not.

6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 986-991, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878994

RESUMO

Objective To study the regulative effect of tumor protein p53 binding protein 2/p53 apoptosis-stimulating protein 2 (TP53BP2/ASPP2) on the autophagy of HepG2 human hepatoma cells and its mechanism. Methods The expression of ASPP2 was up-regulated or down-regulated by HepG2 cells infected with adenovirus and lentivirus. HepG2 cells were cultured in medium without fetal bovine serum for 24 hours. Western blotting was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3), beclin1, P62, autophagy-related gene 5 (ATG5), ATG7, and mammalian target of rapamycin (mTOR) pathway-associated protein mTOR, phospho-mTOR (p-mTOR), eukaryotic transcription initiation factor 4E binding protein 1 (4EBP1), phospho-4EBP1 (p-4EBP1), ribosomal protein S6, phospho-S6 (p-S6), ribosomal S6 kinase B1 (RPS6KB1/p70S6K), phospho-p70S6K (p-p70S6K). Fluorescence microscopy was used to detect the green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) fusion protein expressed by the cells. At the same time, the Hep3B cells without p53 expression were infected with lentivirus, and the levels of ASPP2 in the cells were knocked down. Western blotting was performed to detect the expression of ASPP2 and mTOR pathway-associated protein mTOR, p-mTOR, 4EBP1, p-4EBP1, S6, p-S6, RPS6KB1/p70S6K, p-p70S6K. Results When the expression of ASPP2 was up-regulated, the mTOR complex 1 (mTORC1) pathway was activated, and the expression of autophagy-related proteins and the number of autophagosomes were reduced. After the expression of ASPP2 was down-regulated, the mTORC1 pathway was inhibited, and the expression level of autophagy-related proteins and the number of autophagosomes increased. In Hep3B cells with p53 expression silence, the mTORC1 pathway was still inhibited when ASPP2 wasdown-regulated. Conclusion ASPP2 inhibits the autophagy of HepG2 cells by activating mTOR pathway in a p53-independent manner.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Células Hep G2 , Humanos , Proteína Supressora de Tumor p53
7.
Toxicol Lett ; 316: 85-93, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513885

RESUMO

BACKGROUND: Apoptosis-stimulating protein 2 of p53 (ASPP2) has a variety of biological functions, and is involved in cellular apoptosis, autophagy and inflammatory reaction. However, the role of ASPP2 in acute hepatic injury remains unclear. METHODS: We established an animal model of acute hepatic injury by intraperitoneal injection of CCl4. The expression profile of ASPP2 was measured in wild type (ASPP2+/+) mice with acute hepatic injury induced by CCl4. Hepatic pathological changes and liver function, apoptosis, inflammation and autophagic levels were measured in ASPP2+/+and ASPP2 haploid deletion (ASPP2+/-) mice with acute hepatic injury, respectively. After 3-methyladenine (3-MA) treatment, indicators of hepatic injury were observed in ASPP2+/+and ASPP2+/- mice with CCl4 injection. RESULTS: During the development of acute hepatic injury, ASPP2 expression significantly upregulated at 24 h and 48 h after CCl4 injection. ASPP2 haplotype deletion protected against acute hepatic injury, and this was mainly reflected in decreased ALT and AST levels, less hepatic tissue hemorrhage and necrosis, and reduced cellular inflammation and apoptosis in ASPP2+/- mice compared with ASPP2+/+ mice with acute hepatic injury. ASPP2 haploid deletion activates autophagy in mice with acute hepatic injury, and protects mice from acute hepatic injury via the autophagic signal pathway. CONCLUSION: ASPP2 haplotype deletion protected mice against acute hepatic injury through autophagy activation, which inhibited inflammation and apoptosis in acute hepatic injury.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/metabolismo , Proteínas Supressoras de Tumor/deficiência , Alanina Transaminase/sangue , Animais , Apoptose , Aspartato Aminotransferases/sangue , Autofagia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Haplótipos , Fígado/patologia , Masculino , Camundongos Knockout , Necrose , Fenótipo , Transdução de Sinais , Fatores de Tempo , Proteínas Supressoras de Tumor/genética
8.
Clin Nutr ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472986

