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Delshad M, Sanaei MJ, Mohammadi MH, Sadeghi A, Bashash D. Exosomal Biomarkers: A Comprehensive Overview of Diagnostic and Prognostic Applications in Malignant and Non-Malignant Disorders. Biomolecules 2025; 15:587. [PMID: 40305328 PMCID: PMC12024574 DOI: 10.3390/biom15040587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker.
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Affiliation(s)
- Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
- Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan 1411718541, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
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Latanova A, Karpov V, Starodubova E. Extracellular Vesicles in Flaviviridae Pathogenesis: Their Roles in Viral Transmission, Immune Evasion, and Inflammation. Int J Mol Sci 2024; 25:2144. [PMID: 38396820 PMCID: PMC10889558 DOI: 10.3390/ijms25042144] [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: 12/29/2023] [Revised: 02/04/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
The members of the Flaviviridae family are becoming an emerging threat for public health, causing an increasing number of infections each year and requiring effective treatment. The consequences of these infections can be severe and include liver inflammation with subsequent carcinogenesis, endothelial damage with hemorrhage, neuroinflammation, and, in some cases, death. The mechanisms of Flaviviridae pathogenesis are being actively investigated, but there are still many gaps in their understanding. Extracellular vesicles may play important roles in these mechanisms, and, therefore, this topic deserves detailed research. Recent data have revealed the involvement of extracellular vesicles in steps of Flaviviridae pathogenesis such as transmission, immune evasion, and inflammation, which is critical for disease establishment. This review covers recent papers on the roles of extracellular vesicles in the pathogenesis of Flaviviridae and includes examples of clinical applications of the accumulated data.
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Affiliation(s)
- Anastasia Latanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (V.K.); (E.S.)
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Srinivas AN, Suresh D, Kaur S, Kumar DP. The promise of small particles: extracellular vesicles as biomarkers in liver pathology. J Physiol 2023; 601:4953-4971. [PMID: 35708653 DOI: 10.1113/jp283074] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/07/2022] [Indexed: 11/09/2022] Open
Abstract
Extracellular vesicles (EVs) are nanoscopic packages that are heterogeneous and bona fide players in hepatic physiology and pathology as they are involved in intercellular communication. EVs carrying bioactive cargoes rich in lipids, proteins or nucleic acids are implicated in the onset and progression of liver diseases. Liver pathology using liver biopsy has been assessed for several intricate conditions such as viral hepatitis, alcoholic and non-alcoholic fatty liver disease, hepatic malignancies and drug-induced liver injury. The lacunae, however, lie in early diagnosis and timely treatment of the above conditions, underscoring the need for non-invasive, accurate diagnostic tools that could replace the gold standard method of tissue biopsy. In this regard, EVs have emerged as promising candidates that could serve as potential biomarkers. In the last two decades, EVs, owing to their multifaceted charm in bringing out cell-free therapeutic responses and the ability of their cargoes to be applied to novel biomarkers, have drawn the great attention of researchers with the advancement and clinical application of liquid biopsy. In this review, we recapitulate the role of EVs and provide insights into the promising role of these small packages as biomarkers in liver pathology.
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Affiliation(s)
- Akshatha N Srinivas
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Diwakar Suresh
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Divya P Kumar
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
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El-Daly SM, Gouhar SA, Abd Elmageed ZY. Circulating microRNAs as Reliable Tumor Biomarkers: Opportunities and Challenges Facing Clinical Application. J Pharmacol Exp Ther 2023; 384:35-51. [PMID: 35809898 PMCID: PMC9827506 DOI: 10.1124/jpet.121.000896] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 01/13/2023] Open
Abstract
MicroRNAs (miRNAs) are involved in the development of human malignancies, and cells have the ability to secrete these molecules into extracellular compartments. Thus, cell-free miRNAs (circulating miRNAs) can potentially be used as biomarkers to evaluate pathophysiological changes. Although circulating miRNAs have been proposed as potential noninvasive tumor biomarkers for diagnosis, prognosis, and response to therapy, their routine application in the clinic is far from being achieved. This review focuses on the recent progress regarding the value of circulating miRNAs as noninvasive biomarkers, with specific consideration of their relevant clinical applications. In addition, we provide an in-depth analysis of the technical challenges that impact the assessment of circulating miRNAs. We also highlight the significance of integrating circulating miRNAs with the standard laboratory biomarkers to boost sensitivity and specificity. The current status of circulating miRNAs in clinical trials as tumor biomarkers is also covered. These insights and general guidelines will assist researchers in experimental practice to ensure quality standards and repeatability, thus improving future studies on circulating miRNAs. SIGNIFICANCE STATEMENT: Our review will boost the knowledge behind the inconsistencies and contradictory results observed among studies investigating circulating miRNAs. It will also provide a solid platform for better-planned strategies and standardized techniques to optimize the assessment of circulating cell-free miRNAs.
