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Li P, Liang X, Luo J, Li J. Omics in acute-on-chronic liver failure. Liver Int 2025; 45:e15634. [PMID: 37288724 DOI: 10.1111/liv.15634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/03/2023] [Accepted: 05/24/2023] [Indexed: 06/09/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a critical syndrome that develops in patients with chronic liver disease and is characterized by acute decompensation, single- or multiple-organ failure and high short-term mortality. Over the past few decades, ACLF has been progressively recognized as an independent clinical entity, and several criteria and prognostic scores have been proposed and validated by different scientific societies. However, controversies still exist in some aspects across regions, which mainly involve whether the definition of underlying liver diseases should include cirrhosis and non-cirrhosis. The pathophysiology of ACLF is complicated and remains unclear, although accumulating evidence based on different aetiologies of ACLF shows that it is closely associated with intense systemic inflammation and immune-metabolism disorder, which result in mitochondrial dysfunction and microenvironment imbalance, leading to disease development and organ failure. In-depth insight into the biological pathways involved in the mechanisms of ACLF and potential mechanistic targets that improve patient survival still needs to be investigated. Omics-based analytical techniques, including genomics, transcriptomics, proteomics, metabolomics and microbiomes, have developed rapidly and can offer novel insights into the essential pathophysiologic process of ACLF. In this paper, we briefly reviewed and summarized the current knowledge and recent advances in the definitions, criteria and prognostic assessments of ACLF; we also described the omics techniques and how omics-based analyses have been applied to investigate and characterize the biological mechanisms of ACLF and identify potential predictive biomarkers and therapeutic targets for ACLF. We also outline the challenges, future directions and limitations presented by omics-based analyses in clinical ACLF research.
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Affiliation(s)
- Peng Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinjin Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Oshins R, Huo Z, Greenberg Z, Clark V, Duarte S, Zhou H, West J, He M, Brantly M, Khodayari N. Plasma Extracellular Vesicle-derived MicroRNA Associated with Human Alpha-1 Antitrypsin Deficiency-mediated Liver Disease. J Clin Transl Hepatol 2025; 13:118-129. [PMID: 39917464 PMCID: PMC11797821 DOI: 10.14218/jcth.2024.00253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/30/2024] [Accepted: 11/04/2024] [Indexed: 02/09/2025] Open
Abstract
Background and Aims Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with liver disease, ranging from fibrosis to hepatocellular carcinoma. The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy. Biomarkers offer an advantage for disease evaluation. The presence of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) presents a noninvasive approach to assess the molecular signatures of the disease. In this study, we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals. Methods Using small RNA sequencing and qPCR, we examined plasma EV miRNAs in healthy controls (n = 20) and AATD patients (n = 17). We compared the EV miRNAs of AATD individuals with and without liver disease, developing an approach for detecting liver disease. A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients (n = 45). Results We identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls. We categorized AATD individuals into those with and without liver disease, identifying 39 differentially expressed miRNAs. Six miRNAs were selected to test their ability to discriminate liver disease in AATD. These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals. Our logistic model established composite scores with three- and four-miRNA combinations, achieving areas under the curve of 0.737 and 0.751, respectively, for predicting AATD liver disease. Conclusions We introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease. Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.
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Affiliation(s)
- Regina Oshins
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Zhiguang Huo
- Department of Biostatistics, College of Public Health, University of Florida, Gainesville, FL, USA
| | - Zachary Greenberg
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Virginia Clark
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA
| | - Sergio Duarte
- Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, University of Florida, Gainesville, FL, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond VA Medical Center, Richmond, VA, USA
| | - Jesse West
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Mark Brantly
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Nazli Khodayari
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
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Park YN, Ryu JK, Ju Y. The Potential MicroRNA Diagnostic Biomarkers in Oral Squamous Cell Carcinoma of the Tongue. Curr Issues Mol Biol 2024; 46:6746-6756. [PMID: 39057044 PMCID: PMC11276561 DOI: 10.3390/cimb46070402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) of the tongue is a common type of head and neck malignancy with a poor prognosis, underscoring the urgency for early detection. MicroRNAs (miRNAs) have remarkable stability and are easily measurable. Thus, miRNAs may be a promising biomarker candidate among biomarkers in cancer diagnosis. Biomarkers have the potential to facilitate personalized medicine approaches by guiding treatment decisions and optimizing therapy regimens for individual patients. Utilizing data from The Cancer Genome Atlas, we identified 13 differentially expressed upregulated miRNAs in OSCC of the tongue. Differentially expressed miRNAs were analyzed by enrichment analysis to reveal underlying biological processes, pathways, or functions. Furthermore, we identified miRNAs associated with the progression of OSCC of the tongue, utilizing receiver operating characteristic analysis to evaluate their potential as diagnostic biomarkers. A total of 13 upregulated miRNAs were identified as differentially expressed in OSCC of the tongue. Five of these miRNAs had high diagnostic power. In particular, miR-196b has the potential to serve as one of the most effective diagnostic biomarkers. Then, functional enrichment analysis for the target gene of miR-196b was performed, and a protein-protein interaction network was constructed. This study assessed an effective approach for identifying miRNAs as early diagnostic markers for OSCC of the tongue.
