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Nikapitiya C, Jayathilaka EHTT, Edirisinghe SL, Oh C, De Zoysa M. Characterization, microRNA profiling, and immunomodulatory role of plasma-derived exosomes from olive flounder (Paralichthys olivaceus) in response to viral hemorrhagic septicemia virus. FISH & SHELLFISH IMMUNOLOGY 2025; 162:110316. [PMID: 40239934 DOI: 10.1016/j.fsi.2025.110316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
Viral hemorrhagic septicemia virus (VHSV) is a highly pathogenic virus that frequently infects olive flounder (Paralichthys olivaceus), causing viral hemorrhagic septicemia (VHS), and posing a significant threat to global aquaculture. This study characterizes plasma-derived exosomes from olive flounder following VHSV challenge (VHSV-Exo) or phosphate buffered saline (PBS) injection (PBS-Exo), comparing their morphology, physicochemical properties, molecular profiles, and immunomodulatory functions. Both PBS-Exo (118.3 ± 8.6 nm) and VHSV-Exo (82.6 ± 5.9 nm) exhibited the typical cup-shaped morphology of exosomes. The successful isolation and purity of exosomes were confirmed by the presence of exosome markers (CD81, CD9, and CD63) and the absence of albumin. High-throughput sequencing identified 13 differentially expressed (DE) microRNAs (miRNAs) between PBS-Exo and VHSV-Exo, including six upregulated and seven downregulated miRNAs (log2 fold change ≥1 or ≤ -1). Toxicity assessments revealed that neither PBS-Exo nor VHSV-Exo were toxic to murine macrophage Raw 264.7 cells or zebrafish larvae at tested doses (up to 100 and 400 μg/mL, respectively). The absence of green fluorescence at 96 h post-treatment of VHSV-Exo indicated minimal reactive oxygen species generation, further supporting exosome safety. Functional studies demonstrated that both in vitro (Raw 264.7 cells) and in vivo (adult zebrafish) treatments with exosomes regulated immune-related genes and proteins expression. Notabaly, VHSV-Exo exhibited superior immunomodulatory effects, as evidenced by enhanced immune gene and protein expression. To our knowledge, this is the first study demonstrating the immunomodulatory potential of VHSV-Exo. These findings highlight VHSV-Exo as a promising immunomodulatory agent, with potential applications as a prophylactic vaccine candidate against VHSV infection in aquaculture.
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Affiliation(s)
- Chamilani Nikapitiya
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - E H T Thulshan Jayathilaka
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Shan Lakmal Edirisinghe
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Chulhong Oh
- Jeju Bio Research Center, Korea Institute of Ocean Science and Technology, Gujwa-eup, Jeju, 2670, Republic of Korea
| | - Mahanama De Zoysa
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea.
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2
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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Guney Eskiler G, Karabay O, Tozlu M, Aydin A, Hamarat KF, Alkurt U, Deveci Ozkan A, Gunduz Y. The Predictive Role of miRNAs in Hepatitis B Vaccine Response of Metabolic Dysfunction-Associated Steatotic Liver Disease Patients. Viruses 2024; 16:1799. [PMID: 39599914 PMCID: PMC11598886 DOI: 10.3390/v16111799] [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: 10/01/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024] Open
Abstract
(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Although the changes in the expression levels of microRNAs (miRNAs) in hepatitis B virus-related diseases have been evaluated, no study has evaluated the role of miRNAs in HBV vaccine response in MASLD patients. We aimed to determine the miRNA expression profile in MASLD patients according to HBV vaccine response. (2) Methods: Overall, 100 MASLD patients and 100 controls were included, and anti-HBs levels were measured after three doses of HBV vaccine administration. After collecting blood samples, 22 different miRNA expression profiles were analyzed by RT-PCR analysis, and changes in the expression levels of potential miRNAs were further verified in all study groups. (3) Results: The miR-146a expression level considerably increased in MASLD patients compared to the control group. Furthermore, miR-99a and miR-640 expression levels significantly increased in AntiHBs (-) healthy individuals. (4): Conclusions: miR-146a could be used as the diagnostic marker in MASLD patients. Furthermore, the miR-99a and miR-640 expression levels could predict hepatitis B vaccine response. However, validation studies are required to verify the biomarker potential of miRNAs within a more significant number of patients.
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Affiliation(s)
- Gamze Guney Eskiler
- Department of Medical Biology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye;
| | - Oguz Karabay
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye;
| | - Mukaddes Tozlu
- Department of Gastroenterology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye;
| | - Ayhan Aydin
- Department of Internal Sciences, Sakarya University Training and Research Hospital, 54290 Sakarya, Türkiye;
| | - Kaan Furkan Hamarat
- Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye; (K.F.H.); (U.A.)
| | - Umut Alkurt
- Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye; (K.F.H.); (U.A.)
| | - Asuman Deveci Ozkan
- Department of Medical Biology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye;
| | - Yasemin Gunduz
- Department of Radiology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Türkiye;
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Manea M, Mărunțelu I, Constantinescu I. An In-Depth Approach to the Associations between MicroRNAs and Viral Load in Patients with Chronic Hepatitis B-A Systematic Review and Meta-Analysis. Int J Mol Sci 2024; 25:8410. [PMID: 39125978 PMCID: PMC11313658 DOI: 10.3390/ijms25158410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/22/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Scientists study the molecular activities of the hepatitis B virus (HBV). However, in vivo experiments are scarce. Some microRNAs are HBV-related, but their exact mechanisms are unknown. Our study provides an up-to-date view of the associations between microRNAs and HBV-DNA levels in chronically infected individuals. We conducted this large-scale research on five databases according to PRISMA guidance. Joanna Briggs Institute tools and Newcastle Ottawa Quality Assessment scores helped with quality evaluations. R 4.2.2 performed statistical computations for the meta-analysis. DIANA-microT 2023 and g:Profiler enriched the predictions of liver genes associated with miR-122 and miR-192-5p. From the 1313 records, we eliminated those irrelevant to our theme, non-article methodologies, non-English entries, and duplicates. We assessed associations between microRNAs and HBV-DNA levels. Overall, the pooled correlations favoured the general idea of the connection between non-coding molecules and viremia levels. MiR-122 and miR-192-5p were the most researched microRNAs, significantly associated with HBV-DNA levels. The connections between miR-122, miR-192-5p, let-7, miR-215, miR-320, and viral loads need further in vivo assessment. To conclude, this study evaluates systematically, for the first time, the correlations between non-coding molecules and viremia levels in patients. Our meta-analysis emphasizes potentially important pathways toward new inhibitors of the viral replication cycle.