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Affiliation(s)
- Sherien M El-Daly
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
| | - Zakaria Y Abd Elmageed
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, Egypt (S.M.E-D., S.A.G.); Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt (S.M.E-D.); and Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana-Monroe, Monroe, Louisiana (Z.Y.A.)
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Yin Y, Zhao Y, Chen Q, Chen Y, Mao L. Dual roles and potential applications of exosomes in HCV infections. Front Microbiol 2022; 13:1044832. [PMID: 36578571 PMCID: PMC9791051 DOI: 10.3389/fmicb.2022.1044832] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
The hepatitis C virus (HCV) causes severe liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma, which have high morbidity and mortality. Antibody targeting receptor-mediated HCV infections have limited therapeutic benefits, suggesting that the transmission of HCV infections is possibly mediated via receptor-independent mechanisms. Exosomes are membrane-enclosed vesicles with a diameter of 30-200 nm, which originate from the fusion of endosomal multivesicular bodies with the plasma membrane. Accumulating evidence suggests that exosomes have a pivotal role in HCV infections. Exosomes can transfer viral and cellular bioactive substances, including nucleic acids and proteins, to uninfected cells, thus spreading the infection by masking these materials from immunological recognition. In addition, exosomes originating from some cells can deliver antiviral molecules or prompt the immune response to inhibit HCV infection. Exosomes can be used for the diagnosis of HCV-related diseases, and are being presently evaluated as therapeutic tools for anti-HCV drug delivery. This review summarizes the current knowledge on the dual roles and potential clinical applications of exosomes in HCV infections.
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Panda M, Kalita E, Singh S, Kumar K, Rao A, Prajapati VK. MiRNA-SARS-CoV-2 dialogue and prospective anti-COVID-19 therapies. Life Sci 2022; 305:120761. [PMID: 35787998 PMCID: PMC9249409 DOI: 10.1016/j.lfs.2022.120761] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/24/2022] [Accepted: 06/28/2022] [Indexed: 02/08/2023]
Abstract
COVID-19 is a highly transmissible disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), affects 226 countries and continents, and has resulted in >6.2 million deaths worldwide. Despite the efforts of all scientific institutions worldwide to identify potential therapeutics, no specific drug has been approved by the FDA to treat the COVID-19 patient. SARS-CoV-2 variants of concerns make the potential of publicly known therapeutics to respond to and detect disease onset highly improbable. The quest for universal therapeutics pointed to the ability of RNA-based molecules to shield and detect the adverse effects of the COVID-19 illness. One such candidate, miRNA (microRNA), works on regulating the differential expression of the target gene post-transcriptionally. The prime focus of this review is to report the critical miRNA molecule and their regular expression in patients with COVID-19 infection and associated comorbidities. Viral and host miRNAs control the etiology of COVID-19 infection throughout the life cycle and host inflammatory response, where host miRNAs are identified as a double-edged showing as a proviral and antiviral response. The review also covered the role of viral miRNAs in mediating host cell signaling expression during disease pathology. Studying molecular interactions between the host and the SARS-CoV-2 virus during COVID-19 pathogenesis offers the chance to use miRNA-based therapeutics to reduce the severity of the illness. By utilizing an appropriate delivery vehicle, these small non-coding RNA could be envisioned as a promising biomarker in designing a practical RNAi-based treatment approach of clinical significance.
