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Tsoneva DK, Ivanov MN, Vinciguerra M. Liquid Liver Biopsy for Disease Diagnosis and Prognosis. J Clin Transl Hepatol 2023; 11:1520-1541. [PMID: 38161500 PMCID: PMC10752811 DOI: 10.14218/jcth.2023.00040] [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: 02/05/2023] [Revised: 05/24/2023] [Accepted: 06/07/2023] [Indexed: 01/03/2024] Open
Abstract
Liver diseases are a major burden worldwide, the scope of which is expected to further grow in the upcoming years. Clinically relevant liver dysfunction-related blood markers such as alanine aminotransferase and aspartate aminotransferase have limited accuracy. Nowadays, liver biopsy remains the gold standard for several liver-related pathologies, posing a risk of complication due to its invasive nature. Liquid biopsy is a minimally invasive approach, which has shown substantial potential in the diagnosis, prognosis, and monitoring of liver diseases by detecting disease-associated particles such as proteins and RNA molecules in biological fluids. Histones are the core components of the nucleosomes, regulating essential cellular processes, including gene expression and DNA repair. Following cell death or activation of immune cells, histones are released in the extracellular space and can be detected in circulation. Histones are stable in circulation, have a long half-life, and retain their post-translational modifications. Here, we provide an overview of the current research on histone-mediated liquid biopsy methods for liver diseases, with a focus on the most common detection methods.
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Affiliation(s)
- Desislava K. Tsoneva
- Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Martin N. Ivanov
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Department of Anatomy and Cell Biology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Manlio Vinciguerra
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Faculty of Health, Liverpool John Moores University, Liverpool, United Kingdom
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Moosa MS, Russomanno G, Dorfman JR, Gunter H, Patel C, Costello E, Carr D, Maartens G, Pirmohamed M, Goldring C, Cohen K. Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury. Br J Clin Pharmacol 2023; 89:1844-1851. [PMID: 36639145 PMCID: PMC10952339 DOI: 10.1111/bcp.15661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023] Open
Abstract
AIM Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.
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Affiliation(s)
- Muhammed Shiraz Moosa
- New Somerset Hospital, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Giusy Russomanno
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Jeffrey R. Dorfman
- Division of Medical Virology, Department of PathologyUniversity of StellenboschCape TownSouth Africa
| | - Hannah Gunter
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Chandni Patel
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Dan Carr
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Gary Maartens
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Christopher Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Karen Cohen
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
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Ali FE, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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Liu J, Zhang R, Lian T, Chen Z, Zhang RL, Wang Q. Plasma Exosome-Derived microRNAs Profiles in Patients with Serofast Status: A Cross-Sectional Study. Int J Gen Med 2023; 16:1455-1469. [PMID: 37101664 PMCID: PMC10124566 DOI: 10.2147/ijgm.s404545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/07/2023] [Indexed: 04/28/2023] Open
Abstract
Purpose Syphilis is a sexually transmitted bacterial infection caused by Treponema pallidum (T. pallidum), which can lead to chronic morbidity and adverse complications. In clinical practice, serofast status (SF) patients present with clinical symptoms that are very similar to those of healthy individuals or syphilis-cured patients, and often require prolonged follow-up for diagnosis. Currently, there is increasing interest in the potential of plasma exosome-derived miRNA as a biomarker for the detection of infectious diseases. In this study, we aimed to explore the diagnostic potential of miRNA in SF and its possible biological implications. Patients and Methods Exosome-derived miRNAs were isolated from peripheral plasma samples obtained from 20 patients with secondary syphilis (SS), SF, serologically cured syphilis (SC), and healthy controls (HC), and differentially expressed miRNAs (DEmiRNAs) were identified by microarray analysis. Prediction of potential target genes, functional annotation, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then performed. The expression of selected miRNAs was confirmed in 37 patients by quantitative reverse transcription polymerase chain reaction (RT-qPCR). A receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of these miRNAs in differentiating syphilis from HC or SC. Results The expression profile of plasma exosome-derived miRNA was discovered in individuals with SF through microarray analysis. The targeted genes of DEmiRNAs were found to be involved in diverse biological processes according to GO and KEGG analysis, such as regulation of transcription, mitochondria, Golgi, immune system, apoptosis, Ras signaling pathway, etc. Using RT-qPCR validation, miR-1273g-3p, miR-4485-5p, miR-197-3p, and miR-1908-3p showed significant upregulation in patients with SF. These miRNAs exhibited a superior diagnostic ability, either individually or combined, to distinguish SF from SC or HC. Conclusion The DEmiRNAs in plasma exosomes may play a role in the pathogenesis of SF and have the potential to become a noble and effective diagnostic method.
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Affiliation(s)
- Jinquan Liu
- Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Center for STD Control, China Centers for Disease Control and Prevention, Nanjing, 210042, People’s Republic of China
| | - Ruihua Zhang
- Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Center for STD Control, China Centers for Disease Control and Prevention, Nanjing, 210042, People’s Republic of China
| | - Tingting Lian
- Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Zuoxi Chen
- Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Center for STD Control, China Centers for Disease Control and Prevention, Nanjing, 210042, People’s Republic of China
| | - Rui-Li Zhang
- Department of Dermatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, People’s Republic of China
- Correspondence: Rui-Li Zhang; Qianqiu Wang, Email ;
| | - Qianqiu Wang
- Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Center for STD Control, China Centers for Disease Control and Prevention, Nanjing, 210042, People’s Republic of China
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Advances of microRNAs in regulating mitochondrial function: new potential application in NAFLD treatment. Mol Biol Rep 2022; 49:9841-9853. [PMID: 35612781 DOI: 10.1007/s11033-022-07503-0] [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: 01/17/2022] [Accepted: 04/22/2022] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases and closely associated with lipid disorder. Mitochondrion has been recognized to play a key role in lipid metabolism as the main site of energy metabolism in cells, and its dysfunction is involved in the progression of NAFLD. MicroRNAs (miRNAs), one of regulators in the pathogenesis of NAFLD, are discovered to modulate mitochondrial function by targeting mitochondrial proteins or mitochondrial-related factors, thereby improving or deteriorating NAFLD-associated pathologies. This review summarizes the differentially expressed miRNAs from clinical and experimental models of NAFLD with abilities in regulating mitochondrial function, expounds their underlying molecular mechanism and discusses their prospect and future research direction.