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Affiliation(s)
- Marina Manea
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
| | - Ion Mărunțelu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Ileana Constantinescu
- Immunology and Transplant Immunology, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 022328 Bucharest, Romania
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Yi S, Ren G, Zhu Y, Cong Q. Correlation analysis of hepatic steatosis and hepatitis B virus: a cross-sectional study. Virol J 2024; 21:22. [PMID: 38243304 PMCID: PMC10799397 DOI: 10.1186/s12985-023-02277-8] [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: 11/02/2023] [Accepted: 12/24/2023] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND The co-occurrence of chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) has drawn considerable attention due to its impact on disease outcomes. This study aimed to investigate the association between hepatic steatosis and hepatitis B virus (HBV) and analyzed the influence of hepatic steatosis on hepatitis B virology in patients with CHB. METHODS In this cross-sectional study, 272 patients infected with HBV who were treatment-naïve or had ceased antiviral treatment for > 6 months were categorized into the CHB group (n = 128) and CHB + MAFLD group (n = 144). Furthermore, based on whether HBV DNA was higher than 2000 IU/mL, patients were categorized into the high-level HBV DNA group (n = 129) and the low-level HBV DNA group (n = 143). The impact of hepatic steatosis on hepatitis B virology was analyzed within the CHB cohort. Multivariate logistic regression analysis was employed to identify independent factors influencing pre-genomic RNA (pgRNA) levels below the lower limit of detection (LLD) in patients with CHB. RESULTS Among the 272 patients, compared with CHB group, HBV DNA levels (4.11 vs. 3.62 log10 IU/mL, P = 0.045), hepatitis B surface antigen (HBsAg) levels (3.52 vs. 3.20 log10 IU/mL, P = 0.008) and the hepatitis B e antigen (HBeAg) positive rate (33.6% vs. 22.2%, P = 0.036) were significantly decreased in the CHB + MAFLD group; In 143 low-level HBV DNA patients, the CHB + MAFLD group exhibited decreased levels of pgRNA and HBsAg compared to the CHB group. However, in 129 high-level HBV DNA patients, a more significant decrease was observed in pgRNA (3.85 vs 3.35 log10 copies/mL, P = 0.044) and HBsAg (3.85 vs 3.59 log10 IU/mL, P = 0.033); Spearman correlation analysis revealed a negative correlation between hepatic steatosis and pgRNA (r = - 0.529, P < 0.001), HBV DNA (r = - 0.456, P < 0.001), HBsAg (r = - 0.465, P < 0.001) and HBeAg (r = - 0.339, P < 0.001) levels; Multivariate logistic regression analysis identified HBV DNA (odds ratio [OR] = 0.283, P < 0.001), HBsAg (OR = 0.300, P < 0.001), and controlled attenuation parameter (CAP) values (OR = 1.013, P = 0.038) as independent factors influencing pgRNA levels below the LLD in patients with CHB. CONCLUSIONS This study establishes a negative correlation between hepatic steatosis and hepatitis B virology, demonstrating decreased HBV expression in patients with CHB + MAFLD.
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Affiliation(s)
- Sitong Yi
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Guanghui Ren
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ying Zhu
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Qingwei Cong
- Department of Infectious Disease and Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
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Sartorius K, Sartorius B, Winkler C, Chuturgoon A, Shen TW, Zhao Y, An P. Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study. Int J Mol Sci 2024; 25:975. [PMID: 38256049 PMCID: PMC10815595 DOI: 10.3390/ijms25020975] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2001, South Africa
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, QLD 4102, Australia
| | - Cheryl Winkler
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
| | - Tsai-Wei Shen
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Yongmei Zhao
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Ping An
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
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7
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Liao TL, Chen IC, Chen HW, Tang KT, Huang WN, Chen YH, Chen YM. Exosomal microRNAs as biomarkers for viral replication in tofacitinib-treated rheumatoid arthritis patients with hepatitis C. Sci Rep 2024; 14:937. [PMID: 38195767 PMCID: PMC10776842 DOI: 10.1038/s41598-023-50963-y] [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: 08/03/2023] [Accepted: 12/28/2023] [Indexed: 01/11/2024] Open
Abstract
Notwithstanding recent advances in direct antiviral specialists (DAAs) for hepatitis C infection (HCV), it is yet a pervasive overall issue in patients with rheumatoid arthritis (RA). Exosomal microRNAs (miRNAs) is associated with HCV infection. However, it remains unknown how miRNAs respond following biologic disease-modifying antirheumatic drug (bDMARD) and targeted synthetic DMARD (tsDMARD) treatment in HCV patients with RA. We prospectively recruited RA patients taking anti-tumor necrosis factor-α (TNF-α) inhibitors rituximab (RTX) and tofacitinib. The serum hepatitis C viral load was measured using real-time quantitative reverse transcriptase PCR before and 6 months after bDMARD and tsDMARD therapy. HCV RNA replication activity was measured using an HCV-tricistronic replicon reporter system, and quantitative analysis of hsa-mir-122-5p and hsa-mir-155-5p in patients was performed using quantitative PCR. HCV RNA replication in hepatocytes was not affected by tofacitinib or TNF-α inhibitor treatment. Hsa-mir-155-5p and hsa-mir-122-5p were significantly expanded in RA patients with HCV as compared with those without HCV. We observed a dramatic increase in hsa-mir-122-5p and a decrease in hsa-mir-155-5p expression levels in patients taking RTX in comparison with other treatments. Finally, a reduction in hsa-mir-122-5p and an increase in hsa-mir-155-5p were observed in a time-dependent manner after tofacitinib and DAA therapy in RA-HCV patients. These results showed that hsa-mir-155-5p and hsa-mir-122-5p were significantly increased in RA-HCV patients as compared with those without HCV after taking tofacitinib. Hsa-mir-155-5p and hsa-mir-122-5p may be potential biomarkers for treatment efficacy in RA patients with HCV.