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Affiliation(s)
- Mamta Panda
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Elora Kalita
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Satyendra Singh
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Ketan Kumar
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Abhishek Rao
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Ajmer 305817, Rajasthan, India.
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Roles of microRNAs in Hepatitis C Virus Replication and Pathogenesis. Viruses 2022; 14:v14081776. [PMID: 36016398 PMCID: PMC9413378 DOI: 10.3390/v14081776] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/11/2022] [Accepted: 08/13/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is associated with the development of chronic liver diseases, e.g., fibrosis, cirrhosis, even hepatocellular carcinoma, and/or extra-hepatic diseases such as diabetes. As an obligatory intracellular pathogen, HCV absolutely relies on host cells to propagate and is able to modulate host cellular factors in favor of its replication. Indeed, lots of cellular factors, including microRNAs (miRNAs), have been identified to be dysregulated during HCV infection. MiRNAs are small noncoding RNAs that regulate protein synthesis of their targeting mRNAs at the post-transcriptional level, usually by suppressing their target gene expression. The miRNAs dysregulated during HCV infection could directly or indirectly modulate HCV replication and/or induce liver diseases. Regulatory mechanisms of various miRNAs in HCV replication and pathogenesis have been characterized. Some dysregulated miRNAs have been considered as the biomarkers for the detection of HCV infection and/or HCV-related diseases. In this review, we intend to briefly summarize the identified miRNAs functioning at HCV replication and pathogenesis, focusing on the recent developments.
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Tsuchiya A, Natsui K, Ishii Y, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Terai S. Small extracellular vesicles and liver diseases: From diagnosis to therapy. World J Hepatol 2022; 14:1307-1318. [PMID: 36158910 PMCID: PMC9376785 DOI: 10.4254/wjh.v14.i7.1307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/20/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs), especially small EVs (sEVs) derived from liver cells, have been the focus of much attention in the normal physiology and pathogenesis of various diseases affecting the liver. sEVs are approximately 100 nm in size, enclosed within lipid bilayers, and are very stable. The lipids, proteins, and nucleic acids, including miRNAs, contained within these vesicles are known to play important roles in intercellular communication. This mini-review summarizes the application of sEVs. First, liver diseases and the related diagnostic markers are described, and the current active status of miRNA research in diagnosis of hepatocellular carcinoma (HCC) is reported. Second, the biodistribution and pharmacokinetics of sEVs are described, and the liver is highlighted as the organ with the highest accumulation of sEVs. Third, the relationship between sEVs and the pathogenesis of liver disorders is described with emphesis on the current active status of miRNA research in HCC recurrence and survival. Finally, the possibility of future therapy using sEVs from mesenchymal stem (stromal) cells for cirrhosis and other diseases is described.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata 951-8510, Japan
| | - Kazuki Natsui
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yui Ishii
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yohei Koseki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Nobutaka Takeda
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Kei Tomiyoshi
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Fusako Yamazaki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yuki Yoshida
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Shuji Terai
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
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Pozniak T, Shcharbin D, Bryszewska M. Circulating microRNAs in Medicine. Int J Mol Sci 2022; 23:ijms23073996. [PMID: 35409354 PMCID: PMC8999557 DOI: 10.3390/ijms23073996] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
Circulating microRNAs (c-microRNAs, c-miRNAs), which are present in almost all biological fluids, are promising sensitive biomarkers for various diseases (oncological and cardiovascular diseases, neurodegenerative pathologies, etc.), and their signatures accurately reflect the state of the body. Studies of the expression of microRNA markers show that they can enable a wide range of diseases to be diagnosed before clinical symptoms are manifested, and they can help to assess a patient’s response to therapy in order to correct and personalize treatments. This review discusses the latest trends in the uses of miRNAs for diagnosing and treating various diseases, viral and non-viral. It is concluded that exogenous microRNAs can be used as high-precision therapeutic agents for these purposes.