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Affiliation(s)
- Young-Nam Park
- Department of Dental Hygiene, Gimcheon University, Gimcheon 39528, Republic of Korea;
| | - Jae-Ki Ryu
- Department of Biomedical Laboratory Science, Gimcheon University, Gimcheon 39528, Republic of Korea;
| | - Yeongdon Ju
- Department of Biomedical Laboratory Science, Gimcheon University, Gimcheon 39528, Republic of Korea;
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Dai Q, Shi R, Zhang G, Wang Y, Ye L, Peng L, Guo S, He J, Yang H, Jiang Y. miR-539-5p targets BMP2 to regulate Treg activation in B-cell acute lymphoblastic leukemia through TGF-β/Smads/MAPK. Exp Biol Med (Maywood) 2024; 249:10111. [PMID: 38510491 PMCID: PMC10954254 DOI: 10.3389/ebm.2024.10111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/02/2023] [Indexed: 03/22/2024] Open
Abstract
MicroRNAs (mRNAs) were believed to play an important role in cancers, and this study aimed to explore the mechanism of miRNA regulating Treg in B-cell acute lymphoblastic leukemia (B-ALL). Firstly, the differentially expressed miRNAs and target genes significantly associated with Tregs were screened out by high-throughput sequencing, and their enrichment pathways were analyzed. The binding relationship between miRNA and target genes was further verified, and the effects of miRNA on the proliferation and apoptosis of B-ALL Nalm-6 cells and Treg activation were analyzed. Results showed that differentially expressed miR-539-5p was significantly under-expressed, and its target gene BMP2 was significantly over-expressed in B-ALL, and significantly enriched in the TGF-β1 pathway. In addition, both miR-539-5p and BMP2 were significantly correlated with Treg activity in B-ALL. In vitro experiments further confirmed that miR-539-5p could directly target BMP2. The low expression of miR-539-5p in B-ALL significantly promoted BMP2 expression to promote the proliferation and inhibit apoptosis of Nalm-6 cells. Furthermore, the high expression of BMP2 in B-ALL could cooperate with TGF-β1 to promote the activation of human CD4+CD25-T cells to Treg, and significantly activate the TGF-β/Smads/MAPK pathway. In vivo experiments also confirmed that overexpression of miR-539-5p significantly inhibited BMP2 to suppress Treg activation and Smad1 and Smad2 phosphorylation, and finally inhibit the B-ALL process. In conclusion, miR-539-5p was significantly under-expressed in B-ALL and could target BMP2 to promote its expression, and the overexpressed BMP2 further promoted Treg activation in B-ALL by regulating TGF-β/Smads/MAPK pathway.
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Affiliation(s)
- Qingkai Dai
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Rui Shi
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Ge Zhang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Yuefang Wang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Lei Ye
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Luyun Peng
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Siqi Guo
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Jiajing He
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Hao Yang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
| | - Yongmei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Obstetric and Gynecological and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan, China
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Listopad S, Magnan C, Asghar A, Stolz A, Tayek JA, Liu ZX, Morgan TR, Norden-Krichmar TM. Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples. JHEP Rep 2022; 4:100560. [PMID: 36119721 PMCID: PMC9472076 DOI: 10.1016/j.jhepr.2022.100560] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Liver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples. Methods We collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools. Results Utilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes. Conclusions Our machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases. Lay summary Distinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.
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Key Words
- AC, alcohol-associated cirrhosis
- AH, alcohol-associated hepatitis
- AKR1B10, aldo-keto reductase family 1 member B10
- BTM, blood transcription module
- Classification
- DE, differential expression
- FPKM, fragments per kilobase of exon model per million reads mapped
- GSEA, gene set-enrichment analysis
- IG, information gain
- IPA, Ingenuity Pathway Analysis
- LR, logistic regression
- LTCDS, liver tissue cell distribution system
- LV, liver tissue
- ML, machine learning
- MMP, matrix metalloproteases
- NAFLD, non-alcohol-associated fatty liver disease
- PBMCs, peripheral blood mononuclear cells
- RNA sequencing
- RNA-seq, RNA sequencing
- SCAHC, Southern California Alcoholic Hepatitis Consortium
- SVM, support vector machine
- TNF, tumor necrosis factor
- alcohol-associated liver disease
- biomarker discovery
- kNN, k-nearest neighbors
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Affiliation(s)
- Stanislav Listopad
- Department of Computer Science, University of California, Irvine, CA 92697, USA
| | - Christophe Magnan
- Department of Computer Science, University of California, Irvine, CA 92697, USA
| | - Aliya Asghar
- Medicine and Research Services, VA Long Beach Healthcare System, Long Beach, CA 90822, USA
| | - Andrew Stolz
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - John A. Tayek
- Division of General Internal Medicine, Harbor-UCLA Medical Center, University of California Los Angeles, Torrance, CA 90509, USA
| | - Zhang-Xu Liu
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Timothy R. Morgan
- Medicine and Research Services, VA Long Beach Healthcare System, Long Beach, CA 90822, USA
| | - Trina M. Norden-Krichmar
- Department of Computer Science, University of California, Irvine, CA 92697, USA,Department of Epidemiology and Biostatistics, University of California, Irvine, CA 92697, USA,Corresponding author. Address: Department of Epidemiology and Biostatistics, University of California, Irvine, CA 92697 USA; Tel.: 949-824-8802.
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6
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Loukachov VV, van Dort KA, Maurer I, Takkenberg RB, de Niet A, Reesink HW, Willemse SB, Kootstra NA. Identification of Liver and Plasma microRNAs in Chronic Hepatitis B Virus infection. Front Cell Infect Microbiol 2022; 12:790964. [PMID: 35719345 PMCID: PMC9201251 DOI: 10.3389/fcimb.2022.790964] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 04/25/2022] [Indexed: 01/05/2023] Open
Abstract
Background and Aims With current standard of care a functional cure for Chronic Hepatitis B (CHB) is only achieved in 1-3% of patients and therefore novel therapies are needed. Disease activity during CHB can be determined by a broad range of virological biomarkers, however these biomarkers are also targets for novel treatment strategies. The aim of this study was to identify novel miRNAs that are differentially expressed in plasma and liver in CHB, and determine whether these miRNAs may serve as biomarkers of disease stage or treatment outcome. Methods miRNA Next-Generation-Sequencing of plasma and liver samples from CHB patient and controls was performed to identify differentially expressed miRNAs. The identified candidate miRNAs were validated by qPCR in additional plasma and liver samples from two CHB cohorts. Results Several miRNAs in plasma and liver were found to be differentially expressed between CHB patients and controls. Of the identified miRNAs expression levels of miR-122-5p in plasma were associated with plasma HBsAg, and plasma and liver HBV-DNA levels. Expression levels of miR-223-3p, miR-144-5p and miR-133a-3p in liver were associated with plasma alanine aminotransferase levels. No correlation was observed between miRNA expression levels at baseline and treatment outcome. Conclusions Limited overlap between plasma and liver miRNAs was found, indicating that plasma miRNAs could be useful as biomarkers for treatment outcome or viral activity during treatment. Whereas liver miRNAs are more likely to be regulated by HBV and could be potential therapeutic targets to control viral activity in liver.