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Affiliation(s)
- Tsai-Ling Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Rong-Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - I-Chieh Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hong-Wei Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kuo-Tung Tang
- Rong-Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650, Section 4, Taiwan Boulevard, Xitun Dist., Taichung, 407, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Wen-Nan Huang
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650, Section 4, Taiwan Boulevard, Xitun Dist., Taichung, 407, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Hsing Chen
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650, Section 4, Taiwan Boulevard, Xitun Dist., Taichung, 407, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
- Rong-Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan.
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650, Section 4, Taiwan Boulevard, Xitun Dist., Taichung, 407, Taiwan.
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan.
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
- Precision Medicine Research Center, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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8
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Bobkova MR. Cellular proteins as potential targets for antiretroviral therapy. Vopr Virusol 2023; 68:488-504. [PMID: 38156565 DOI: 10.36233/0507-4088-207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Indexed: 12/30/2023]
Abstract
The review article conducts an in-depth analysis of information gleaned from a comprehensive literature search across Scopus, Web of Science, and MedLine databases. The focal point of this search revolves around the identification and exploration of the mechanisms orchestrated by host cell factors in the replication cycle of the human immunodeficiency virus (HIV-1, Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1). The article delves into two primary categories of proteins, namely HIV dependence factors (such as CypA, LEDGF, TSG101) and restriction factors (including SERINС5, TRIM5α, APOBEC3G), providing illustrative examples. The current understanding of the functioning mechanisms of these proteins is elucidated, and an evaluation is presented on the potential development of drugs for treating HIV infection. These drugs aim to either inhibit or stimulate the activity of host factors, offering insights into promising avenues for future research and therapeutic advancements.
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Affiliation(s)
- M R Bobkova
- I. Mechnikov Research Institute for Vaccines and Sera
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Liang YJ, Chiou YW, Chiu APT, Shiao MS, Teng W, Lin CW, Cheng ML, Huang YH, Liang KH, Su CW, Lai CY, Chen CL, Wu JC. Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122. J Med Virol 2023; 95:e29325. [PMID: 38108211 DOI: 10.1002/jmv.29325] [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: 06/28/2023] [Revised: 11/27/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.
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Affiliation(s)
- Yuh-Jin Liang
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yu-Wei Chiou
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Abby Pei-Ting Chiu
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, USA
- Department of Biology, University of Washington, Seattle, Washington, USA
| | - Ming-Shi Shiao
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Wei Teng
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC
| | - Chin-Wei Lin
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Mei-Ling Cheng
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
- Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan, ROC
| | - Yen-Hua Huang
- Center for Systems and Synthetic Biology and Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Kung-Hao Liang
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chien-Wei Su
- Department of Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medicine, Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medicine, Division of Holistic and Multidisciplinary Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Internal Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chi-Yu Lai
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chih-Li Chen
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC
| | - Jaw-Ching Wu
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Cavallone D, Ornos EDB, Ricco G, Oliveri F, Coco B, Colombatto P, De Rosa L, Dalmacio LMM, Bonino F, Brunetto MR. The Circulating miRNA Profile of Chronic Hepatitis D and B Patients Is Comparable but Differs from That of Individuals with HBeAg-Negative HBV Infection. Viruses 2023; 15:2257. [PMID: 38005933 PMCID: PMC10675264 DOI: 10.3390/v15112257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
miRNAs circulating in whole serum and HBsAg-particles are differentially expressed in chronic hepatitis B (CHB) and HBeAg-negative-HBV infection (ENI); their profiles are unknown in chronic hepatitis D (CHD). Serum- and HBsAg-associated miRNAs were analyzed in 75 subjects of 3 well-characterized groups (CHB 25, CHD 25, ENI 25) using next-generation sequencing (NGS). Overall miRNA profiles were consonant in serum and HBsAg-particles but significantly different according to the presence of hepatitis independently of Hepatitis D Virus (HDV)-co-infection. Stringent (Bonferroni Correction < 0.001) differential expression analysis showed 39 miRNAs upregulated in CHB vs. ENI and 31 of them also in CHD vs. ENI. miRNA profiles were coincident in CHB and CHD with only miR-200a-3p upregulated in CHB. Three miRNAs (miR-625-3p, miR-142-5p, and miR-223-3p) involved in immune response were upregulated in ENI. All 3 hepatocellular miRNAs of MiR-B-Index (miR-122-5p, miR-99a-5p, miR-192-5p) were overexpressed in both CHB and CHD patients. In conclusion, CHD and CHB patients showed highly similar serum miRNA profiling that was significantly different from that of individuals with HBeAg-negative infection and without liver disease.