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Affiliation(s)
- Tetiana Pozniak
- Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus, 220072 Minsk, Belarus
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 02000 Kyiv, Ukraine
- Correspondence: (T.P.); (D.S.)
| | - Dzmitry Shcharbin
- Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus, 220072 Minsk, Belarus
- Correspondence: (T.P.); (D.S.)
| | - Maria Bryszewska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
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Kumar A, Kim S, Su Y, Sharma M, Kumar P, Singh S, Lee J, Furdui CM, Singh R, Hsu FC, Kim J, Whitlow CT, Nader MA, Deep G. Brain cell-derived exosomes in plasma serve as neurodegeneration biomarkers in male cynomolgus monkeys self-administrating oxycodone. EBioMedicine 2021; 63:103192. [PMID: 33418508 PMCID: PMC7804975 DOI: 10.1016/j.ebiom.2020.103192] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/16/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023] Open
Abstract
Background The United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA). Methods MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively. Findings We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells. Interpretation These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA. Funding NIH
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Affiliation(s)
- Ashish Kumar
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Susy Kim
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Yixin Su
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Mitu Sharma
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Pawan Kumar
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Sangeeta Singh
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States
| | - Jingyun Lee
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, United States; Proteomics and Metabolomics Shared Resource, Wake Forest Baptist Health, United States
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, United States; Proteomics and Metabolomics Shared Resource, Wake Forest Baptist Health, United States; Comprehensive Cancer Center, Wake Forest Baptist Health, United States
| | - Ravi Singh
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States; Comprehensive Cancer Center, Wake Forest Baptist Health, United States
| | - Fang-Chi Hsu
- Comprehensive Cancer Center, Wake Forest Baptist Health, United States; Biostatistics and Data Science, Wake Forest Baptist Health, United States
| | - Jeongchul Kim
- Radiology Informatics and Image Processing Laboratory, Wake Forest School of Medicine, United States; Department of Radiology, Section of Neuroradiology, Wake Forest School of Medicine, United States
| | - Christopher T Whitlow
- Comprehensive Cancer Center, Wake Forest Baptist Health, United States; Biostatistics and Data Science, Wake Forest Baptist Health, United States; Radiology Informatics and Image Processing Laboratory, Wake Forest School of Medicine, United States; Department of Radiology, Section of Neuroradiology, Wake Forest School of Medicine, United States; Department of Biomedical Engineering, Wake Forest School of Medicine, United States; Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, United States
| | - Michael A Nader
- Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, United States; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, NRC 546, Winston-Salem, NC 27157, United States.
| | - Gagan Deep
- Department of Cancer Biology, Wake Forest Baptist Medical Center, United States; Comprehensive Cancer Center, Wake Forest Baptist Health, United States; Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, United States; Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, United States.
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11
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Thietart S, Rautou PE. Extracellular vesicles as biomarkers in liver diseases: A clinician's point of view. J Hepatol 2020; 73:1507-1525. [PMID: 32682050 DOI: 10.1016/j.jhep.2020.07.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 07/05/2020] [Accepted: 07/06/2020] [Indexed: 02/09/2023]
Abstract
Extracellular vesicles are membrane-bound vesicles containing proteins, lipids, RNAs and microRNAs. They can originate from both healthy and stressed cells, and provide a snapshot of the cell of origin in physiological and pathological circumstances. Various processes that may give rise to the release of extracellular vesicles occur in liver diseases, including hepatocyte apoptosis, hepatic stellate cell activation, liver innate immune system activation, systemic inflammation, and organelle dysfunction (mitochondrial dysfunction and endoplasmic reticulum stress). Numerous studies have therefore investigated the potential role of extracellular vesicles as biomarkers in liver diseases. This review provides an overview of the methods that can be used to measure extracellular vesicle concentrations in clinical settings, ranging from plasma preparation to extracellular vesicle measurement techniques, as well as looking at the challenges of using extracellular vesicles as biomarkers. We also provide a comprehensive review of studies that test extracellular vesicles as diagnostic, severity and prognostic biomarkers in various liver diseases, including non-alcoholic and alcoholic steatohepatitis, viral hepatitis B and C infections, cirrhosis, primary liver cancers, primary sclerosing cholangitis and acute liver failure. In particular, extracellular vesicles could be useful tools to evaluate activity and fibrosis in non-alcoholic fatty liver disease, predict risk of hepatitis B virus reactivation, predict complications and mortality in cirrhosis, detect early hepatocellular carcinoma, detect malignant transformation in primary sclerosing cholangitis and predict outcomes in acute liver failure. While most studies draw on data derived from pilot studies, which still require clinical validation, some extracellular vesicle subpopulations have already been evaluated in solid prospective studies.