RESUMO

BACKGROUND & AIMS: The objective nutritional assessment indicators, body mass index (BMI), upper arm muscle circumference (MAMC), and triceps skinfold thickness (TSF), are often limited due to ascites. This study investigated the prognostic value of the third lumbar vertebrae skeletal muscle mass index (L3 SMI) in addition to the objective nutritional evaluation indicators (BMI, MAMC and TSF) in patients with liver cirrhosis and ascites. METHODS: In this retrospective analysis, a total of 147 patients with liver cirrhosis and ascites were included. The L3 SMI, BMI, MAMC and TSF were detected in all patients. The severity of liver disease was assessed by the Model End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) classification. These variables were compared between non-surviving and surviving patients who were classified according to 5-year mortality. RESULTS: Of the 147 patients, 62 (42.2%) died and 85 (57.8%) survived within 5 years. The L3 SMI of patients was significantly lower than that of the normal control group (39.58 ± 7.18 cm2/m2 vs. 53.73 ± 7.92 cm2/m,2p < 0.001). The L3 SMI (OR 4.02; 95% CI 2.17-9.63; p < 0.001), MELD score (OR 2.11; 95% CI 1.12-4.13; p < 0.001) and CTP class (OR 2.69; 95% CI 1.09-5.06; p < 0.001) were independent predictive indicators of 5-year mortality. Furthermore, the performance of the two variables (L3 SMI and MELD) together (AUROC: 0.812) was significantly better than that of MELD alone (AUROC: 0.787) for prediction of 5-year mortality (p < 0.001). CONCLUSION: Compared with MAMC, TSF and BMI, L3 SMI is an independent risk factor for 5-year mortality in patients with liver cirrhosis and ascites. Further nutritional intervention studies are needed to confirm the impact of the L3 SMI index on clinical outcomes.

9.
BMC Gastroenterol ; 19(1): 148, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429707

RESUMO

BACKGROUND: Caspase-1 is an evolutionarily conserved enzyme that proteolytically cleaves the precursors of the inflammatory cytokines interleukin 1ß and interleukin 18. However, the role of caspase-1 in determining the severity of acute-on-chronic liver failure (ACLF) has yet to be elucidated. We evaluated the expression levels of caspase-1 in HBV-related liver disease and assessed its utility as a biomarker predicting the severity of ACLF. METHODS: The gene, protein and activity levels of caspase-1 were measured in the liver and/or serum of subjects with HBV-related disease. We also analysed the correlation between the expression levels of caspase-1 and liver injury of ACLF. RESULTS: Compared with the values observed in normal subjects, the relative caspase-1 mRNA and protein levels in livers were decreased in patients with CHB, LC, and HCC but increased in those with ACLF; moreover, ACLF patients had the lowest serum level and hepatic activity of caspase-1 among the five groups. The serum caspase-1 levels in ACLF patients showed a negative correlation with total serum bilirubin and a positive correlation with serum total protein and albumin. Importantly, the serum caspase-1 levels in the surviving group with ACLF were higher than those in the non-surviving group and showed different dynamic trends. Analyses of the area under the receiver operating characteristic curve indicated that caspase-1 (AUC = 0.84, AUC of MELD score = 0.72) may be a useful marker for independently predicting ACLF. CONCLUSION: Caspase-1 is a potential non-invasive biomarker of disease progression and prognosis in ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada , Caspase 1 , Hepatite B Crônica , Fígado , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas Sanguíneas/análise , Caspase 1/sangue , Caspase 1/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Humanos , Fígado/enzimologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença
10.
World J Gastroenterol ; 25(25): 3281-3282, 2019 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-31333318

RESUMO

[This retracts the article on p. 224 in vol. 23, PMID: 28127196.].