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Affiliation(s)
- Daniela Cavallone
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
| | - Eric David B. Ornos
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Department of Medical Microbiology, College of Medicine, University of the Philippines Manila, Pedro Gil Street, Ermita, Manila 1000, Philippines
- Fondazione Italiana Fegato (FIF), 34149 Trieste, Italy
| | - Gabriele Ricco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Laura De Rosa
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy;
- Department of Information Engineering and Computer Science, University of Trento, 38123 Trento, Italy
| | - Leslie Michelle M. Dalmacio
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Pedro Gil Street, Ermita, Manila 1000, Philippines;
| | - Ferruccio Bonino
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
| | - Maurizia Rossana Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
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11
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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12
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Mirzaei R, Karampoor S, Korotkova NL. The emerging role of miRNA-122 in infectious diseases: Mechanisms and potential biomarkers. Pathol Res Pract 2023; 249:154725. [PMID: 37544130 DOI: 10.1016/j.prp.2023.154725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
microRNAs (miRNAs) are small, non-coding RNA molecules that play crucial regulatory roles in numerous cellular processes. Recent investigations have highlighted the significant involvement of miRNA-122 (miR-122) in the pathogenesis of infectious diseases caused by diverse pathogens, encompassing viral, bacterial, and parasitic infections. In the context of viral infections, miR-122 exerts regulatory control over viral replication by binding to the viral genome and modulating the host's antiviral response. For instance, in hepatitis B virus (HBV) infection, miR-122 restricts viral replication, while HBV, in turn, suppresses miR-122 expression. Conversely, miR-122 interacts with the hepatitis C virus (HCV) genome, facilitating viral replication. Regarding bacterial infections, miR-122 has been found to regulate host immune responses by influencing inflammatory cytokine production and phagocytosis. In Vibrio anguillarum infections, there is a significant reduction in miR-122 expression, contributing to the pathophysiology of bacterial infections. Toll-like receptor 14 (TLR14) has been identified as a novel target gene of miR-122, affecting inflammatory and immune responses. In the context of parasitic infections, miR-122 plays a crucial role in regulating host lipid metabolism and immune responses. For example, during Leishmania infection, miR-122-containing extracellular vesicles from liver cells are unable to enter infected macrophages, leading to a suppression of the inflammatory response. Furthermore, miR-122 exhibits promise as a potential biomarker for various infectious diseases. Its expression level in body fluids, particularly in serum and plasma, correlates with disease severity and treatment response in patients affected by HCV, HBV, and tuberculosis. This paper also discusses the potential of miR-122 as a biomarker in infectious diseases. In summary, this review provides a comprehensive and insightful overview of the emerging role of miR-122 in infectious diseases, detailing its mechanism of action and potential implications for the development of novel therapeutic strategies.
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Affiliation(s)
- Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Nadezhda Lenoktovna Korotkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Russia; Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation (FSBEI HE PRMU MOH Russia), Russia
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13
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Paluschinski M, Schira-Heinen J, Pellegrino R, Heij LR, Bednarsch J, Neumann UP, Longerich T, Stuehler K, Luedde T, Castoldi M. Uncovering Novel Roles of miR-122 in the Pathophysiology of the Liver: Potential Interaction with NRF1 and E2F4 Signaling. Cancers (Basel) 2023; 15:4129. [PMID: 37627157 PMCID: PMC10453129 DOI: 10.3390/cancers15164129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
MicroRNA miR-122 plays a pivotal role in liver function. Despite numerous studies investigating this miRNA, the global network of genes regulated by miR-122 and its contribution to the underlying pathophysiological mechanisms remain largely unknown. To gain a deeper understanding of miR-122 activity, we employed two complementary approaches. Firstly, through transcriptome analysis of polyribosome-bound RNAs, we discovered that miR-122 exhibits potential antagonistic effects on specific transcription factors known to be dysregulated in liver disease, including nuclear respiratory factor-1 (NRF1) and the E2F transcription factor 4 (E2F4). Secondly, through proteome analysis of hepatoma cells transfected with either miR-122 mimic or antagomir, we discovered changes in several proteins associated with increased malignancy. Interestingly, many of these proteins were reported to be transcriptionally regulated by NRF1 and E2F4, six of which we validated as miR-122 targets. Among these, a negative correlation was observed between miR-122 and glucose-6-phosphate dehydrogenase levels in the livers of patients with hepatitis B virus-associated hepatocellular carcinoma. This study provides novel insights into potential alterations of molecular pathway occurring at the early stages of liver disease, driven by the dysregulation of miR-122 and its associated genes.
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Affiliation(s)
- Martha Paluschinski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
| | - Jessica Schira-Heinen
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
- Molecular Proteomics Laboratory (MPL), Institute for Molecular Medicine, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
| | - Rossella Pellegrino
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (R.P.); (T.L.)
| | - Lara R. Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Ulf P. Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (R.P.); (T.L.)