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Affiliation(s)
- Vladimir V. Loukachov
- Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
| | - Karel A. van Dort
- Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
| | - Irma Maurer
- Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers , University of Amsterdam, Amsterdam, Netherlands
| | - Anniki de Niet
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers , University of Amsterdam, Amsterdam, Netherlands
| | - Henk W. Reesink
- Department of Gastroenterology and Hepatology, Leids University Medical Center, Leiden, Netherlands
| | - Sophie B. Willemse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers , University of Amsterdam, Amsterdam, Netherlands
| | - Neeltje A. Kootstra
- Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
- *Correspondence: Neeltje A. Kootstra,
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Jiang J, Xin J, Ding W, Shi D, Sun S, Guo B, Zhou X, Zheng C, Li J. MicroRNA Profile of Human Bone Marrow Mesenchymal Stem Cells during Hepatic Differentiation and Therapy. Int J Med Sci 2022; 19:152-163. [PMID: 34975309 PMCID: PMC8692113 DOI: 10.7150/ijms.67639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/26/2021] [Indexed: 12/05/2022] Open
Abstract
Background and Aims: MicroRNAs (miRNAs) play important roles in hepatocyte differentiation from human bone marrow mesenchymal stem cells (hBMSCs) and the therapeutic application in vivo. However, the mechanisms of miRNA regulation are still unknown. This study aimed to profile the miRNA basis for improving the function of hBMSC-differentiated hepatocyte-like cells (hBMSC-Heps). Methods: Characteristic miRNAs of hBMSC-Heps were identified by transcriptome sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). An in vivo hBMSC transplantation model was used to assess the regulatory effects of miRNAs on liver regeneration during hBMSC therapy in pigs with fulminant hepatic failure (FHF). The biological functions of significant miRNA molecules were confirmed by transfection of miRNA activators or inhibitors into hBMSCs during hepatogenic differentiation. Results: The transcriptome of hBMSC-Heps showed characteristics distinct from those of undifferentiated hBMSCs. A total of 77 miRNAs were significantly differentially expressed in hBMSC-Heps at day 10 and day 20 after hBMSC differentiation that were directly related to the functions of hepatocytes. Among the top 10 significantly differentially expressed and the top 10 most abundant miRNAs, nine miRNAs that exhibited a pattern of gradual change were chosen for further analysis. The expression of nine miRNAs was confirmed by qRT-PCR in vitro and showed the same changing trends in vivo in an hBMSC transplantation model in pigs. Functional experiments with these miRNAs showed that activators of hsa-miR-26b-5p and hsa-miR-148a-3p and an inhibitor of hsa-miR-423-3p were sufficient to improve the differentiation of hBMSCs into hepatocyte-like cells. Conclusions: Transcriptome profiles of miRNA revealed the basis of the differentiation and development of hBMSC-Heps. Manipulation of three miRNAs (hsa-miR-26b-5p, hsa-miR-148a-3p and hsa-miR-423-3p) significantly improved hepatocyte generation and liver regeneration, indicating the potential of these miRNAs for future clinical applications.
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Affiliation(s)
- Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Wenchao Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Suwan Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Xingping Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Chufan Zheng
- Hangzhou No.14 High School, 580 Fengqi Rd, Gongshu District, Hangzhou, 310006, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
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Ma S, Xie Z, Zhang L, Yang Y, Jiang H, Ouyang X, Zhao Y, Liu Q, Xu X, Li L. Identification of a Potential miRNA-mRNA Regulatory Network Associated With the Prognosis of HBV-ACLF. Front Mol Biosci 2021; 8:657631. [PMID: 33996909 PMCID: PMC8113841 DOI: 10.3389/fmolb.2021.657631] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
Background Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening disease with a high mortality rate; the systemic inflammatory response plays a vital role in disease progression. We aimed to determine if a miRNA–mRNA co-regulatory network exists in the peripheral blood mononuclear cells (PBMCs) of HBV-ACLF patients, which might be important for prognosis. Methods Transcriptome-wide microRNA (miRNA) and mRNA microarrays were used to define the miRNA and mRNA expression profiles of the PBMCs of HBV-ACLF patients in a discovery cohort. The targets of the miRNAs were predicted. We built a miRNA-mRNA regulatory network through bioinformatics analysis, and used quantitative real-time polymerase chain reaction (qRT-PCR) to assess the importance of candidate miRNAs and mRNAs. We also assessed the direct and transcriptional regulatory effects of miRNAs on target mRNAs using a dual-luciferase reporter assay. Results The miRNA/mRNA PBMC expression profiles of the discovery cohort, of whom eight survived and eight died, revealed a prognostic interactive network involving 38 miRNAs and 313 mRNAs; this was constructed by identifying the target genes of the miRNAs. We validated the expression data in another cohort, of whom 43 survived and 35 died; miR-6840-3p, miR-6861-3p, JADE2, and NR3C2 were of particular interest. The levels of miR-6840-3p and miR-6861-3p were significantly increased in the PBMCs of the patients who died, and thus predicted prognosis (areas under the curve values = 0.665 and 0.700, respectively). The dual-luciferase reporter assay indicated that miR-6840-3p directly targeted JADE2. Conclusion We identified a prognostic miRNA-mRNA co-regulatory network in the PBMCs of HBV-ACLF patients. miR-6840-3p-JADE2 is a potential miRNA–mRNA pair contributing to a poor prognosis.