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Fang Q, Chen W, Jian Y, Li Y, Lian W, Wan H, Chen S, Li F, Chen Y. Serum Expression Level of MicroRNA-122 and Its Significance in Patients with Hepatitis B Virus Infection. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:8430276. [PMID: 35251580 PMCID: PMC8894023 DOI: 10.1155/2022/8430276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 01/26/2022] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To analyze the expression of miR-122 and evaluate its significance in patients with HBV infection in different phases. METHODS Eleven chronic hepatitis B (CHB), 26 hepatitis B virus (HBV)-induced cirrhosis, 16 HBV-associated hepatocellular carcinoma (HCC) patients and 10 healthy control cases were enrolled. The serum levels of miR-122 were detected by RT-PCR and compared between healthy individuals and CHB at different stages. RESULTS Compared with healthy control cases, serum miR-122 levels were markedly increased in HBV infection cases (AUC = 0.795, P=0.002). In the CHB group, miR-122 levels were positively associated with albumin levels (P < 0.05) but had no significant associations with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P > 0.05). In the cirrhosis group, miR-122 expression was remarkably lower in the Child C group in comparison with the Child A group (P=0.025). At the same time, miR-122 amounts had a negative correlation with HVPG (P < 0.05). In the HCC group, miR-122 amounts were negatively associated with alkaline phosphatase (AKP) and alpha-fetoprotein (AFP) (P < 0.05). Serum miR-122 amounts in 3 patients who died were lower than the survival group (5.520 ± 0.522 vs. 5.860 ± 1.183, P > 0.05). CONCLUSION Serum miR-122 can be leveraged to screen patients with HBV infection. In HBV sufferers, the serum miR-122 expression level is related to liver disease progression, hence making it an underlying molecular biomarker for predicting the development of CHB.
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Affiliation(s)
- Qingqing Fang
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Wei Chen
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Yourong Jian
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Yu Li
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Wei Lian
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Hongyu Wan
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Shiyao Chen
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Feng Li
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying Chen
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201199, China
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MicroRNA in dried blood spots from patients with Aagenaes syndrome and evaluation of pre-analytical and analytical factors. Pediatr Res 2021; 89:1780-1787. [PMID: 32932426 DOI: 10.1038/s41390-020-01153-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/07/2020] [Accepted: 08/31/2020] [Indexed: 11/08/2022]
Abstract
BACKGROUND Circulatory miRNAs are promising biomarkers. The feasibility of using miRNA from dried blood spots (DBS) was investigated using newborn screening cards from patients with cholestasis-lymphedema syndrome (Aagenaes syndrome) and controls. METHODS Total amount of miRNA and specific miRNAs from DBS were analyzed. miRNA was also obtained from newborn screening cards in patients with cholestasis-lymphedema syndrome/Aagenaes syndrome and in healthy newborns. RESULTS No differences in miRNA concentrations were found between multispotted samples and samples with one single drop of blood and between central and peripheral punches. Ten repeated freeze-thaw cycles did not significantly change miRNA levels from controls. miR-299 (1.73-fold change, p = 0.034) and miR-365 (1.46-fold change, p = 0.011) were upregulated and miR-30c (0.72-fold change, p = 0.0037), miR-652 (0.85-fold change, p = 0.025), and miR-744 (0.72-fold change, p = 0.0069) were downregulated in patients with Aagenaes syndrome at birth compared to controls. CONCLUSIONS miRNAs were not affected by multispotting or punch location and were stable throughout repeated freeze-thaw cycles. miRNA in dried blood spots could be used to detect differential expression of miRNA in newborns with Aagenaes syndrome and healthy controls in newborn screening cards. Dried blood spots may be a useful source to explore circulating miRNA as biomarkers. IMPACT Circulating miRNAs can be useful biomarkers. miRNAs from dried blood spots were not affected by multispotting or punch location and were stable throughout repeated freeze-thaw cycles. Discrimination between patients and controls are allowed even with few individuals. Early after birth, patients with cholestasis-lymphedema syndrome exhibit miRNA profiles associated with liver fibrosis. This study demonstrated that newborn screening cards may be a useful source for studying miRNA as the technical variability is smaller than biological variation.
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Mokhtari F, Mohebbi SR, Sharifian A, Ramandi M, Razzaghi MR. Circulating non-coding RNAs as potential diagnostic biomarkers in liver diseases. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2021; 14:S10-S23. [PMID: 35154598 PMCID: PMC8817748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/23/2021] [Indexed: 11/07/2022]
Abstract
The liver plays a principal role in the human body as a metabolic and detoxifying unit. Liver diseases are the world's major health problems and affect millions of people worldwide. Early detection of liver diseases is certainly effective in timely treatment and prevention of their progression. Liver injury is associated with significant alterations in immune responses and pattern changes in various tissue-related gene expressions and cytokine production. Increasing or decreasing the specific spectrum of non-coding RNAs in different phases of liver disease can be a criterion for diagnosis. Novel diagnostic biomarkers are needed for liver diseases. Currently, micro-RNAs (miRNAs) are known to play important roles in the diagnosis of liver diseases. Circulating biomarkers such as miRNA-assisted diagnosis can conceivably be helpful for the early treatment of liver diseases. In this review, we look at miRNAs and their potential applications in liver diseases as diagnostic biomarkers were investigated.
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Affiliation(s)
- Fedra Mokhtari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afsaneh Sharifian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Ramandi
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Research Trends in the Efficacy of Stem Cell Therapy for Hepatic Diseases Based on MicroRNA Profiling. Int J Mol Sci 2020; 22:ijms22010239. [PMID: 33383629 PMCID: PMC7795580 DOI: 10.3390/ijms22010239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver diseases, despite the organ’s high regenerative capacity, are caused by several environmental factors and persistent injuries. Their optimal treatment is a liver transplantation. However, this option is limited by donor shortages and immune response issues. Therefore, many researchers have been interested in identifying the therapeutic potential in treating irreversible liver damage based on stem cells and developing suitable therapeutic agents. Mesenchymal stem cells (MSCs), which are representative multipotent stem cells, are known to be highly potential stem cell therapy compared to other stem cells in the clinical trial worldwide. MSCs have therapeutic potentials for several hepatic diseases such as anti-fibrosis, proliferation of hepatocytes injured, anti-inflammation, autophagic mechanism, and inactivation of hepatic stellate cells. There are much data regarding clinical treatments, however, the data for examining the efficacy of stem cell treatment and the correlation between the stem cell engraftment and the efficacy in liver diseases is limited due to the lack of monitoring system for treatment effectiveness. Therefore, this paper introduces the characteristics of microRNAs (miRNAs) and liver disease-specific miRNA profiles, and the possibility of a biomarker that miRNA can monitor stem cell treatment efficacy by comparing miRNAs changed in liver diseases following stem cell treatment. Additionally, we also discuss the miRNA profiling in liver diseases when treated with stem cell therapy and suggest the candidate miRNAs that can be used as a biomarker that can monitor treatment efficacy in liver diseases based on MSCs therapy.