| | - Kai Stuehler
- Molecular Proteomics Laboratory (MPL), Institute for Molecular Medicine, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
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14
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Mokhtari F, Kaboosi H, Mohebbi SR, Asadzadeh Aghdaei H, Zali MR. Circulating Plasma miR-122 and miR-583 Levels Are Involved in Chronic Hepatitis B Virus Pathogenesis and Serve As Novel Diagnostic Biomarkers. Genet Test Mol Biomarkers 2023; 27:232-238. [PMID: 37643324 DOI: 10.1089/gtmb.2023.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023] Open
Abstract
Background: MicroRNAs regulate many biological processes and are involved in the pathogenesis of many diseases including chronic hepatitis B (CHB). Moreover, besides investigation of their roles in hepatitis B virus (HBV) infection, a noninvasive, sensitive, and specific biomarker is essential in the diagnosis of liver diseases. This study was designed to evaluate the role of miR-122, miR-583, and miR-24 in the pathogenesis of CHB both in active chronic hepatitis (ACH) patients and in inactive carriers (IC). Materials and Methods: Plasma samples and all relevant clinical features were collected from 43 patients with CHB (28 ACH and 15 IC) and 43 healthy controls. Quantitative real-time PCR was performed to detect the plasma levels of miR-122, miR-583, and miR-24. Results: Results show miR-122 (p = 0.0001) and miR-583 (p = 0.006) but not miR-24 (p = 0.65) were upregulated in patients with CHB versus the control group. Interestingly, there was a significant increase in the plasma expression of miR-583 in IC versus ACH. Moreover, receiver operating characteristic curve analysis determined plasma levels of miR-122 (area under the ROC curve [AUC] = 0.89, p < 0.0001, sensitivity: 100%, specificity: 62.5%) and miR-583 (AUC = 0.71, p = 0.0007, sensitivity: 90%, specificity: 47.62%) as sensitive biomarkers to discriminate CHB patients from controls. Conclusion: Our data showed an increase in the plasma levels of miR-583 in IC versus ACH patients. Moreover, we demonstrated that miR-122 and miR-583 may serve as potential biomarkers for CHB diagnosis and activity.
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Affiliation(s)
- Fedra Mokhtari
- Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
| | - Hami Kaboosi
- Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, 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
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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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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16
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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17
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Hassan M, El-Ahwany E, Elzallat M, Rahim AA, Abu-Taleb H, Abdelrahman Y, Hassanein M. Role of MicroRNAs in the Development of Chronic Liver Disease in Hepatitis Virus-Infected Egyptian Population. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.10902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: The identification of miRNAs that play a role in the regulation of the viral life cycle and its related liver illness opens the door to the development of diagnostic biomarkers that can categorize patients at higher risk for developing end-stage liver disease. This study was designed to investigate the role of miRNAs in the development of viral hepatitis-induced chronic liver disease (CLD) in the Egyptian population, as well as their potential as possible diagnostic biomarkers for chronic hepatitis virus infection.
Methodology: The study involved 100 CLD patients; 55 cases of hepatitis C virus (HCV) and 45 cases of non-viral hepatitis, in addition to 40 healthy controls. The expression of five miRNAs (miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431) was assessed using real-time PCR.
Results: Serum levels of miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431 were significantly higher in all patients than the control group (p<0.01). Also, they were significantly greater in viral hepatitis cases compared to the non-viral hepatitis group (p<0.01). The sensitivities and specificities of miR-122a, miR‐30, miR‐296, miR‐351, and miR‐431 were (85.71%, 83.33%), (82.35%, 83.33%), (85.71%, 69.44%), (88.64%, 75.76%), and (87.80%, 65.79%), respectively.
Conclusions: miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431 play key roles in the development of CLD as a consequence of viral infection. So, they have the potential to be targeted for the early detection of chronic hepatitis virus infection and allow for exploring a new frontier in the discovery of innovative therapeutics to combat chronic viral infection and its serious life-threatening complications including liver cancer.
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18
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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19
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Liu C, Hou X, Mo K, Li N, An C, Liu G, Pan Z. Serum non-coding RNAs for diagnosis and stage of liver fibrosis. J Clin Lab Anal 2022; 36:e24658. [PMID: 35989522 PMCID: PMC9550980 DOI: 10.1002/jcla.24658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/01/2022] [Accepted: 08/02/2022] [Indexed: 11/24/2022] Open
Abstract
Background All chronic liver diseases could lead to liver fibrosis. Accurate diagnosis and stage of fibrosis were important for the medical determination, management, and therapy. Liver biopsy was considered to be the gold criteria of fibrosis diagnosis. However, liver biopsy was an invasive method with some drawbacks. Non‐invasive tests for liver fibrosis included radiologic method and serum‐based test. Radiologic examination was influenced by obesity, cost, and availability. Serum‐based test was widely used in the screening and diagnostic of liver fibrosis. However, the accuracy was still needed to be improved. Methods Recent studies showed serum non‐coding RNAs: microRNA, long non‐coding RNA(lncRNA), and circular RNA(circRNA), which have the potentiality to be non‐invasive markers for liver fibrosis. The recent progress was summarized in this review. Results These studies showed serum non‐coding RNAs exerted a good diagnostic performance for liver fibrosis. A panel that included several non‐coding RNAs could increase the accuracy of single marker. Conclusions Serum microRNAs, lncRNAs, and circRNAs could be potential non‐invasive markers for diagnosis and stage of liver fibrosis. More high‐quality clinical study is needed for further research.
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Affiliation(s)
- Chao Liu
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
| | - Xueyun Hou
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
| | - Kaixin Mo
- Clinical Laboratory, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Nannan Li
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
| | - Cheng An
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
| | - Guijian Liu
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
| | - Zongdai Pan
- Clinical Laboratory, Guang'anmen HospitalChina Academy of Chinese Medical SciencesBeijingChina
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20
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Chun KH. Molecular Targets and Signaling Pathways of microRNA-122 in Hepatocellular Carcinoma. Pharmaceutics 2022; 14:1380. [PMID: 35890276 PMCID: PMC9316959 DOI: 10.3390/pharmaceutics14071380] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading global causes of cancer mortality. MicroRNAs (miRNAs) are small interfering RNAs that alleviate the levels of protein expression by suppressing translation, inducing mRNA cleavage, and promoting mRNA degradation. miR-122 is the most abundant miRNA in the liver and is responsible for several liver-specific functions, including metabolism, cellular growth and differentiation, and hepatitis virus replication. Recent studies have shown that aberrant regulation of miR-122 is a key factor contributing to the development of HCC. In this review, the signaling pathways and the molecular targets of miR-122 involved in the progression of HCC have been summarized, and the importance of miR-122 in therapy has been discussed.