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Affiliation(s)
- Shanshan Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongyang Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - He Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxi Ouyang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qiuhong Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowei Xu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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9
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Wei H, Wang X, Niu X, Jiao R, Li X, Wang S. miR‑34c‑5p targets Notch1 and suppresses the metastasis and invasion of cervical cancer. Mol Med Rep 2020; 23:120. [PMID: 33300051 PMCID: PMC7751466 DOI: 10.3892/mmr.2020.11759] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022] Open
Abstract
Micro (mi)RNAs are crucial participants in the progression of cervical cancer (CC). Growing evidence indicates that miRNA (miR)-34c-5p is a pivotal tumor suppressor in numerous types of cancer and its functions in CC require further investigating. The present study demonstrated that there was a decreased level of miR-34c-5p in CC-associated cell lines compared with healthy control samples. It also demonstrated that miR-34c-5p targeted Notch1 and suppressed CC progression. Dual-Luciferase reporter assays verified the targeted relationship of miR-34c-5p and Notch1. The expression of Notch1 in HeLa cells was markedly reduced following miR-34c-5p overexpression and the proliferation, migration and invasion of HeLa cells were reduced although apoptosis was accelerated. However, overexpression of miR-34c-5p was reversed following the addition of Notch1, which supported the finding of the targeted relationship between miR-34c-5p and Notch1. Flow cytometry demonstrated that miR-34c-5p inhibited the proliferation of HeLa cells while accelerating apoptosis. The present study concluded that miR-34c-5p was a tumor suppressor in CC and may be a novel measure for the future treatment of CC.
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Affiliation(s)
- Huali Wei
- Department of Gynecology and Obstetrics, Emergency General Hospital, Beijing 100028, P.R. China
| | - Xiaolan Wang
- Department of Gynecology and Obstetrics, Emergency General Hospital, Beijing 100028, P.R. China
| | - Xiumin Niu
- Department of Gynecology and Obstetrics, Emergency General Hospital, Beijing 100028, P.R. China
| | - Ruili Jiao
- Department of Gynecology and Obstetrics, Chaoyang District Maternal and Child Health Hospital, Beijing 100020, P.R. China
| | - Xiaojuan Li
- Department of Medical Records and Statistics, Emergency General Hospital, Beijing 100028, P.R. China
| | - Sumei Wang
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
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10
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Li Q, Wang J, Lu M, Qiu Y, Lu H. Acute-on-Chronic Liver Failure From Chronic-Hepatitis-B, Who Is the Behind Scenes. Front Microbiol 2020; 11:583423. [PMID: 33365018 PMCID: PMC7750191 DOI: 10.3389/fmicb.2020.583423] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is an acute syndrome accompanied with decompensation of cirrhosis, organ failure with high 28-day mortality rate. Systemic inflammation is the main feature of ACLF, and poor outcome is closely related with exacerbated systemic inflammatory responses. It is well known that severe systemic inflammation is an important event in chronic hepatitis B (CHB)-ACLF, which eventually leads to liver injury. However, the initial CHB-ACLF events are unclear; moreover, the effect of these events on host immunity as well as that of immune imbalance on CHB-ACLF progression are unknown. Here, we investigate the initial events of ACLF progression, discuss possible mechanisms underlying ACLF progression, and provide a new model for ACLF prediction and treatment. We review the characteristics of ACLF, and consider its plausible immune predictors and alternative treatment strategies.
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Affiliation(s)
- Qian Li
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Jun Wang
- Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Yuanwang Qiu
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Hongzhou Lu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
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11
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The miR-21 potential of serving as a biomarker for liver diseases in clinical practice. Biochem Soc Trans 2020; 48:2295-2305. [PMID: 33119045 DOI: 10.1042/bst20200653] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/18/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis. We elucidate the disease condition under which miR-21 testing can reach the expected performance. Though miR-21 is a key regulator of liver diseases, microRNAs coordinate with each other in the complex regulatory network. As a result, the performance of miR-21 is better when combined with other microRNAs or classical biomarkers under certain clinical circumstances.
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12
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Ozkan H, Tuzun F, Taheri S, Korhan P, Akokay P, Yılmaz O, Duman N, Özer E, Tufan E, Kumral A, Özkul Y. Epigenetic Programming Through Breast Milk and Its Impact on Milk-Siblings Mating. Front Genet 2020; 11:569232. [PMID: 33133155 PMCID: PMC7565666 DOI: 10.3389/fgene.2020.569232] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Background The epigenetic effects of transmission of certain regulatory molecules, such as miRNAs, through maternal milk on future generations, are still unknown and have not been fully understood yet. We hypothesized that breastfeeding regularly by adoptive-mother may cause transmission of miRNAs as epigenetic regulating factors to the infant, and the marriage of milk-siblings may cause various pathologies in the future generations. Results A cross-fostering model using a/a and Avy/a mice had been established. F2 milk-sibling and F2 control groups were obtained from mating of milk-siblings or unrelated mice. Randomized selected animals in the both F2 groups were sacrificed for miRNA expression studies and the remainings were followed for phenotypic changes (coat color, obesity, hyperglycemia, liver pathology, and life span). The lifespan in the F2 milk-sibling group was shorter than the control group (387 vs 590 days, p = 0.011) and they were more obese during the aging period. Histopathological examination of liver tissues revealed abnormal findings in F2 milk-sibling group. In order to understand the epigenetic mechanisms leading to these phenotypic changes, we analyzed miRNA expression differences between offspring of milk-sibling and control matings and focused on the signaling pathways regulating lifespan and metabolism. Bioinformatic analysis demonstrated that differentially expressed miRNAs were associated with pathways regulating metabolism, survival, and cancer development such as the PI3K-Akt, ErbB, mTOR, and MAPK, insulin signaling pathways. We further analyzed the expression patterns of miR-186-5p, miR-141-3p, miR-345-5p, and miR-34c-5p and their candidate target genes Mapk8, Gsk3b, and Ppargc1a in ovarian and liver tissues. Conclusion Our findings support for the first time that the factors modifying the epigenetic mechanisms may be transmitted by breast milk and these epigenetic interactions may be transferred transgenerationally. Results also suggested hereditary epigenetic effects of cross-fostering on future generations and the impact of mother-infant dyad on epigenetic programming.