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Hanif H, Khan MM, Ali MJ, Shah PA, Satiya J, Lau DT, Aslam A. A New Endemic of Concomitant Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B. Microorganisms 2020; 8:1526. [PMID: 33020450 PMCID: PMC7601829 DOI: 10.3390/microorganisms8101526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Muzammil M. Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Mukarram J. Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Pir A. Shah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA
| | - Jinendra Satiya
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Daryl T.Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Aysha Aslam
- Department of Medicine, Louis A Weiss Memorial Hospital, Chicago, IL 60640, USA
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Ren S, Chen J, Wang Q, Li X, Xu Y, Zhang X, Mu Y, Zhang H, Huang S, Liu P. MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis. Hepatol Int 2019; 13:814-825. [PMID: 31643031 PMCID: PMC7400990 DOI: 10.1007/s12072-019-09993-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/28/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). METHODS Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched. RESULTS The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LC patients' sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. CONCLUSIONS MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.
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Affiliation(s)
- Shuang Ren
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Traditional Chinese Medicine Department, First Affiliated Hospital of China Medical University, Shenyang, 201203, Liaoning, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qinglan Wang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xuewei Li
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Xu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shuang Huang
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Diagnostic value of circulating miRNA-122 for hepatitis B virus and/or hepatitis C virus-associated chronic viral hepatitis. Biosci Rep 2019; 39:BSR20190900. [PMID: 31427483 PMCID: PMC6732529 DOI: 10.1042/bsr20190900] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 07/25/2019] [Accepted: 08/16/2019] [Indexed: 12/16/2022] Open
Abstract
Background: The liver-specific microRNA-122 (miR-122) has been demonstrated as a powerful and promising biomarker of hepatic diseases. However, the researches on the accuracy of miR122 detection in chronic viral hepatitis have been inconsistent, leading us to conduct this meta-analysis to systematically summarize the diagnostic value of circulating miR-122 in patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)-associated chronic viral hepatitis.Methods: A comprehensive literature search (updated to January 30, 2019) in PubMed, Cochrane library, EMBASE, CNKI, Wanfang, and CQVIP databases was performed to identify eligible studies. The sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were pooled to explore the diagnostic performance of circulating miR-122. Subgroup and threshold effect analysis were further carried out to explore the heterogeneity.Results: Overall, 15 studies were finally included in this meta-analysis according to the exclusion and inclusion criteria. The pooled estimates indicated a moderately high diagnostic accuracy for circulating miR-122, with a sensitivity of 0.92 [95% confidence interval (CI), 0.86-0.95], a specificity of 0.84 (95% CI, 0.78-0.89), a PLR of 5.7 (95% CI, 4.7-8.1), a NLR of 0.1 (95% CI, 0.06-0.18), a DOR of 57 (95% CI 25-129), and an AUC of 0.93 (95% CI, 0.91-0.95). The subgroup analysis demonstrated that diagnostic accuracy was better for HCV-associated chronic viral hepatitis patients and non-Chinese compared with other subgroups. In addition, we found that serum might be a more promising matrix for detecting the expression of miR-122 than plasma.Conclusions: Our results demonstrated that circulating miR-122 have a relatively high diagnostic value for chronic viral hepatitis detection, especially in the patients with HCV-associated chronic viral hepatitis. However, further large cohort studies are still required to confirm our findings.
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Poore GD, Ko ER, Valente A, Henao R, Sumner K, Hong C, Burke TW, Nichols M, McClain MT, Huang ES, Ginsburg GS, Woods CW, Tsalik EL. A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies. Front Microbiol 2018; 9:2957. [PMID: 30619110 PMCID: PMC6298190 DOI: 10.3389/fmicb.2018.02957] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 11/16/2018] [Indexed: 12/22/2022] Open
Abstract
Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8-100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0-98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.
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Affiliation(s)
- Gregory D. Poore
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Emily R. Ko
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
- Department of Hospital Medicine, Duke Regional Hospital, Durham, NC, United States
| | - Ashlee Valente
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Ricardo Henao
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Kelsey Sumner
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Christopher Hong
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Thomas W. Burke
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Marshall Nichols
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Micah T. McClain
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
- Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, United States
- Medicine Service, Durham VA Medical Center, Durham, NC, United States
| | - Erich S. Huang
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, United States
- Duke Clinical and Translational Science Institute, Durham, NC, United States
| | - Geoffrey S. Ginsburg
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Christopher W. Woods
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
- Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, United States
- Medicine Service, Durham VA Medical Center, Durham, NC, United States
| | - Ephraim L. Tsalik
- Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States
- Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, United States
- Emergency Medicine Service, Durham VA Health Care System, Durham, NC, United States
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MiR-27a as a predictor for the activation of hepatic stellate cells and hepatitis B virus-induced liver cirrhosis. Oncotarget 2017; 9:1075-1090. [PMID: 29416678 PMCID: PMC5787420 DOI: 10.18632/oncotarget.23262] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 12/06/2017] [Indexed: 12/16/2022] Open
Abstract
Circulating microRNAs (miRNAs) can be employed as biomarkers to diagnose liver and other diseases. Noninvasive approaches are needed to complement and improve the current strategies for screening for biomarkers liver cirrhosis. We determined whether the serum levels of miRNAs can distinguish between chronic hepatitis B (CHB) and CHB-induced cirrhosis (HBC) and investigated the potential mechanisms involved. We found that serum miR-27a was significantly up-regulated in HBC, distinguishing HBC from CHB and healthy controls (Ctrl) (P<0.0001, the area of under the curve (AUC) =0.82 and 0.87, respectively). Specifically, when miR-27a was combined with miR-122, HBC was differentiated from CHB with an AUC=0.94. The serum miR-27a level in HBC patients with hepatic decompensation was significantly higher than that in patients with compensated HBC (P=0.0009). MiR-27a was also significantly up-regulated in the serum of rats with DMN-induced liver cirrhosis compared to that in saline-treated rats (P<0.0001). Furthermore, the down-regulation of miR-27a inhibited the proliferation and overexpression of miR-27a in activated hepatic stellate cells (HSCs) through the up-regulation of α-SMA and COL1A2 expression by targeting PPARγ, FOXO1, APC, P53 and RXRα. Our study demonstrated that circulating miR-27a can be used as a predictor for the activation of HSCs and the occurrence and development of HBC.