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Affiliation(s)
- Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Korea
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21
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Li J, Xu J, Wang Y, Li Q, Sun X, Fu W, Zhang B. Association of Nucleostemin Polymorphisms with Chronic Hepatitis B Virus Infection in Chinese Han Population. Genet Test Mol Biomarkers 2022; 26:255-262. [PMID: 35638911 PMCID: PMC9150128 DOI: 10.1089/gtmb.2021.0181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Chronic hepatitis B virus infection (CHB) is a common infectious disease that poses a global economic and health burden due to its high morbidity and mortality. Studies have demonstrated that host genetic factors play critical roles in the susceptibility and outcome of CHB. Aims: In this study, we aimed to assess the potential role of genetic variants of the nucleostemin (NS) gene with respect to CHB susceptibility. Materials and Methods: Four single nucleotide polymorphisms (SNPs) in the NS gene were genotyped in 446 patients with CHB and 399 healthy controls all of Chinese Han origin using the polymerase chain reaction-ligation detection reaction method. Results: The results showed that the three SNPs, rs3733039, rs1866268, and rs11177, were significantly associated with CHB. After a Bonferroni correction, the positive association of the rs3733039 SNP with CHB remained significant. Further analyses based on gender demonstrated that these SNPs are associated with CHB in both the female and male subgroups. After correction for multiple comparisons, all three SNPs in the female group were associated with CHB, whereas only the rs1866268 SNP in the male group was associated with CHB. Haplotype analysis showed that the C-C-G and T-T-T haplotypes in the block consisting of rs3733039-rs1866268-rs11177 were significantly associated with CHB. Conclusion: Our study demonstrated a genetic association between SNPs in the NS gene and the risk of CHB in the Chinese Han population for the first time. Thus, variations in the NS gene might serve as potential genetic biomarkers of CHB.
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Affiliation(s)
- Jixia Li
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Jinya Xu
- Department of Clinical Laboratory, Yantai Qishan Hospital, Yantai, China
| | - Yangui Wang
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Qin Li
- Department of Clinical Laboratory, Yantai Yuhuangding Hospital, Yantai, China
| | - Xilian Sun
- Department of Nursing, Yantaishan Hospital, Yantai, China
| | - Wen Fu
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Bo Zhang
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Yantai, China
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22
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Ran Z, Wu S, Ma Z, Chen X, Liu J, Yang J. Advances in exosome biomarkers for cervical cancer. Cancer Med 2022; 11:4966-4978. [PMID: 35578572 PMCID: PMC9761094 DOI: 10.1002/cam4.4828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 02/03/2023] Open
Abstract
Cervical cancer (CC) ranks as the fourth most frequently diagnosed malignancy in females worldwide. Exosomes are a subclass of extracellular vesicles released by nearly all types of cells that act as cargo transport vehicles, carrying proteins, and genetic material (such as miRNAs, long noncoding RNAs, and mRNAs) derived from their parent cells may affect receiving cells and thus have emerged as key players in several biological processes, including inflammatory pathways. In this review, we concentrated on the findings of exosome investigations in CC, particularly their components. They direct the actions of CC cells by inducing surface molecules associated with various biological pathways. We summarized the current knowledge of exosomal RNAs and proteins from CC cells and discussed the feasibility of exosomes as potential biomarkers for CC. We suggest that cancer-derived exosomes promote metastasis in CC by supporting EMT, controlling the proliferation, invasion, or migration of cancer cells, as well as influencing immune escape and aiding angiogenesis. Overall, cancer-derived exosomes are critical in the progression of CC, and further studies are necessary to advance our understanding of the clinical value of exosomes in CC.
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Affiliation(s)
- Zihan Ran
- Department of ResearchShanghai University of Medicine & Health Sciences Affiliated Zhoupu HospitalShanghaiChina,Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Shaobo Wu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Zijng Ma
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Xiuwen Chen
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Jing Liu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina
| | - Jingcheng Yang
- The Genius Medicine Consortium (TGMC)ShanghaiChina,State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer CenterFudan UniversityShanghaiChina,Greater Bay Area Institute of Precision MedicineGuangzhouChina
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23
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Rajendren S, Karijolich J. The Impact of RNA modifications on the Biology of DNA Virus Infection. Eur J Cell Biol 2022; 101:151239. [PMID: 35623231 PMCID: PMC9549750 DOI: 10.1016/j.ejcb.2022.151239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/26/2022] Open
Abstract
Approximately 170 RNA modifications have been identified and these are critical for determining the fate and function of cellular RNAs. Similar to human transcripts, viral RNAs possess an extensive RNA modification landscape. While initial efforts largely focused on investigating the RNA modification landscape in the context of RNA virus infection, a growing body of work has explored the impact of RNA modifications on DNA virus biology. These studies have revealed roles for RNA modifications in DNA virus infection, including gene regulation and viral pathogenesis. In this review, we will discuss the current knowledge on how RNA modifications impact DNA virus biology.