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Affiliation(s)
- Sara Thietart
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, F-75018 Paris, France
| | - Pierre-Emmanuel Rautou
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, F-75018 Paris, France; Service d'Hépatologie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France; Centre de Référence des Maladies Vasculaires du Foie, French Network for Rare Liver Diseases (FILFOIE), European Reference Network (ERN) 'Rare-Liver'.
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12
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Latini A, Borgiani P, Novelli G, Ciccacci C. miRNAs in drug response variability: potential utility as biomarkers for personalized medicine. Pharmacogenomics 2020; 20:1049-1059. [PMID: 31559917 DOI: 10.2217/pgs-2019-0089] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. Almost all physiological conditions are probably modulated by miRNAs, including pharmacological response. Indeed, acting on the regulation of numerous genes involved in the pharmacokinetics and pharmacodynamics of drugs, differences in the levels of circulating miRNAs or genetic variants in the sequences of the miRNA genes can contribute to interindividual variability in drug response, both in terms of toxicity and efficacy. For their stability in body fluids and the easy availability and accurate quantification, miRNAs could be ideal biomarkers of individual response to drugs. This review aims to give an overview on the available studies that have investigated the relationship between miRNAs and response to drugs in different classes of diseases and considered their possible clinical application as therapy response predictive biomarkers. A comprehensive search was conducted from the international web database PubMed. We included papers that investigated the relationship between miRNAs and response to drugs, published before January 2019.
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Affiliation(s)
- Andrea Latini
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly.,IRCCS Neuromed, 86077, Pozzilli, IS, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, taly.,UniCamillus, Saint Camillus International University of Health Sciences, 00131, Rome, Italy
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13
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Tribolet L, Kerr E, Cowled C, Bean AGD, Stewart CR, Dearnley M, Farr RJ. MicroRNA Biomarkers for Infectious Diseases: From Basic Research to Biosensing. Front Microbiol 2020; 11:1197. [PMID: 32582115 PMCID: PMC7286131 DOI: 10.3389/fmicb.2020.01197] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
In the pursuit of improved diagnostic tests for infectious diseases, several classes of molecules have been scrutinized as prospective biomarkers. Small (18–22 nucleotide), non-coding RNA transcripts called microRNAs (miRNAs) have emerged as promising candidates with extensive diagnostic potential, due to their role in numerous diseases, previously established methods for quantitation and their stability within biofluids. Despite efforts to identify, characterize and apply miRNA signatures as diagnostic markers in a range of non-infectious diseases, their application in infectious disease has advanced relatively slowly. Here, we outline the benefits that miRNA biomarkers offer to the diagnosis, management, and treatment of infectious diseases. Investigation of these novel biomarkers could advance the use of personalized medicine in infectious disease treatment, which raises important considerations for validating their use as diagnostic or prognostic markers. Finally, we discuss new and emerging miRNA detection platforms, with a focus on rapid, point-of-care testing, to evaluate the benefits and obstacles of miRNA biomarkers for infectious disease.