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15
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Expression Profiling of Cellular MicroRNA in Asymptomatic HBsAg Carriers and Chronic Hepatitis B Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6484835. [PMID: 28913356 PMCID: PMC5587942 DOI: 10.1155/2017/6484835] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 05/31/2017] [Accepted: 06/22/2017] [Indexed: 12/13/2022]
Abstract
Background MicroRNAs (miRNAs) may serve as potential molecular markers to predict liver injury resulting from chronic hepatitis B (CHB). In the present study, we want to study the expression profile and clinical significance of miRNAs at different stages of CHB virus infection. Methods Using miRNA microarray, we investigated the global expression profiles of cellular miRNA in asymptomatic hepatitis B antigen carriers (ASCs) and CHB patients, compared with healthy controls (HCs). Results We identified 79 and 203 differentially expressed miRNAs in the peripheral blood mononuclear cells of ASCs and CHB patients compared to HCs, respectively. Some of these miRNAs were common to ASCs and CHB patients, but another set of miRNAs that showed differential expression between ASCs and CHB patients was also identified. Gene ontology and pathway enrichment analysis showed that the target genes of the identified miRNAs played a role in important biological functions, such as learning or memory, cell-cell adherens junction, ion channel inhibitor activity, TGF-beta signaling pathway, and p53 signaling pathway. Conclusion We identified some significant differentially expressed miRNA in different phases of HBV infection, which might serve as biomarkers or therapeutic targets in the future.
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16
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Zhang J, Ma J, Wang H, Guo L, Li J. Serum microRNA-30c levels are correlated with disease progression in Xinjiang Uygur patients with chronic hepatitis B. ACTA ACUST UNITED AC 2017; 50:e6050. [PMID: 28492809 PMCID: PMC5441278 DOI: 10.1590/1414-431x20176050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 03/02/2017] [Indexed: 02/07/2023]
Abstract
We aimed to investigate the potential role and mechanism of microRNA-30c (miR-30c) in the pathological development of chronic hepatitis B (CHB). The serum levels of miR-30c in hepatitis B virus (HBV) carrier Xinjiang Uygur patients with inactive, low-replicative, high-replicative and HBe antigen-positive CHB were investigated. HepG2 cells were co-transfected with pHBV1.3 and miR-30c mimic or inhibitor or scramble RNA. The effects of miR-30c dysregulation on HBV replication and gene expression, cell proliferation and cell cycle were then investigated. miR-30c was down-regulated in Xinjiang Uygur patients with CHB compared to healthy controls and its expression level discriminated HBV carrier patients with inactive, low-replicative, high-replicative and HBe antigen-positive risk for disease progression. Overexpression of miR-30c significantly inhibited HBV replication and the expressions of HBV pgRNA, capsid-associated virus DNA and Hbx in hepatoma cells. Moreover, overexpression of miR-30c significantly inhibited cell proliferation and delayed G1/S phase transition in hepatoma cells. Opposite effects were obtained after suppression of miR-30c. Our results indicate that miR-30c was down-regulated in Xinjiang Uygur patients with CHB, and miR-30c levels could serve as a marker for risk stratification of HBV infection. Down-regulation of miR-30c may result in the progression of CHB via promoting HBV replication and cell proliferation.
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Affiliation(s)
- J Zhang
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - J Ma
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - H Wang
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - L Guo
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - J Li
- Department of Emergency, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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17
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Correia CN, Nalpas NC, McLoughlin KE, Browne JA, Gordon SV, MacHugh DE, Shaughnessy RG. Circulating microRNAs as Potential Biomarkers of Infectious Disease. Front Immunol 2017; 8:118. [PMID: 28261201 PMCID: PMC5311051 DOI: 10.3389/fimmu.2017.00118] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022] Open
Abstract
microRNAs (miRNAs) are a class of small non-coding endogenous RNA molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. Thousands of these molecules have been discovered to date, and multiple miRNAs have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology, and control of infection. The fundamental regulatory role of miRNAs in a variety of biological processes suggests that differential expression of these transcripts may be exploited as a novel source of molecular biomarkers for many different disease pathologies or abnormalities. This has been emphasized by the recent discovery of remarkably stable miRNAs in mammalian biofluids, which may originate from intracellular processes elsewhere in the body. The potential of circulating miRNAs as biomarkers of disease has mainly been demonstrated for various types of cancer. More recently, however, attention has focused on the use of circulating miRNAs as diagnostic/prognostic biomarkers of infectious disease; for example, human tuberculosis caused by infection with Mycobacterium tuberculosis, sepsis caused by multiple infectious agents, and viral hepatitis. Here, we review these developments and discuss prospects and challenges for translating circulating miRNA into novel diagnostics for infectious disease.