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24
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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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25
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Yang H, Rui F, Li R, Yin S, Xue Q, Hu X, Xu Y, Wu C, Shi J, Li J. ADAR1 Inhibits HBV DNA Replication via Regulating miR-122-5p in Palmitic Acid Treated HepG2.2.15 Cells. Diabetes Metab Syndr Obes 2022; 15:4035-4047. [PMID: 36582505 PMCID: PMC9793725 DOI: 10.2147/dmso.s373385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 11/01/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND AIMS Changes in living standards and diet structure, non-alcoholic fatty liver disease (NAFLD) is prevalent globally, including in Asia, where chronic hepatitis B (CHB) is endemic. As such, cooccurrence of NAFLD with CHB is common in Asia. However, the pathogenesis underlying the onset of fatty liver in CHB prognosis has not been fully elucidated. Therefore, we aimed to investigate the effects and mechanisms of lipotoxicity on hepatitis B virus (HBV) DNA replication. METHODS The expression of adenosine deaminase acting on RNA-1 (ADAR1) and miR-122 was evaluated in liver tissues from patients with CHB concurrent NAFLD. Palmitic acid-treated HepG2.2.15 cells were used as the cell model. The effect of lipotoxicity on HBV DNA replication was evaluated in vitro by transfecting the ADAR1 overexpression or knockdown lentiviral vector into HepG2.2.15 cells, respectively. qRT-PCR, western blotting and immunofluorescence were performed to determine ADAR1 expression. RESULTS The expression of ADAR1 in the liver tissues of CHB patients with concurrent NAFLD was significantly down-regulated compared with that in CHB patients. Enforced expression of ADAR1 inhibited the HBV DNA replication, whereas ADAR1 knockdown resulted in increased HBV DNA expression in palmitic acid - treated HepG2.2.15 cells. Additionally, ADAR1 inhibited the HBV DNA replication by upregulating miR-122, which is most abundant in the liver and mainly inhibits HBV DNA replication. CONCLUSIONS ADAR1 may act as a suppressor of HBV replication in palmitic acid -treated HepG2.2.15 cells by increasing miR-122 levels. Thus, ADAR1 may serve as a potential biomarker and therapeutic target for CHB with concurrent NAFLD.
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Affiliation(s)
- Hongli Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji’nan, People’s Republic of China
| | - Fajuan Rui
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing, People’s Republic of China
| | - Rui Li
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, People’s Republic of China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
| | - Qi Xue
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji’nan, People’s Republic of China
| | - Xinyu Hu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Ji’nan, People’s Republic of China
| | - Yayun Xu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Ji’nan, People’s Republic of China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
| | - Junping Shi
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, People’s Republic of China
- Junping Shi, Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, Zhejiang, People’s Republic of China, Email
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China
- Correspondence: Jie Li, Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China, Email
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26
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Qian Z, Yang C, Xu L, Mickael HK, Chen S, Zhang Y, Xia Y, Li T, Yu W, Huang F. Hepatitis E virus-encoded microRNA promotes viral replication by inhibiting type I interferon. FASEB J 2021; 36:e22104. [PMID: 34918388 DOI: 10.1096/fj.202101042r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/18/2021] [Accepted: 12/01/2021] [Indexed: 02/05/2023]
Abstract
MicroRNAs (miRNAs), the non-coding RNAs of ~22 nucleotides (nt) in length, play a vital role in regulating viral replication. Hepatitis E virus (HEV), a single-stranded RNA virus, is a predominant pathogen of acute hepatitis worldwide. Virus-encoded miRNAs regulate the viral life cycle and escape from the host innate immune system. However, it is rarely known about HEV-encoded miRNA (HEV-miR-A6). In the present study, HEV-miR-A6 was screened by microarray, and further identified in vivo and in vitro. HEV-miR-A6 originated from the methylase (MeT) of HEV open reading frame 1 (ORF1) and was highly conserved in eight HEV genotypes. HEV-miR-A6 expression was growing during HEV replication, and significantly increased in acute hepatitis E patients than convalescence patients. Furthermore, HEV-miR-A6 was specifically detected in liver, spleen, kidney and colon by in situ hybridization. To identify the specificity of HEV-miR-A6, its mutants (HEV-miR-A6M1 and HEV-miR-A6M2) were constructed to change the stem-loop structure. Interestingly, over-expression of HEV-miR-A6 or HEV-miR-A6M1 significantly facilitated viral replication, while HEV-miR-A6M2, another mutant completely changed the stem-loop structure was invalid. SIRP-α, a candidate target gene of HEV-miR-A6, was activated when HEV-miR-A6 over-expressed to inhibit the phosphorylation of IRF3, and subsequently suppressed the expression of type I interferon β (IFN-β). The promotion of viral replication by HEV-miR-A6 further identified in vivo. Significant suppression of IFN-β production in the serum of HEV-infected mice pre-treated with HEV-miR-A6 was observed. In summary, HEV-miR-A6 activates SIRP-α to promote viral replication by inhibition of IFN-β expression.
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Affiliation(s)
- Zhongyao Qian
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Chenchen Yang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Liangheng Xu
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Houfack K Mickael
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Shuangfeng Chen
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Yike Zhang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Yueping Xia
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Tengyuan Li
- Medical School, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
| | - Fen Huang
- Medical School, Kunming University of Science and Technology, Kunming, PR China
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27
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Hao Q, Wang Q, Qian H, Jiang J, Liu X, Xia W. Identification and functional characterization of miR-451a as a novel plasma-based biomarker for occult hepatitis B virus infection. Microb Pathog 2021; 161:105233. [PMID: 34626767 DOI: 10.1016/j.micpath.2021.105233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/07/2021] [Accepted: 10/01/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Numerous studies have indicated that miRNAs might play significant roles in the development of hepatitis B virus (HBV) infection. while the miRNAs in occult HBV infection (OBI) are still largely unknown. METHODS Initially, 15 HBV infection-related miRNAs in plasma of 10 OBI and 10 healthy controls (HCs) was analyzed by qRT-PCR. Significantly dysregulated miRNAs were subsequently validated in another 64 OBI, 20HCs, 31 chronic hepatitis B (CHB) and 20 asymptomatic HBsAg carriers (ASC). Furthermore, the potential biological functions and molecular mechanisms of miR-451a in HBV infection were investigated using HBV-expressing hepatoma cell lines. RESULTS Compared to HCs, plasma miR-451a and miR-340-3p were significantly up-regulated in OBI, ASC and CHB patients, while no significant difference was found among OBI, ASC and CHB patients. ROC curve analysis indicated that both plasma miR-451a and miR-340-3p could moderately distinguish OBI from HCs, with AUCs of 0.76 and 0.78, respectively. When combined, the differentiation efficiency of this miRNA panel was better, with an AUC of 0.82. While, they both could not specifically separate the stage of chronic HBV infection. Functional experiments showed that overexpression of miR-451a might suppress HBV replication and gene expression in hepatoma cell lines. Mechanistically, miR-451a might inhibit HBV replication and gene expression by directly targeting ATF2. CONCLUSIONS A plasma panel, including miR-340-3p and miR-451a that might suppress HBV replication by targeting ATF2, has the potential as biomarkers for HBV infection. In the setting of blood donations, this panel would be more practical to moderately differentiate OBI in HBsAg-negative donors.