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Affiliation(s)
- Leon Tribolet
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Emily Kerr
- Institute for Frontier Materials, Deakin University, Geelong, VIC, Australia
| | - Christopher Cowled
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Andrew G D Bean
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Cameron R Stewart
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Megan Dearnley
- Diagnostics, Surveillance and Response (DSR), Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Ryan J Farr
- Diagnostics, Surveillance and Response (DSR), Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
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14
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Delivery of microRNAs by Extracellular Vesicles in Viral Infections: Could the News be Packaged? Cells 2019; 8:cells8060611. [PMID: 31216738 PMCID: PMC6627707 DOI: 10.3390/cells8060611] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/04/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
Extracellular vesicles (EVs) are released by various cells and recently have attracted attention because they constitute a refined system of cell-cell communication. EVs deliver a diverse array of biomolecules including messenger RNAs (mRNAs), microRNAs (miRNAs), proteins and lipids, and they can be used as potential biomarkers in normal and pathological conditions. The cargo of EVs is a snapshot of the donor cell profile; thus, in viral infections, EVs produced by infected cells could be a central player in disease pathogenesis. In this context, miRNAs incorporated into EVs can affect the immune recognition of viruses and promote or restrict their replication in target cells. In this review, we provide an updated overview of the roles played by EV-delivered miRNAs in viral infections and discuss the potential consequences for the host response. The full understanding of the functions of EVs and miRNAs can turn into useful biomarkers for infection detection and monitoring and/or uncover potential therapeutic targets.
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15
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Shwetha S, Sharma G, Raheja H, Goel A, Aggarwal R, Das S. Interaction of miR-125b-5p with Human antigen R mRNA: Mechanism of controlling HCV replication. Virus Res 2018; 258:1-8. [PMID: 30253192 DOI: 10.1016/j.virusres.2018.09.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/21/2018] [Accepted: 09/12/2018] [Indexed: 12/13/2022]
Abstract
Cellular miRNAs influence Hepatitis C virus (HCV) infection in multiple ways. In this study, we demonstrate that miR-125b-5p is upregulated in HCV infected patient serum samples as well as in HCV infected liver carcinoma cells and is involved in translational regulation of one of its predicted targets, Human antigen R (HuR). We used miRNA mimics and antagomiRs to confirm that HuR is a bonafide miR-125b target. Previously, we have shown that HuR is a positive regulator of HCV replication, whereas we noticed that miR-125b is a negative regulator of HCV infection. As a connecting link between these two observations, we showed that knockdown of miR-125b-5p increased HuR protein levels and rescued HCV replication when the availability of HuR in the cytoplasm was compromised using siRNAs against HuR or an inhibitor of HuR export to the cytoplasm. Overall, the study sheds light on the ability of host cell to use a miRNA as a tool to control virus propagation.
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Affiliation(s)
- Shivaprasad Shwetha
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Geetika Sharma
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Harsha Raheja
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
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16
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Fischer T, Spohn M, Olearo F, Zinser ME, Kasonta R, Stubbe HC, Rechtien A, Ly ML, Schmiedel S, Lohse AW, Grundhoff A, Addo MM, Dahlke C. Dynamic changes of circulating miRNAs induced by the Ebola virus vaccine VSV-EBOV. Vaccine 2018; 36:7083-7094. [PMID: 30244872 DOI: 10.1016/j.vaccine.2018.09.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/02/2018] [Accepted: 09/08/2018] [Indexed: 12/18/2022]
Abstract
VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013-2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level. The miRNA-mediated control has emerged as a critical regulatory principle in the immune system, which strongly influences the balance of innate and adaptive immune responses by modulation of signaling pathways critical for differentiation of immune cells. We investigated expression levels of circulating miRNAs (c-miRNAs) in plasma from healthy vaccinees, as they may reflect cellular dynamics following VSV-EBOV immunization and additionally may serve as potential biomarkers for vaccine efficacy. As part of the WHO-led VEBCON consortium, we investigated safety and immunogenicity of VSV-EBOV in a phase I trial. A comprehensive analysis of expression levels on c-miRNAs from plasma samples following VSV-EBOV immunization (day 0, 1, 3 post vaccination) was conducted using RT-qPCR assays. Potential biological relevance was assessed using in silico analyses. Additionally, we correlated dynamics of miRNA expressions with our previously reported data on vaccine-induced antibody and cytokine responses and finally evaluated the prognostic power by generating ROC curves. We identified four promising miRNAs (hsa-miR-146a, hsa-miR-126, hsa-miR-199a, hsa-miR-484), showing a strong association with adaptive immune responses, exhibited favourable prognostic performance and are implicated in immunology-related functions. Our results provide evidence that miRNAs may serve as useful biomarkers for prediction of vaccine-induced immunogenicity. Furthermore, our unique data set provides insight into molecular mechanisms that underlie VSV-EBOV-mediated protective immune responses, which may help to decipher VSV-EBOV immune signature and accelerate strategic vaccine design or personalized approaches.