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Affiliation(s)
- Carolina N Correia
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Nicolas C Nalpas
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Kirsten E McLoughlin
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - John A Browne
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Stephen V Gordon
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland; University College Dublin, UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
| | - David E MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland; University College Dublin, UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
| | - Ronan G Shaughnessy
- UCD School of Veterinary Medicine, University College Dublin , Dublin , Ireland
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18
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Tao X, Xu Z, Men X. Analysis of Serum microRNA Expression Profiles and Comparison with Small Intestinal microRNA Expression Profiles in Weaned Piglets. PLoS One 2016; 11:e0162776. [PMID: 27632531 PMCID: PMC5025173 DOI: 10.1371/journal.pone.0162776] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/29/2016] [Indexed: 01/27/2023] Open
Abstract
Weaning stress induces tissue injuries and impairs health and growth in piglets, especially during the first week post-weaning. MicroRNAs (miRNAs) play vital roles in regulating stresses and diseases. Our previous study found multiple differentially expressed miRNAs in small intestine of piglets at four days post-weaning. To better understand the roles of miRNAs during weaning stress, we analyzed the serum miRNA expressional profile in weaned piglets (at four days post-weaning) and in suckling piglets (control) of the same age using miRNA microarray technology. We detected a total of 300 expressed miRNAs, 179 miRNAs of which were differentially expressed between the two groups. The miRNA microarray results were validated by RT-qPCR. The biological functions of these differentially expressed miRNAs were predicted by GO terms and KEGG pathway annotations. We identified 10 highly expressed miRNAs in weaned piglets including miR-31, miR-205, and miR-21 (upregulated) and miR-144, miR-30c-5p, miR-363, miR-194a, miR-186, miR-150, and miR-194b-5p (downregulated). Additionally, miR-194b-5p expression was significantly downregulated in serum and small intestine of weaned piglets. Our results suggest that weaning stress affects serum miRNA profiles in piglets. And serum miR-194b-5p levels can reflect its expressional changes in small intestine of piglets by weaning stress.
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Affiliation(s)
- Xin Tao
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - Ziwei Xu
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
- * E-mail:
| | - Xiaoming Men
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
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19
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Zhou M, Hara H, Dai Y, Mou L, Cooper DKC, Wu C, Cai Z. Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation. Int J Mol Sci 2016; 17:ijms17081232. [PMID: 27490531 PMCID: PMC5000630 DOI: 10.3390/ijms17081232] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 12/16/2022] Open
Abstract
Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation.
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Affiliation(s)
- Ming Zhou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
- Institute of Immunology, Zhongshan School of Medicine, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-sen University, Guangzhou 510275, China.
| | - Hidetaka Hara
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 210029, China.
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
| | - David K C Cooper
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Changyou Wu
- Institute of Immunology, Zhongshan School of Medicine, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-sen University, Guangzhou 510275, China.
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
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20
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Fiorino S, Bacchi-Reggiani ML, Visani M, Acquaviva G, Fornelli A, Masetti M, Tura A, Grizzi F, Zanello M, Mastrangelo L, Lombardi R, Di Tommaso L, Bondi A, Sabbatani S, Domanico A, Fabbri C, Leandri P, Pession A, Jovine E, de Biase D. MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis B- and C-related-hepatocellular-carcinoma. World J Gastroenterol 2016; 22:3907-3936. [PMID: 27099435 PMCID: PMC4823242 DOI: 10.3748/wjg.v22.i15.3907] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/05/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
Aim of the present review is to summarize the current knowledge about the potential relationship between miRNAs and hepatitis B virus (HBV)-hepatitis C virus (HCV) related liver diseases. A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine miRNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma (HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HCV", "hepatocellular carcinoma", "microRNAs", "miRNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma miRNAs, including miR-21, miR-122, mi-125a/b, miR-199a/b, miR-221, miR-222, miR-223, miR-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of miRNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of miRNAs for HCC early detection and prognosis.
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21
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Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades. Sci Rep 2016; 6:23709. [PMID: 27045805 PMCID: PMC4820692 DOI: 10.1038/srep23709] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 03/10/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatic steatosis is characterised by excessive triglyceride accumulation in the form of lipid droplets (LD); however, mechanisms differ in drug induced (DIS) and/or non-alcoholic fatty liver disease (NAFLD). Here we hypothesized distinct molecular circuits of microRNA/LD-associated target genes and searched for mechanistically linked serum and tissue biomarkers that would distinguish between DIS and human NAFLD of different grades. We analysed >800 rat hepatic whole genome data for 17 steatotic drugs and identified 157 distinct miRNAs targeting 77 DIS regulated genes. Subsequently, genomic data of N = 105 cases of human NAFLD and N = 32 healthy controls were compared to serum miRNA profiles of N = 167 NAFLD patients. This revealed N = 195 tissue-specific miRNAs being mechanistically linked to LD-coding genes and 24 and 9 miRNAs were commonly regulated in serum and tissue of advanced and mild NAFLD, respectively. The NASH serum regulated miRNAs informed on hepatic inflammation, adipocytokine and insulin signalling, ER-and caveolae associated activities and altered glycerolipid metabolism. Conversely, serum miRNAs associated with blunt steatosis specifically highlighted activity of FOXO1&HNF4α on CPT2, the lipid droplet and ER-lipid-raft associated PLIN3 and Erlin1. Altogether, serum miRNAs informed on the molecular pathophysiology of NAFLD and permitted differentiation between DIS and NAFLD of different grades.
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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Xing T, Xu H, Yu W, Wang B, Zhang J. Expression profile and clinical significance of miRNAs at different stages of chronic hepatitis B virus infection. Int J Clin Exp Med 2015; 8:5611-20. [PMID: 26131144 PMCID: PMC4483863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 04/03/2015] [Indexed: 06/04/2023]
Abstract
OBJECTIVE To study the expression profile and clinical significance of microRNAs (miRNAs) at different stages of chronic hepatitis B virus (HBV) infection. METHODS The miRNA expression profiles of peripheral blood mononuclear cells (PBMCs) at different stages of chronic HBV infection were screened using miRNA microarray and validated using real-time quantitative polymerase chain reaction (qPCR). RESULTS Significant differences in miRNA expression profiles of PBMCs were observed between patients in IA and IT phases of CHB. Expression was significantly down-regulated in the former but up-regulated in the latter group. No significant differences in inactive hepatitis B surface antigen carriers were observed. Changes in expression of six miRNAs determined by real-time qPCR were consistent with those determined by microarray. Areas under the receiver operation characteristic curve of the six miRNAs distinguishing immune tolerance and clearance of chronic HBV infection were 99.4%, 98.4%, 96.7%, 100%, 100%, and 99.6%. Positive correlation was found between the levels of hsa- miR-146a and ALT (r = 0.56, P < 0.01) while negative correlation was found between the levels of hsa-miR-548ah-5p and HBV DNA (r = -0.73, P < 0.01). CONCLUSIONS Abnormal expression of miRNAs and the resulting gradual decline in the various immune states of patients with chronic HBV infection may play important roles in maintenance of the immune homeostatic mechanisms of chronic HBV infection. Hsa-miR-548ah-5p, hsa-miR-3191-5p and hsa-miR-4711-3p can be used as potential molecular markers to distinguish among different stages of chronic HBV infection.