11.
Med Sci Monit ; 25: 3941-3956, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31132294

RESUMO

BACKGROUND Adenocarcinoma of the lung is a type of non-small cell lung cancer (NSCLC). Clinical outcome is associated with tumor grade, stage, and subtype. This study aimed to identify RNA expression profiles, including long noncoding RNA (lncRNA), microRNA (miRNA), and mRNA, associated with clinical outcome in adenocarcinoma of the lung using bioinformatics data. MATERIAL AND METHODS The miRNA and mRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database, and lncRNA expression profiles were downloaded from The Atlas of Noncoding RNAs in Cancer (TANRIC) database. The independent dataset, the Gene Expression Omnibus (GEO) accession dataset, GSE81089, was used. RNA expression profiles were used to identify comprehensive prognostic RNA signatures based on patient survival time. RESULTS From 7,704 lncRNAs, 787 miRNAs, and 28,937 mRNAs of 449 patients, four joint RNA molecular signatures were identified, including RP11-909N17.2, RP11-14N7.2 (lncRNAs), MIR139 (miRNA), KLHDC8B (mRNA). The random forest (RF) classifier was used to test the prediction ability of patient survival risk and showed a good predictive accuracy of 71% and also showed a significant difference in overall survival (log-rank P=0.0002; HR, 3.54; 95% CI, 1.74-7.19). The combined RNA signature also showed good performance in the identification of patient survival in the validation and independent datasets. CONCLUSIONS This study identified four RNA sequences as a prognostic molecular signature in adenocarcinoma of the lung, which may also provide an increased understanding of the molecular mechanisms underlying the pathogenesis of this malignancy.


Assuntos
Adenocarcinoma de Pulmão/genética , Perfilação da Expressão Gênica/métodos , Transcriptoma/genética , Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , Prognóstico , Modelos de Riscos Proporcionais , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Curva ROC , Análise de Sobrevida
12.
Exp Ther Med ; 17(5): 4273-4278, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30988799

RESUMO

MicroRNAs (miRs) are widely involved in regulating tumor development and progression. miR-758-3p has been reported to suppress the progression of various cancer types, including hepatocellular carcinoma. However, whether miR-758-3p has a role in bladder cancer (BC) has not been previously reported, and was thus investigated in the present study. It was revealed that miR-758-3p was downregulated in BC tissues and cell lines. Transfection with miR-758-3p mimics suppressed the proliferation, migration and invasion of BC cells, and inhibition of miR-758-3p had the opposite effect. In terms of the underlying mechanisms, a luciferase reporter assay revealed that Notch receptor 2 (NOTCH2) is a direct target gene of miR-758-3p in BC cells. Transfection with miR-758-3p mimics decreased the mRNA and protein levels of NOTCH2. Furthermore, an inverse correlation between miR-758-3p and NOTCH2 levels was identified. Finally, overexpression of NOTCH2 significantly rescued the proliferation, migration and invasion of BC cells transfected with miR-758-3p mimics. Taken together, the present study indicated that miR-758-3p suppresses BC cell proliferation, migration and invasion by targeting NOTCH2.

13.
iScience ; 14: 1-14, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30921732

RESUMO

The limited efficiency of the available tools for genetic manipulation of Pseudomonas limits fundamental research and utilization of this genus. We explored the properties of a lambda Red-like operon (BAS) from Pseudomonas aeruginosa phage Ab31 and a Rac bacteriophage RecET-like operon (RecTEPsy) from Pseudomonas syringae pv. syringae B728a. Compared with RecTEPsy, the BAS operon was functional at a higher temperature indicating potential to be a generic system for Pseudomonas. Owing to the lack of RecBCD inhibitor in the BAS operon, we added Redγ or Pluγ and found increased recombineering efficiencies in P. aeruginosa and Pseudomonas fluorescens but not in Pseudomonas putida and P. syringae. Overexpression of single-stranded DNA-binding protein enhanced recombineering in several contexts including RecET recombination in E. coli. The utility of these systems was demonstrated by engineering P. aeruginosa genomes to create an attenuated rhamnolipid producer. Our work enhances the potential for functional genomics in Pseudomonas.