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Affiliation(s)
- Hasan Ozkan
- Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Funda Tuzun
- Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Serpil Taheri
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.,Erciyes University's Betul-Ziya Eren Genome and Stem Cell (Genkok), Kayseri, Turkey
| | - Peyda Korhan
- İzmir Biomedicine and Genome Center, Dokuz Eylul University, İzmir, Turkey
| | - Pınar Akokay
- Department of Medical Laboratory Techniques, İzmir Kavram University, İzmir, Turkey
| | - Osman Yılmaz
- The Experimental Animal Laboratory, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Nuray Duman
- Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Erdener Özer
- Department of Pathology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Esra Tufan
- Erciyes University's Betul-Ziya Eren Genome and Stem Cell (Genkok), Kayseri, Turkey
| | - Abdullah Kumral
- Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Yusuf Özkul
- Erciyes University's Betul-Ziya Eren Genome and Stem Cell (Genkok), Kayseri, Turkey.,Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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13
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Lu Y, Fang Z, Li M, Chen Q, Zeng T, Lu L, Chen Q, Zhang H, Zhou Q, Sun Y, Xue X, Hu Y, Chen L, Su S. Dynamic edge-based biomarker non-invasively predicts hepatocellular carcinoma with hepatitis B virus infection for individual patients based on blood testing. J Mol Cell Biol 2020; 11:665-677. [PMID: 30925583 PMCID: PMC6788726 DOI: 10.1093/jmcb/mjz025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/27/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths in Asia and Africa. Developing effective and non-invasive biomarkers of HCC for individual patients remains an urgent task for early diagnosis and convenient monitoring. Analyzing the transcriptomic profiles of peripheral blood mononuclear cells from both healthy donors and patients with chronic HBV infection in different states (i.e. HBV carrier, chronic hepatitis B, cirrhosis, and HCC), we identified a set of 19 candidate genes according to our algorithm of dynamic network biomarkers. These genes can both characterize different stages during HCC progression and identify cirrhosis as the critical transition stage before carcinogenesis. The interaction effects (i.e. co-expressions) of candidate genes were used to build an accurate prediction model: the so-called edge-based biomarker. Considering the convenience and robustness of biomarkers in clinical applications, we performed functional analysis, validated candidate genes in other independent samples of our collected cohort, and finally selected COL5A1, HLA-DQB1, MMP2, and CDK4 to build edge panel as prediction models. We demonstrated that the edge panel had great performance in both diagnosis and prognosis in terms of precision and specificity for HCC, especially for patients with alpha-fetoprotein-negative HCC. Our study not only provides a novel edge-based biomarker for non-invasive and effective diagnosis of HBV-associated HCC to each individual patient but also introduces a new way to integrate the interaction terms of individual molecules for clinical diagnosis and prognosis from the network and dynamics perspectives.
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Affiliation(s)
- Yiyu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhaoyuan Fang
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Meiyi Li
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Minhang Branch, Zhongshan Hospital/Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
| | - Qian Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Zeng
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lina Lu
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qilong Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianmei Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Sun
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China
| | - Xuefeng Xue
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China
| | - Yiyang Hu
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.,School of Life Science and Technology, Shanghai Tech University, Shanghai, China.,Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
| | - Shibing Su
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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14
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Iacob DG, Rosca A, Ruta SM. Circulating microRNAs as non-invasive biomarkers for hepatitis B virus liver fibrosis. World J Gastroenterol 2020; 26:1113-1127. [PMID: 32231417 PMCID: PMC7093315 DOI: 10.3748/wjg.v26.i11.1113] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
Viruses can alter the expression of host microRNAs (MiRNA s) and modulate the immune response during a persistent infection. The dysregulation of host MiRNA s by hepatitis B virus (HBV) contributes to the proinflammatory and profibrotic changes within the liver. Multiple studies have documented the differential regulation of intracellular and circulating MiRNA s during different stages of HBV infection. Circulating MiRNA s found in plasma and/or extracellular vesicles can integrate data on viral-host interactions and on the associated liver injury. Hence, the detection of circulating MiRNA s in chronic HBV hepatitis could offer a promising alternative to liver biopsy, as their expression is associated with HBV replication, the progression of liver fibrosis, and the outcome of antiviral treatment. The current review explores the available data on miRNA involvement in HBV pathogenesis with an emphasis on their potential use as biomarkers for liver fibrosis.
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Affiliation(s)
- Diana Gabriela Iacob
- Infectious Diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Bucharest Emergency University Hospital, Bucharest 050098, Romania
| | - Adelina Rosca
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Simona Maria Ruta
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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15
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Vyas HS, Upadhyay KK, Devkar RV. miRNAs Signatures In Patients With Acute Liver Injury: Clinical Concerns and Correlations. Curr Mol Med 2019; 20:325-335. [PMID: 31823701 DOI: 10.2174/1566524020666191211153546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 11/22/2022]
Abstract
Non-coding RNAs can be highly exploited for their biological significance in living systems. miRNAs are in the upstream position of cellular regulation cascade and hold merit in its state. A plethora of information is available on a wide variety of miRNAs that undergo alterations in experimentally induced models of liver injuries. The underlying mechanisms governed by these miRNAs have been inferred through cellbased experiments but the scientific knowledge on miRNA signatures in patients with liver injury are primordial and lack scientific clarity. Hence, it is crucial to get insight into the status and synergy of miRNAs in patients, with varying degrees of acute toxic manifestations in the liver. Though some miRNAs are being investigated in clinical trials, a major research lacuna exists with regard to the functional role of other miRNAs in liver diseases. This review article is a meticulous compilation of disease based or drug/alcohol based acute liver injuries in patients and resultant alteration in their miRNA profile. Investigative reports on underlying miRNA-liver crosstalk in cell-based or murine models are also discussed herein to draw a correlation with clinical findings.