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Affiliation(s)
- Tongjing Xing
- Department of Infectious Diseases, Taizhou People's Hospital Taizhou 225300, Jiangsu Province, China
| | - Hongtao Xu
- Department of Infectious Diseases, Taizhou People's Hospital Taizhou 225300, Jiangsu Province, China
| | - Wenqing Yu
- Department of Infectious Diseases, Taizhou People's Hospital Taizhou 225300, Jiangsu Province, China
| | - Bian Wang
- Department of Infectious Diseases, Taizhou People's Hospital Taizhou 225300, Jiangsu Province, China
| | - Jing Zhang
- Department of Infectious Diseases, Taizhou People's Hospital Taizhou 225300, Jiangsu Province, China
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Tan Y, Pan T, Ye Y, Ge G, Chen L, Wen D, Zou S. Serum microRNAs as potential biomarkers of primary biliary cirrhosis. PLoS One 2014; 9:e111424. [PMID: 25347847 PMCID: PMC4210265 DOI: 10.1371/journal.pone.0111424] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/25/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Circulating microRNAs (miRNAs), which are extremely stable and protected from RNAse-mediated degradation in body fluids, have emerged as candidate biomarkers for many diseases. The present study aimed to identify a serum microRNA (miRNA) expression profile that could serve as a novel diagnostic biomarker for primary biliary cirrhosis (PBC). METHODS Serum miRNA expression was investigated using four cohorts comprising 380 participants (healthy controls and patients with PBC) recruited between August 2010 and June 2013. miRNA expression was initially analyzed by Illumina sequencing using serum samples pooled from 3 patients and 3 controls. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was then used to evaluate the expression of selected miRNAs in a screening set (n = 40). A logistic regression model was then constructed using a training cohort (n = 192) and validated using another cohort (n = 142). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. RESULTS We identified a miRNA panel (hsa-miR-122-5p, hsa-miR-141-3p, and hsa-miR-26b-5p) with a high diagnostic accuracy for PBC (AUC = 0.905, 95% confidence interval (CI) = 0.857 to 0.953; sensitivity = 80.5%, specificity = 88.3%). There was a significant difference between AUC values of the miRNA panel and those of alkaline phosphatase (ALP) (AUC = 0.537, difference between areas = 0.314, 95% CI = 0.195 to 0.434, P<0.001), and those of antinuclear antibody (ANA) (AUC = 0.739, difference between areas = 0.112, 95% CI = 0.012 to 0.213, P = 0.0282). CONCLUSION We identified a serum microRNA panel with considerable clinical value in PBC diagnosis. The results indicate that the miRNA panel is a more sensitive and specific biomarker for PBC than ALP and ANA.
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Affiliation(s)
- Youwen Tan
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Tengli Pan
- Department of Infection, The People’s Hospital of Bozhou, Bozhou, China
| | - Yun Ye
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Guohong Ge
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Li Chen
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Danfeng Wen
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Shengqiang Zou
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
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Fan HX, Tang H. Complex interactions between microRNAs and hepatitis B/C viruses. World J Gastroenterol 2014; 20:13477-13492. [PMID: 25309078 PMCID: PMC4188899 DOI: 10.3748/wjg.v20.i37.13477] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 03/28/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
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Circulating RNA molecules as biomarkers in liver disease. Int J Mol Sci 2014; 15:17644-66. [PMID: 25272224 PMCID: PMC4227182 DOI: 10.3390/ijms151017644] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 09/04/2014] [Accepted: 09/17/2014] [Indexed: 02/07/2023] Open
Abstract
Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results.
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Tan Y, Ge G, Pan T, Wen D, Chen L, Yu X, Zhou X, Gan J. A serum microRNA panel as potential biomarkers for hepatocellular carcinoma related with hepatitis B virus. PLoS One 2014; 9:e107986. [PMID: 25238238 PMCID: PMC4169601 DOI: 10.1371/journal.pone.0107986] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 08/16/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The identification of new high-sensitivity and high-specificity markers for HCC are essential. We aimed to identify serum microRNAs (miRNAs) as biomarkers to be used in diagnosing hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). METHODS We investigated serum miRNA expression in (261 HCC patients, 233 cirrhosis patients, and 173 healthy controls), recruited between August 2010 and June 2013. An initial screening of miRNA expression by Illumina sequencing was performed using serum samples pooled from HCC patients and controls. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to evaluate the expression of selected miRNAs. A logistic regression model was constructed using a training cohort (n = 357) and then validated using an independent cohort (n = 241). The area under the receiver operating characteristic curve (AUC) was used to evaluate the accuracy of the use of the biomarkers for disease diagnosis. RESULTS We identified 8 miRNAs (hsa-miR-206, hsa-miR-141-3p, hsa-miR-433-3p, hsa-miR-1228-5p, hsa-miR-199a-5p, hsa-miR-122-5p, hsa-miR-192-5p, and hsa-miR-26a-5p) and constructed an miRNA set that provided high diagnostic accuracy for HCC (AUC = 0.887 and 0.879 for training and validation sets, respectively). The miRNAs could also be used to differentiate HCC patients from healthy (AUC = 0.893) and cirrhosis (AUC = 0.892) patients. CONCLUSIONS We identified a serum of miRNA panel that has considerable clinical value in HCC diagnosis.