14.
Exp Ther Med ; 17(3): 2256-2262, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30867710

RESUMO

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury with no effective treatment. Chrysin is an anti-inflammatory, anti-oxidant and anti-cancer agent. However, the effect of chrysin on renal IR injury remains unknown. In this study, sham operation, IR and IR+chrysin group mice were treated with or without renal IR injury. For renal IR, bilateral renal pedicles were clamped for 30 min and then released for 48 h of reperfusion. Blood and kidney samples were collected for analysis. Results demonstrated that chrysin pretreatment remarkably decreased the levels of serum creatinine and blood urea nitrogen and attenuated morphological abnormalities in renal IR injury. Consistently, tubular cell apoptosis and inflammation were more attenuated in the chrysin pretreatment group compared with the IR group. Chrysin pretreatment decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in renal IR injury. Furthermore, chrysin administration decreased the mRNA and protein levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Furthermore, the IκBα/nuclear factor-κB signaling pathway was more suppressed in the chrysin pretreatment group compared with the IR group. In conclusion, chrysin protects against tubular cell apoptosis and inflammation in renal IR injury.

15.
J Cell Mol Med ; 23(4): 2457-2467, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30675758

RESUMO

Acute kidney injury (AKI) has become a common disorder with a high risk of morbidity and mortality, which remains major medical problem without reliable and effective therapeutic intervention. Apoptosis-stimulating protein two of p53 (ASPP2) is a proapoptotic member that belongs to p53 binding protein family, which plays a key role in regulating apoptosis and cell growth. However, the role of ASPP2 in AKI has not been reported. To explore the role of ASPP2 in the progression of AKI, we prepared an AKI mouse model induced by ischaemia reperfusion (I/R) in wild-type (ASPP2+/+ ) mice and ASPP2 haploinsufficient (ASPP2+/- ) mice. The expression profile of ASPP2 were examined in wild-type mice. The renal injury, inflammation response, cellular apoptosis and autophagic pathway was assessed in ASPP2+/+ and ASPP2+/- mice. The renal injury, inflammation response and cellular apoptosis was analysed in ASPP2+/+ and ASPP2+/- mice treated with 3-methyladenine or vehicle. The expression profile of ASPP2 showed an increase at the early stage while a decrease at the late stage during renal injury. Compared with ASPP2+/+ mice, ASPP2 deficiency protected mice against renal injury induced by I/R, which mainly exhibited in slighter histologic changes, lower levels of blood urea nitrogen and serum creatinine, and less apoptosis as well as inflammatory response. Furthermore, ASPP2 deficiency enhanced autophagic activity reflecting in the light chain 3-II conversion and p62 degradation, while the inhibition of autophagy reversed the protective effect of ASPP2 deficiency on AKI. These data suggest that downregulation of ASPP2 can ameliorate AKI induced by I/R through activating autophagy, which may provide a novel therapeutic strage for AKI.

16.
J Cell Mol Med ; 23(1): 306-316, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30338905

RESUMO

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. Although some genes and miRNAs related with HCM have been studied, the molecular regulatory mechanisms between miRNAs and transcription factors (TFs) in HCM have not been systematically elucidated. In this study, we proposed a novel method for identifying dysregulated miRNA-TF feed-forward loops (FFLs) by integrating sample matched miRNA and gene expression profiles and experimentally verified interactions of TF-target gene and miRNA-target gene. We identified 316 dysregulated miRNA-TF FFLs in HCM, which were confirmed to be closely related with HCM from various perspectives. Subpathway enrichment analysis demonstrated that the method was outperformed by the existing method. Furthermore, we systematically analysed the global architecture and feature of gene regulation by miRNAs and TFs in HCM, and the FFL composed of hsa-miR-17-5p, FASN and STAT3 was inferred to play critical roles in HCM. Additionally, we identified two panels of biomarkers defined by three TFs (CEBPB, HIF1A, and STAT3) and four miRNAs (hsa-miR-155-5p, hsa-miR-17-5p, hsa-miR-20a-5p, and hsa-miR-181a-5p) in a discovery cohort of 126 samples, which could differentiate HCM patients from healthy controls with better performance. Our work provides HCM-related dysregulated miRNA-TF FFLs for further experimental study, and provides candidate biomarkers for HCM diagnosis and treatment.