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Affiliation(s)
- Hitarthi S Vyas
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Kapil K Upadhyay
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Ranjitsinh V Devkar
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
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16
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Kim JY, Jun JH, Park SY, Yang SW, Bae SH, Kim GJ. Dynamic Regulation of miRNA Expression by Functionally Enhanced Placental Mesenchymal Stem Cells PromotesHepatic Regeneration in a Rat Model with Bile Duct Ligation. Int J Mol Sci 2019; 20:ijms20215299. [PMID: 31653075 PMCID: PMC6862171 DOI: 10.3390/ijms20215299] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/22/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Placenta-derived mesenchymal stem cells (PD-MSCs) were highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs)were found to mediate one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with migrated naïve PD-MSCs, migrated PRL-1(+) PD-MSCs showed improved integrin-dependent migration abilitythrough Ras homolog (RHO) family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplantedPRL-1(+) PD-MSCs through the integrin family. Additionally, an increase inplatelet-derived growth factor receptor A (PDGFRA) by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSC transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs byactivating the interleukin-6 (IL-6) signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understandingof therapeutic mechanisms based on miRNA-mediated stem-cell therapy in liver diseases.
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Affiliation(s)
- Jae Yeon Kim
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
| | - Ji Hye Jun
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
| | - Soo Young Park
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
| | - Seong Wook Yang
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120749, Korea.
| | - Si Hyun Bae
- Department of Internal Medicine, Catholic University Medical College, Seoul 03312, Korea.
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
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17
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MicroRNA signature of human blood mononuclear cells. Mol Cell Biochem 2019; 462:167-172. [PMID: 31485855 DOI: 10.1007/s11010-019-03619-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 08/24/2019] [Indexed: 01/12/2023]
Abstract
MicroRNAs (miRNAs) regulate a wide range of cellular processes and functions. Blood mononuclear cells (BMNCs) participate in the immune response, inflammatory reaction and angiogenesis. In 2010, a total of 157 miRNAs were quantified by RT-qPCR and a miRNA signature was determined for human peripheral BMNCs. With the advent of technologies such as RNA sequencing, many new miRNAs have been identified. This study was designed to provide an up-to-date miRNA signature for human BMNCs. Peripheral BMNCs were isolated by Ficoll density gradient centrifugation. Using the qPCR array assay, we identified 108 highly expressed miRNAs (Ct value < 30) in human BMNCs. Further validation of the array results by quantifying select miRNAs with RT-qPCR revealed a strong correlation between Ct values derived from array analysis and RT-qPCR, suggesting the array results presented in this study are accurate and reliable. Of note, the function of the majority of the highly expressed miRNAs we have identified has not yet been studied. Our findings may help direct further studies of the regulatory roles of miRNAs in BMNC function.
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18
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Liu X, Li C, Zhu J, Li W, Zhu Q. Dysregulation of FTX/miR-545 signaling pathway downregulates Tim-3 and is responsible for the abnormal activation of macrophage in cirrhosis. J Cell Biochem 2019; 120:2336-2346. [PMID: 30304545 DOI: 10.1002/jcb.27562] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 08/02/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Accumulating evidence has suggested the involvement of miR-545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR-545 and lncRNA FTX in hepatitis B virus (HBV)-related cirrhosis. METHOD The level of Tim-3, TLR-4, and endotoxin was detected in CD14+ , CD14 + CD16 + , and CD14 + CD16 - monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), IL-1β, and Nuclear factor kB (NF-kB). In-silico analysis, luciferase assay, real-time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR-545 and Tim-3. RESULTS The levels of Tim-3, Tim-3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim-3 was also decreased in the CD14 + CD16 - monocytes isolated from patients with cirrhosis, whereas the level of Tim-3 in CD14 + CD16 + monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR-4 was highly expressed in CD14 + CD16 + monocytes isolated from patients with cirrhosis, whereas Tim-3 was negatively regulated by endotoxin and the correlation coefficient was -0.5287. After the LPS stimulation, although the level of TNF-a, IL-6, IL-1β, and NF-kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim-3, but a higher level of miR-545. Moreover, miR-545 directly bound to the 3'untranslated region (3'UTR) of Tim-3 and inhibited the luciferase activity of cells cotransfected with miR-545 mimics and wild-type 3'UTR of Tim-3. Furthermore, FTX downregulated the expression of miR-545, TNF-a, IL-6, IL-1β, and NF-kB, but upregulated the expression of Tim-3. CONCLUSION The results of this study confirmed the effect of FTX, miR-545, and Tim-3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV-related cirrhosis.