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Affiliation(s)
- Youwen Tan
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China
- * E-mail:
| | - Guohong Ge
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Tengli Pan
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Danfeng Wen
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Li Chen
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Xuejun Yu
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Xinbei Zhou
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Jianhe Gan
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China
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Rawlings-Goss RA, Campbell MC, Tishkoff SA. Global population-specific variation in miRNA associated with cancer risk and clinical biomarkers. BMC Med Genomics 2014; 7:53. [PMID: 25169894 PMCID: PMC4159108 DOI: 10.1186/1755-8794-7-53] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 08/12/2014] [Indexed: 12/30/2022] Open
Abstract
Background MiRNA expression profiling is being actively investigated as a clinical biomarker and diagnostic tool to detect multiple cancer types and stages as well as other complex diseases. Initial investigations, however, have not comprehensively taken into account genetic variability affecting miRNA expression and/or function in populations of different ethnic backgrounds. Therefore, more complete surveys of miRNA genetic variability are needed to assess global patterns of miRNA variation within and between diverse human populations and their effect on clinically relevant miRNA genes. Methods Genetic variation in 1524 miRNA genes was examined using whole genome sequencing (60x coverage) in a panel of 69 unrelated individuals from 14 global populations, including European, Asian and African populations. Results We identified 33 previously undescribed miRNA variants, and 31 miRNA containing variants that are globally population-differentiated in frequency between African and non-African populations (PD-miRNA). The top 1% of PD-miRNA were significantly enriched for regulation of genes involved in glucose/insulin metabolism and cell division (p < 10−7), most significantly the mitosis pathway, which is strongly linked to cancer onset. Overall, we identify 7 PD-miRNAs that are currently implicated as cancer biomarkers or diagnostics: hsa-mir-202, hsa-mir-423, hsa-mir-196a-2, hsa-mir-520h, hsa-mir-647, hsa-mir-943, and hsa-mir-1908. Notably, hsa-mir-202, a potential breast cancer biomarker, was found to show significantly high allele frequency differentiation at SNP rs12355840, which is known to affect miRNA expression levels in vivo and subsequently breast cancer mortality. Conclusion MiRNA expression profiles represent a promising new category of disease biomarkers. However, population specific genetic variation can affect the prevalence and baseline expression of these miRNAs in diverse populations. Consequently, miRNA genetic and expression level variation among ethnic groups may be contributing in part to health disparities observed in multiple forms of cancer, specifically breast cancer, and will be an essential consideration when assessing the utility of miRNA biomarkers for the clinic.
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Tan Y, Ge G, Pan T, Wen D, Gan J. A pilot study of serum microRNAs panel as potential biomarkers for diagnosis of nonalcoholic fatty liver disease. PLoS One 2014; 9:e105192. [PMID: 25141008 PMCID: PMC4139327 DOI: 10.1371/journal.pone.0105192] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 07/19/2014] [Indexed: 12/12/2022] Open
Abstract
Background The invasive nature of liver biopsy makes the histopathological diagnosis of non-alcoholic fatty liver disease (NAFLD) difficult and its diagnostic performance unsatisfactory. The present study aimed to identify a serum microRNA (miRNA) expression profile that could serve as a novel diagnostic biomarker for NAFLD. Methods Serum miRNA expression was investigated using three cohorts comprising 465 participants (healthy controls and NAFLD patients) recruited between August 2010 and June 2013. miRNA expression was initially screened by Illumina sequencing using serum samples pooled from 20 patients and 20 controls. Quantitative reverse transcriptase polymerase chain reaction assay was then used to evaluate the expression of selected miRNAs. A logistic regression model was constructed using a training cohort (n = 242) and validated using another cohort (n = 183). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. Results We identified an miRNA panel (hsa-miR-122-5p, hsa-miR-1290, hsa-miR-27b-3p, and hsa-miR-192-5p) with a high diagnostic accuracy for NAFLD. The satisfactory diagnostic performance of the miRNA panel remained regardless of the NAFLD activity score (NAS) status. There was significant difference between the AUC values of the miRNA panel and those of ALT (AUC = 0.786, 95% CI = 0.717–0.855; P = 0.142) and FIB-4 (AUC = 0.795, 95% CI = 0.730–0.860; sensitivity = 69.9%, specificity = 83.7%. Conclusion We identified a serum microRNA panel with considerable clinical value in NAFLD diagnosis. The results indicate that the miRNA panel is a more sensitive and specific biomarker for NAFLD than ALT and FIB-4.
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Affiliation(s)
- Youwen Tan
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Guohong Ge
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Tengli Pan
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Danfeng Wen
- Department of Hepatosis, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Jianhe Gan
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China
- * E-mail:
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Characteristic Analysis from Excessive to Deficient Syndromes in Hepatocarcinoma Underlying miRNA Array Data. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:324636. [PMID: 24382976 PMCID: PMC3870617 DOI: 10.1155/2013/324636] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 11/12/2013] [Indexed: 01/07/2023]
Abstract
Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for many diseases. In this study, the characteristics among excessive, excessive-deficient, and deficient syndromes of Hepatocellular carcinoma (HCC) were studied using miRNA array data. We first calculated the differentially expressed miRNAs based on random module t-test and classified three TCM syndromes of HCC using SVM method. Then, the weighted miRNA-target networks were constructed for different TCM syndromes using predicted miRNA targets. Subsequently, the prioritized target genes of upexpression network of TCM syndromes were analyzed using DAVID online analysis. The results showed that there are distinctly different hierarchical cluster and network structure of TCM syndromes in HCC, but the excessive-deficient combination syndrome is extrinsically close to deficient syndrome. GO and pathway analysis revealed that the molecular mechanisms of excessive-deficient and deficient syndromes of HCC are more complex than excessive syndrome. Furthermore, although excessive-deficient and deficient syndromes have similar complex mechanisms, excessive-deficient syndrome is more involved than deficient syndrome in development of cancer process. This study suggested that miRNAs might be important mediators involved in the changing process from excessive to deficient syndromes and could be potential molecular markers for the diagnosis of TCM syndromes in HCC.
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Shah N, Nelson JE, Kowdley KV. MicroRNAs in Liver Disease: Bench to Bedside. J Clin Exp Hepatol 2013; 3:231-42. [PMID: 25755505 PMCID: PMC3940370 DOI: 10.1016/j.jceh.2013.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3'UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure.
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Key Words
- ALD, alcoholic liver disease
- ALF, acute liver failure
- DILI, drug-induced liver injury
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HSC, hepatic stellate cell
- IFN, interferon
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PPAR γ, peroxisome proliferator-activated receptor γ
- TGF, transforming growth factor
- TNF, tumor necrosis factor
- UTR, untranslated region
- down-regulation
- liver
- miR-122
- miRs/miRNA, microRNA
- microRNA
- up-regulation
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Affiliation(s)
- Nihar Shah
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - James E. Nelson
- Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - Kris V. Kowdley
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States,Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States,Address for correspondence: Kris V. Kowdley, MD, 1201 9th Ave., Seattle, WA 98101, United States. Tel.: +1 (206) 287 1083; fax: +1 (206) 341 1934.