17.
Brief Bioinform ; 20(1): 203-209, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28968812

RESUMO

Complex diseases cannot be understood only on the basis of single gene, single mRNA transcript or single protein but the effect of their collaborations. The combination consequence in molecular level can be captured by the alterations of metabolites. With the rapidly developing of biomedical instruments and analytical platforms, a large number of metabolite signatures of complex diseases were identified and documented in the literature. Biologists' hardship in the face of this large amount of papers recorded metabolic signatures of experiments' results calls for an automated data repository. Therefore, we developed MetSigDis aiming to provide a comprehensive resource of metabolite alterations in various diseases. MetSigDis is freely available at http://www.bio-annotation.cn/MetSigDis/. By reviewing hundreds of publications, we collected 6849 curated relationships between 2420 metabolites and 129 diseases across eight species involving Homo sapiens and model organisms. All of these relationships were used in constructing a metabolite disease network (MDN). This network displayed scale-free characteristics according to the degree distribution (power-law distribution with R2 = 0.909), and the subnetwork of MDN for interesting diseases and their related metabolites can be visualized in the Web. The common alterations of metabolites reflect the metabolic similarity of diseases, which is measured using Jaccard index. We observed that metabolite-based similar diseases are inclined to share semantic associations of Disease Ontology. A human disease network was then built, where a node represents a disease, and an edge indicates similarity of pair-wise diseases. The network validated the observation that linked diseases based on metabolites should have more overlapped genes.


Assuntos
Doença , Metaboloma , Metabolômica/estatística & dados numéricos , Animais , Biologia Computacional/métodos , Bases de Dados Factuais/estatística & dados numéricos , Doença/genética , Humanos , Ferramenta de Busca
18.
Chin J Integr Med ; 25(1): 51-58, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26542309

RESUMO

OBJECTIVE: To investigate the potential antifibrotic mechanisms of Chinese medicine Ganshuang Granules (, GSG) and to provide clinical therapeutic evidence of its effects. METHODS: A cirrhotic mouse model was established by intraperitoneally injecting a mixture of CCl4 (40%) and oil (60%) at 0.2 mL per 100 g of body weight twice a week for 12 weeks. After 12-week modeling, GSG was intragastric administrated to the mice for 2 weeks, and the mice were divided into low-, medium- and high-dose groups at doses of 1, 2 and 4 g/(kg·day), respectively. Liver morphology changes were observed using Masson's trichrome staining and B-ultrasound. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hyaluronic acid (HA) in serum were detected using an automatic biochemistry analyzer. The expressions of desmin, smooth muscle actin (SMA) and Foxp3 in liver were detected by immunoflfluorescence. The regulatory T cell (Treg) frequency was determined through flflow cytometry analysis. Collagen-I, SMA, IL-6, tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and transforming growth factor ß1 (TGF-ß1) expression levels were measured using quantitative polymerase chain reaction (qPCR). RESULTS: Masson's staining result showed fewer pseudolobule structures and fibrous connective tissue in the GSG-treatment groups than in the spontaneous recovery group. Ultrasonography showed that GSG treatment reduced the number of punctate hyperechoic lesions in mice cirrhotic livers. The serum ALT, AST, HA levels were significantly ameliorated by GSG treatment (ALT: F=8.104, P=0.000; AST: F=7.078, P=0.002; and HA: F=7.621, P=0.001). The expression levels of collagen-I and SMA in the cirrhotic livers were also attenuated by GSG treatment (collagen-I: F=3.938, P=0.011; SMA: F=4.115, P=0.009). Tregs, which were elevated in the fibrotic livers, were suppressed by GSG treatment (F=8.268, P=0.001). The expressions of IL-6, TNF-α and IL-1ß increased, and TGF-ß levels decreased in the cirrhotic livers after GSG treatment (IL-6: F=5.457, P=0.004; TNF-α: F=6.023, P=0.002; IL-1ß: F=6.658, P=0.001; and TGF-ß1: F=11.239, P=0.000). CONCLUSIONS: GSG promoted the resolution/regression of cirrhosis and restored liver functions in part by suppressing Treg cell differentiation, which may be mediated by hepatic stellate cells.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática Experimental/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
19.
Biomed Pharmacother ; 111: 468-475, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30594786