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Affiliation(s)
- Xia Liu
- Department of Gastroenterology, Shandong Provincial Hospital Afflilated to Shandong University, Jinan, Shandong, China.,Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Cong Li
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Zhu
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenshuai Li
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiang Zhu
- Department of Gastroenterology, Shandong Provincial Hospital Afflilated to Shandong University, Jinan, Shandong, China
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19
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Zhao Y, Li Y, Tong L, Liang X, Zhang H, Li L, Fan G, Wang Y. Analysis of microRNA Expression Profiles Induced by Yiqifumai Injection in Rats with Chronic Heart Failure. Front Physiol 2018; 9:48. [PMID: 29467665 PMCID: PMC5808162 DOI: 10.3389/fphys.2018.00048] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 01/15/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Yiqifumai Injection (YQFM) is clinically used to treat various cardiovascular diseases including chronic heart failure (CHF). The efficacy of YQFM for treating heart failure has been suggested, but the mechanism of action for pharmacological effects of YQFM is unclear. Methods: Echocardiography detection, left ventricular intubation evaluation, histopathology and immunohistochemical examination were performed in CHF rats to evaluate the cardioprotective effect of YQFM. Rat miRNA microarray and bioinformatics analysis were employed to investigate the differentially expressed microRNAs. In vitro models of AngII-induced hypertrophy and t-BHP induced oxidative stress in H9c2 myocardial cells were used to validate the anti-hypertrophy and anti-apoptosis effects of YQFM. Measurement of cell surface area, ATP content and cell viability, Real-time PCR and Western blot were performed. Results: YQFM significantly improved the cardiac function of CHF rats by increasing left ventricular ejection fraction and fractional shortening, decreasing left ventricular internal diameter and enhancing cardiac output. Seven microRNAs which have a reversible regulation by YQFM treatment were found. Among them, miR-21-3p and miR-542-3p are related to myocardial hypertrophy and cell proliferation, respectively and were further verified by RT-PCR. Target gene network was established and potential related signaling pathways were predicted. YQFM could significantly alleviate AngII induced hypertrophy in cellular model. It also significantly increased cell viabilities and ATP content in t-BHP induced apoptotic cell model. Western blot analysis showed that YQFM could increase the phosphorylation of Akt. Conclusion: Our findings provided scientific evidence to uncover the mechanism of action of YQFM on miRNAs regulation against CHF by miRNA expression profile technology. The results indicated that YQFM has a potential effect on alleviate cardiac hypertrophy and apoptosis in chronic heart failure.
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Affiliation(s)
- Yu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yunfei Li
- State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin, China
| | - Ling Tong
- State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin, China
| | - Xinying Liang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Han Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lan Li
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanwei Fan
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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20
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Chen M, Peng Y, Li A, Li Z, Deng Y, Liu W, Liao B, Dai C. A novel information diffusion method based on network consistency for identifying disease related microRNAs. RSC Adv 2018; 8:36675-36690. [PMID: 35558942 PMCID: PMC9088870 DOI: 10.1039/c8ra07519k] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 10/17/2018] [Indexed: 12/27/2022] Open
Abstract
The abnormal expression of miRNAs is directly related to the development of human diseases. Predicting the potential candidate miRNAs associated with diseases can contribute to the detection, diagnosis, treatment and prevention of human complex diseases. The effective inference of the calculation method of the relationship between miRNAs and diseases is an effective supplement to biological experiments. It is of great help in the prevention, treatment and prognosis of complex diseases. This paper proposes a novel information diffusion method based on network consistency (IDNC) for identifying disease related microRNAs. The model first synthesizes the miRNA family information and the miRNA function similarity to reconstruct the miRNA network, and reconstruct the disease network by using the known disease and miRNA-related information and the semantic score between diseases. Then the global similarity of the two networks is obtained by using the Laplacian score of graphs. The global similarity score is a measure of the similarity between diseases and miRNAs. The disease–miRNA relation network was reconstructed by integrating the global similarity relation. The network consistency diffusion seed is then obtained by combining the global similarity network with the reconstructed disease–miRNA association network. Thereafter, the stable diffusion spectrum is generated as the prediction score by using the restarted random walk algorithm. The AUC value obtained by performing the LOOCV in the gold benchmark dataset is 0.8814. The AUC value obtained by performing the LOOCV in the predictive dataset is 0.9512. Compared with other frontier methods, our method has higher accuracy, which is further illustrated by case studies of breast neoplasms and colon neoplasms to prove that IDNC is valuable. The abnormal expression of miRNAs is directly related to the development of human diseases.![]()
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Affiliation(s)
- Min Chen
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
- College of Information Science and Engineering
| | - Yan Peng
- College of International Communication
- Hunan Institute of Technology
- 421002 Hengyang
- China
| | - Ang Li
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
| | - Zejun Li
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
- College of Information Science and Engineering
| | - Yingwei Deng
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
| | - Wenhua Liu
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
| | - Bo Liao
- College of Information Science and Engineering
- Hunan University
- Changsha 410082
- China
| | - Chengqiu Dai
- College of Computer Science and Technology
- Hunan Institute of Technology
- 421002 Hengyang
- China
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21
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Parkinson NJ, Buechner-Maxwell VA, Witonsky SG, Pleasant RS, Werre SR, Ahmed SA. Characterization of basal and lipopolysaccharide-induced microRNA expression in equine peripheral blood mononuclear cells using Next-Generation Sequencing. PLoS One 2017; 12:e0177664. [PMID: 28552958 PMCID: PMC5446123 DOI: 10.1371/journal.pone.0177664] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Accepted: 05/01/2017] [Indexed: 02/03/2023] Open
Abstract
The innate immune response to lipopolysaccharide contributes substantially to the morbidity and mortality of gram-negative sepsis. Horses and humans share an exquisite sensitivity to lipopolysaccharide and thus the horse may provide valuable comparative insights into this aspect of the inflammatory response. MicroRNAs, small non-coding RNA molecules acting as post-transcriptional regulators of gene expression, have key roles in toll-like receptor signaling regulation but have not been studied in this context in horses. The central hypothesis of this study was that lipopolysaccharide induces differential microRNA expression in equine peripheral blood mononuclear cells in a manner comparable to humans. Illumina Next Generation Sequencing was used to characterize the basal microRNA transcriptome in isolated peripheral blood mononuclear cells from healthy adult horses, and to evaluate LPS-induced changes in microRNA expression in cells cultured for up to four hours. Selected expression changes were validated using quantitative reverse-transcriptase PCR. Only miR-155 was significantly upregulated by LPS, changing in parallel with supernatant tumor necrosis factor-α concentration. Eight additional microRNAs, including miR-146a and miR-146b, showed significant expression change with time in culture without a clear LPS effect. Target predictions indicated a number of potential immunity-associated targets for miR-155 in the horse, including SOCS1, TAB2 and elements of the PI3K signaling pathway, suggesting that it is likely to influence the acute inflammatory response to LPS. Gene alignment showed extensive conservation of the miR-155 precursor gene and associated promoter regions between horses and humans. The basal and LPS-stimulated microRNA expression pattern characterized here were similar to those described in human leukocytes. As well as providing a resource for further research into the roles of microRNAs in immune responses in horses, this will facilitate inter-species comparative study of the role of microRNAs in the inflammatory cascade during endotoxemia and sepsis.