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Progression from Excessive to Deficient Syndromes in Chronic Hepatitis B: A Dynamical Network Analysis of miRNA Array Data. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:945245. [PMID: 23690867 PMCID: PMC3652179 DOI: 10.1155/2013/945245] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 03/16/2013] [Indexed: 01/01/2023]
Abstract
Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for chronic hepatitis B (CHB), which requires a traditional diagnosis method to distinguish the TCM syndrome. In this study, we study the differences and similarities among excessive, excessive-deficient, and deficient syndromes, by an integrative and comparative analysis of weighted miRNA expression or miRNA-target network in CHB patients. We first calculated the differential expressed miRNAs based on random module t-test and classified three CHB TCM syndromes using SVM method. Then, miRNA target genes were obtained by validated database and predicted programs subsequently, the weighted miRNA-target networks were constructed for different TCM syndromes. Furthermore, prioritize target genes of networks of CHB TCM syndromes progression analyzed using DAVID online analysis. The results have shown that the difference between TCM syndromes is distinctly based on hierarchical cluster and network structure. GO and pathway analysis implicated that three CHB syndromes more likely have different molecular mechanisms, while the excessive-deficient and deficient syndromes are more dangerous than excessive syndrome in the process of tumorigenesis. This study suggested that miRNAs are important mediators for TCM syndromes classification as well as CHB development progression and therefore could be potential diagnosis and therapeutic molecular markers.
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Zhang H, Guan Y, Lu YY, Hu YY, Huang S, Su SB. Circulating miR-583 and miR-663 Refer to ZHENG Differentiation in Chronic Hepatitis B. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2013; 2013:751341. [PMID: 23554832 PMCID: PMC3608186 DOI: 10.1155/2013/751341] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2013] [Accepted: 02/09/2013] [Indexed: 01/08/2023]
Abstract
Traditional Chinese medicine (TCM) ZHENG as the key pathological principle is to understand the human homeostasis and guide TCM treatment. Here, circulating microRNAs (miRNAs) were utilized to differentiate between ZHENGs including liver-gallbladder dampness-heat syndrome (LGDHS) and liver-kidney yin deficiency syndrome (LKYDS) in chronic hepatitis B (CHB). Sera samples of CHB patients with LGDHS (n = 35), LKYDS (n = 24), and healthy controls (Ctrls, n = 21) were analyzed by microarray and real-time RT-PCR. Receiver-operator characteristic (ROC) curves were established to evaluate the levels of serum miRNA for discriminating LGDHS and LKYDS. The target genes of miRNAs were predicted by TargetScan. Gene Ontology (GO) and pathways were analyzed using DAVID tool. The results showed that 22 miRNAs were differentially expressed between LGDHS and LKYDS (fold change >2.0 and P < 0.01). Circulating miR-583 and miR-663 were significantly higher (P < 0.001) in CHB patients with LGDHS than those with LKYDS and Ctrls. ROC curve analysis revealed that miR-583 and miR-663 were sensitive and specific enough to distinguish LGDHS from LKYDS. Pathway enrichment analysis indicated that 354 putative targets for miR-583 and 68 putative targets for miR-663 were mainly involved in Axon guidance, Neurotrophin, and MAPK signaling pathway. miR-583 and miR-663 may be potential markers for ZHENG differentiation in CHB.
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Affiliation(s)
- Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai 201203, China
| | - Yan Guan
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai 201203, China
| | - Yi-Yu Lu
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai 201203, China
| | - Yi-Yang Hu
- Institute of Liver Diseases, Shanghai Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases of Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong, Shanghai 201203, China
| | - Shuang Huang
- Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai 201203, China
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Li H, Yang BB. Stress response of glioblastoma cells mediated by miR-17-5p targeting PTEN and the passenger strand miR-17-3p targeting MDM2. Oncotarget 2012; 3:1653-68. [PMID: 23391506 PMCID: PMC3681502 DOI: 10.18632/oncotarget.810] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 12/31/2012] [Indexed: 12/28/2022] Open
Abstract
Tumor development not only destroys the homeostasis of local tissues but also the whole body, and thus the tumor cells have to face the body's defense system, a shortage of nutrition and oxygen, and chemotherapeutic drug treatment. In response to these stresses, tumor cells often alter gene expression and microRNA levels to facilitate survival. We have demonstrated that glioblastoma cells deprived of nutrition or treated with chemotherapeutics drugs expressed increased levels of miR-17. Ectopic transfection of miR-17 prolonged glioblastoma cell survival when the cells were deprived with nutrition or treated with chemotherapeutic drugs. Expression of miR-17 also promoted cell motility, invasion, and tube-like structure formation. We found that these phenotypes were the results of miR-17 targeting PTEN. As a consequence, HIF1α and VEGF were up-regulated. Ectopic expression of miR-17 was found to facilitate enrichment of stem-like tumor cells, since the cells became drug-resistant, showed increased capacity to form colonies and neurospheres, and expressed higher levels of CD133, a phenotype similar to ectopic expression of HIF1α. To further confirm the phenotypic property of stem cells, we demonstrated that glioblastoma cells transfected with miR-17 proliferated slower in different nutritional conditions by facilitating more cells staying in the G1 phase than the control cells. Finally, we demonstrated that miR-17 could repress MDM2 levels, resulting in decreased cell proliferation and drug-resistance. Our results added a new layer of functional mechanism for the well-studied miRNA miR-17.
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MESH Headings
- AC133 Antigen
- Antigens, CD/metabolism
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Survival/drug effects
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Genotype
- Glioblastoma/blood supply
- Glioblastoma/genetics
- Glioblastoma/metabolism
- Glioblastoma/pathology
- Glycoproteins/metabolism
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- MicroRNAs/metabolism
- Neoplasm Invasiveness
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic
- PTEN Phosphohydrolase/genetics
- PTEN Phosphohydrolase/metabolism
- Peptides/metabolism
- Phenotype
- Proto-Oncogene Proteins c-mdm2/genetics
- Proto-Oncogene Proteins c-mdm2/metabolism
- Stress, Physiological/genetics
- Time Factors
- Transfection
- Up-Regulation
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Haoran Li
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto
| | - Burton B Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto
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