RESUMO

Kaempferol is a flavonoid compound that has many functions, such as anti-inflammation and antioxidation. Acute liver failure (ALF) is a life-threatening illness accompanied by serious inflammation and extensive hepatocyte apoptosis. The aim of this study was to examine the therapeutic potential of kaempferol and its mechanism in ALF. In a murine ALF model induced by d-galactosamine (d-GalN, 700 mg/kg) / lipopolysaccharide (LPS, 10 µg/kg), mice were pretreated with kaempferol at 2 h before d-GalN/LPS administration and then sacrificed 6 h after d-GalN/LPS injection. Lethality, liver damage, endoplasmic reticulum(ER) stress, hepatocyte viability and apoptosis were evaluated. Whether pretreatment of kaempferol protected hepatocytes from ER stress-induced apoptosis was detected in vitro. Pretreatment of kaempferol decreased lethality, prolonged the survival time and significantly protected against liver injury, which was indicated by decreased transaminase levels and the well-preserved liver structure. The protective effect of kaempferol on the ALF mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, pretreatment of kaempferol increased the expression of glucose-regulated/binding immunoglobulin protein 78 (Grp78), decreased the expression of C/EBP-homologous protein (CHOP), and protected hepatocytes from ER stress-induced apoptosis in vitro. Our results showed that pretreatment of Grp78 siRNA partially negated the hepatic protection from kaempferol and reversed the inhibition of CHOP protein expression in d-GalN/LPS-induced ALF mice. In conclusion, kaempferol inhibits hepatocyte apoptosis to protect mice from liver failure by regulating the ER stress-Grp78-CHOP signaling pathway. Therefore, kaempferol may be used to treat ALF.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Galactosamina/toxicidade , Proteínas de Choque Térmico/biossíntese , Quempferóis/uso terapêutico , Falência Hepática Aguda/metabolismo , Fator de Transcrição CHOP/biossíntese , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Estresse do Retículo Endoplasmático/fisiologia , Proteínas de Choque Térmico/agonistas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Quempferóis/farmacologia , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Transcrição CHOP/antagonistas & inibidores
20.
Sci Rep ; 8(1): 17927, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30560875

RESUMO

Although liver regeneration has been intensively studied in various ways, the mechanisms underlying liver regeneration remain elusive. Apoptosis-stimulating protein two of p53 (ASPP2) was discovered as a binding partner of p53 and plays an important role in regulating cell apoptosis and growth. However, the role of ASPP2 in hepatocyte proliferation and liver regeneration has not been reported. The expression profile of ASPP2 was measured in a mouse model with 70% partial hepatectomy (PHX). Liver regeneration and hepatocyte proliferation were detected in wild-type (ASPP2+/+) and ASPP2 haploinsufficient (ASPP2+/-) mice with PHX. The mammalian target of rapamycin (mTOR) and autophagy pathways were analyzed in the ASPP2+/+ and ASPP2+/- mice with PHX. After rapamycin or 3-methyladenine (3-MA) treatment, hepatocyte proliferation and liver regeneration were analyzed in the ASPP2+/+ and ASPP2+/- mice with PHX. ASPP2 expression was shown to be upregulated at the early stage and downregulated at the late stage. Compared to the ASPP2+/+ mice, liver regeneration was enhanced in ASPP2+/- mice with 70% PHX. In addition, compared to the ASPP2+/+ mice, the mTORC1 pathway was significantly upregulated and the autophagic pathway was downregulated in ASPP2+/-mice with 70% PHX. Inhibition of the mTORC1 pathway significantly suppressed liver regeneration in ASPP2+/- mice with 70% PHX. In contrast, disruption of the autophagic pathway further enhanced liver regeneration in ASPP2+/- mice with 70% PHX. ASPP2 deficiency can promote liver regeneration through activating the mTORC1 pathway, which further regulates downstream molecules, such as those related to autophagy and p70S6K expression in mouse model post-PHX.


Assuntos
Regeneração Hepática , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Haploinsuficiência , Hepatócitos/citologia , Hepatócitos/metabolismo , Camundongos , Sirolimo/farmacologia
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