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Affiliation(s)
- Nicholas J. Parkinson
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
- * E-mail:
| | - Virginia A. Buechner-Maxwell
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
| | - Sharon G. Witonsky
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
| | - R. Scott Pleasant
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
| | - Stephen R. Werre
- Laboratory for Study Design and Statistical Analysis, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
| | - S. Ansar Ahmed
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, Virginia, United States of America
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22
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Zhou Q, Ding W, Jiang L, Xin J, Wu T, Shi D, Jiang J, Cao H, Li L, Li J. Comparative transcriptome analysis of peripheral blood mononuclear cells in hepatitis B-related acute-on-chronic liver failure. Sci Rep 2016; 6:20759. [PMID: 26861114 PMCID: PMC4748289 DOI: 10.1038/srep20759] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 01/07/2016] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is essential to elucidate the pathogenesis of HBV-ACLF and identify HBV-ACLF-specific biomarkers. In this study, high-throughput sequencing was performed to characterize the transcriptome of PMBCs from patients with HBV-ACLF. Specifically, 2381 differentially expressed genes (DEGs) and 776 differentially expressed transcripts were identified through comparisons with patients with chronic hepatitis B (CHB) and healthy controls. Gene Ontology (GO) analysis identified 114 GO terms that were clustered into 12 groups. We merged 10 dysregulated genes selected from these grouped GO terms and non-clustered terms with four significant genes with a specificity of >0.8 in the HBV-ACLF patients to obtain a set of 13 unique genes. The quantitative real-time polymerase chain reaction (qRT-PCR) validation of the top six genes (CYP19A1, SEMA6B, INHBA, DEFT1P, AZU1 and DEFA4) was consistent with the results of messenger ribonucleic acid (mRNA) sequencing. A further receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curves of the six genes were all >0.8, which indicated their significant diagnostic potentials for HBV-ACLF. CONCLUSION The transcriptome characteristics of PBMCs are altered in patients with HBV-ACLF, and six genes may serve as biomarkers of HBV-ACLF.
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Affiliation(s)
- Qian Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Wenchao Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Longyan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Tianzhou Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
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23
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Zheng QF, Zhang JY, Wu JS, Zhang Y, Liu M, Bai L, Zhang JY, Zhao J, Chen Y, Duan ZP, Zheng SJ. Upregulation of miRNA-130a Represents Good Prognosis in Patients With HBV-Related Acute-on-Chronic Liver Failure: A Prospective Study. Medicine (Baltimore) 2016; 95:e2639. [PMID: 26871786 PMCID: PMC4753881 DOI: 10.1097/md.0000000000002639] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 01/01/2016] [Accepted: 01/07/2016] [Indexed: 12/19/2022] Open
Abstract
Prompt and accurate prediction of the outcome is the key to make correct medical decision and to reduce the mortality in patients with HBV-related acute-on-chronic liver failure (ACLF). Increasing evidence have certified that small, noncoding microRNAs (miRNAs) play critically regulatory roles in the pathogenesis of liver diseases. However, it remains unclear whether and how miRNAs involve in the prognosis of ACLF.Microarray analysis was performed to characterize the miRNA expression profiles in liver tissues from 1 HBV-related ACLF patient and 1 matched healthy control. Nine miRNAs with at least 5 folds difference between these 2 persons were picked out. The present prospective study involving 39 HBV-related ACLF patients including 20 recovered and 19 nonrecovered patients, which include death (n = 9) and liver transplantation (n = 10). The serum expression of these miRNAs detected by quantitative real-time Polymerase Chain Reaction (qRT-RCR) was then compared between the 2 groups. Moreover, the correlation between the serum miRNAs and the prognostic indexes for ACLF was analyzed.The result of microarray analysis showed 9 miRNAs had different expression in liver tissues of ACLF patient compared with healthy control (upregulated: miRNA-130a, -21, -143, and -200a; downregulated: miRNA-486-5p, -192, -148a, -122, and -194). Unlike the expression profiles in liver tissue, 8 serum miRNAs except miRNA-194 were markedly upregulated in ACLF patients (P < 0.05). Remarkably, the serum expression of miRNA-130a and miRNA-486-5p was higher in recovered than nonrecovered ACLF patients (P < 0.05). Especially, the serum miRNA-130a was negatively correlated with international normalized ratio, prothrombin time, Model for End-Stage Liver Disease score, and positively correlated with prothrombin time activity. The AUC for recovered versus nonrecovered patients of miRNA-130a was 0.741 (P = 0.02).miRNA-130a might be a useful prognosis biomarker in patients with HBV-related ACLF.
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Affiliation(s)
- Qing-Fen Zheng
- From the Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China (Q-F Z, J-Y Z, M L, L B, J-Y Z, J Z, Y C, Z-P D, S-J Z); Department of hepatobiliary surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China (J-S W); Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (Q-F Z); Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical College, Weihui, China (Q-F Z); and Intensive Care Unit of Liver Disease, The 302 hospital of Chinese PLA, Beijing, China (Y Z)
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