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Affiliation(s)
- T Fischer
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany
| | - M Spohn
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - F Olearo
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany
| | - M E Zinser
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany
| | - Rahel Kasonta
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany
| | - H C Stubbe
- Division of Infectious Diseases, Department of Medicine II, LMU, Munich, Germany
| | - A Rechtien
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - M L Ly
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; University Medical Center Hamburg-Eppendorf (UKE), Division of Infectious Diseases, Hamburg, Germany
| | - S Schmiedel
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; University Medical Center Hamburg-Eppendorf (UKE), Division of Infectious Diseases, Hamburg, Germany
| | - A W Lohse
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany
| | - A Grundhoff
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | | | - M M Addo
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; University Medical Center Hamburg-Eppendorf (UKE), Division of Infectious Diseases, Hamburg, Germany.
| | - C Dahlke
- University Medical Center Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; University Medical Center Hamburg-Eppendorf (UKE), Division of Infectious Diseases, Hamburg, Germany.
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Morishita A, Yoneyama H, Iwama H, Fujita K, Watanabe M, Hirose K, Tadokoro T, Oura K, Sakamoto T, Mimura S, Nomura T, Oryu M, Himoto T, Shimotohno K, Masaki T. Circulating microRNA-636 is associated with the elimination of hepatitis C virus by ombitasvir/paritaprevir/ritonavir. Oncotarget 2018; 9:32054-32062. [PMID: 30174796 PMCID: PMC6112829 DOI: 10.18632/oncotarget.25889] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection causes sustained inflammation and fibrosis. Several oral direct-acting antivirals (DAAs) including ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) were recently developed for HCV elimination. The combination of DAAs brought a higher sustained viral response (SVR) rate to anti-HCV therapy compared to interferon (IFN)-based regimens. However, 5% of hepatitis C patients who undergo DAA therapy still suffer from a sustained HCV infection. MicroRNA (miRNA) is essentially interfering, endogenous noncoding RNA that has been investigated as a new biomarker for the response to DAA in hepatitis C patients. Here we used a miRNA array and real-time polymerase chain reaction (PCR) to determine the targetable miRNA before and 12 weeks after OBV/PTV/r treatment for refractory hepatitis C. We used replicon cells, in which genotype 1b type HCV is stably transfected in Huh7 cells, to determine whether miRNA can inhibit HCV replication. Among 2,555 miRNAs, three were significantly up-regulated and eight miRNAs were down-regulated in serum 12 weeks after OBV/PTV/r treatment. An unsupervised hierarchical clustering analysis, using Pearson's correlation, showed that the miRNA profiles between before and 12 weeks after OBV/PTV/r treatment were clustered separately. At 12 weeks after OBV/PTV, miR-636 was targeted among the eight down-regulated miRNAs, and the expression level of circulating miR-636 was significantly diminished. The amount of HCV-RNA was significantly diminished 48 hours after miR-636 inhibitor transfection in HCV replicon cells. In conclusion, miR-636 might be one of the essential targetable molecules in HCV patients who undergo DAA therapy and still suffer from a sustained HCV infection.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Miwako Watanabe
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Kayo Hirose
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Makoto Oryu
- Department of Internal Medicine, Kagawa Saiseikai Hospital, Tahikamimachi, Takamatsu, Kagawa 761-8076, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Hara, Mure-cho, Takamatsu, Kagawa 761-0123, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Kohnodai, Ichikawa, Chiba 272-8516, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Ikenobe Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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