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Affiliation(s)
- Qingqin Hao
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Qinghui Wang
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Huizhong Qian
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Jian Jiang
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China
| | - Xiao Liu
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China.
| | - Wei Xia
- Department of Clinical Laboratory, Wuxi Blood Center, Wuxi, 214000, China.
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Crosstalk between Environmental Inflammatory Stimuli and Non-Coding RNA in Cancer Occurrence and Development. Cancers (Basel) 2021; 13:cancers13174436. [PMID: 34503246 PMCID: PMC8430834 DOI: 10.3390/cancers13174436] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Increasing evidence has indicated that chronic inflammatory processes have an influence on tumor occurrence and all stages of tumor development. A dramatic increase of studies into non-coding RNAs (ncRNAs) biology has shown that ncRNAs act as oncogenic drivers and tumor suppressors in various inflammation-induced cancers. Thus, this complex network of inflammation-associated cancers and ncRNAs offers targets for prevention from the malignant transformation from inflammation and treatment of malignant diseases. Abstract There is a clear relationship between inflammatory response and different stages of tumor development. Common inflammation-related carcinogens include viruses, bacteria, and environmental mutagens, such as air pollutants, toxic metals, and ultraviolet light. The expression pattern of ncRNA changes in a variety of disease conditions, including inflammation and cancer. Non-coding RNAs (ncRNAs) have a causative role in enhancing inflammatory stimulation and evading immune responses, which are particularly important in persistent pathogen infection and inflammation-to-cancer transformation. In this review, we investigated the mechanism of ncRNA expression imbalance in inflammation-related cancers. A better understanding of the function of inflammation-associated ncRNAs may help to reveal the potential of ncRNAs as a new therapeutic strategy.
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29
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Qu B, Brown RJP. Strategies to Inhibit Hepatitis B Virus at the Transcript Level. Viruses 2021; 13:v13071327. [PMID: 34372533 PMCID: PMC8310268 DOI: 10.3390/v13071327] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/11/2022] Open
Abstract
Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription or destabilize viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA. Small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA, while small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrated templates. These antivirals mediate their effects by reducing viral transcripts abundance, some leading to a loss of surface antigen expression, and they can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.
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Affiliation(s)
- Bingqian Qu
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- European Virus Bioinformatics Center, 07743 Jena, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
| | - Richard J. P. Brown
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
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30
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Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol 2021; 27:3182-3207. [PMID: 34163105 PMCID: PMC8218364 DOI: 10.3748/wjg.v27.i23.3182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/23/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.
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Affiliation(s)
- Prashika Singh
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Dylan Kairuz
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Kristie Bloom
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
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31
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Analysis of Serum MicroRNA-122 Expression at Different Stages of Chronic Hepatitis B Virus Infection. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9957440. [PMID: 34212044 PMCID: PMC8208847 DOI: 10.1155/2021/9957440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/21/2021] [Indexed: 01/30/2023]
Abstract
Objective To investigate the expression of microRNA-122 (miR-122) in the progression of chronic hepatitis B virus- (HBV-) infected liver diseases, thus determining the role of serum miR-122 as a marker of HBV-caused liver injury. Methods Sera were collected from patients with different stages of HBV infection (n = 63) and healthy volunteers (n = 11). And the serum miR-122 levels were detected using RT-qPCR. Moreover, an analysis was applied for identifying the specific correlation of the miR-122 level with HBV DNA, HBeAg, and ALT levels. After liver biopsy, Ishak scoring was utilized for evaluation of the fibrosis stage and the histological activity index (HAI). Results We confirmed, in the serum, increased miR-122 expression in HBV-infected patients and its highest expression in chronic HBV carriers, based on such comparison between the healthy controls and patients. The correlation analysis results were taken as confirmation of the positive relationship of miR-122 with HBV DNA (r = 0.354, P = 0.005) and ALT (r = 0.331, P = 0.009). But no correlation of this molecule with HBeAg levels was found (P = 0.187). In comparison with the HBeAg-negative patients, serum miR-122 expression showed an increase in the HBeAg-positive patients (P = 0.001). miR-122 expression, in addition, was of a significant correlation with HAI, but not with the liver fibrosis score. Conclusion The peak of the serum miR-122 expression normally occurs in the early stage of the progression from the HBV carrier phase to chronic hepatitis to cirrhosis. This molecule can be considered as a marker for evaluation of HBV-caused liver injury.
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Tan B, Liu M, Wang L, Wang J, Xiong F, Bao X, Gao Y, Yu L, Lu J. Serum microRNAs predict response of patients with chronic hepatitis B to antiviral therapy. Int J Infect Dis 2021; 108:37-44. [PMID: 33992764 DOI: 10.1016/j.ijid.2021.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/01/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To investigate the feasibility of using serum microRNAs to predict the response of chronic hepatitis B (CHB) patients to antiviral therapy over 48 weeks. METHODS Sixty-five CHB patients were divided into responder and non-responder groups according to whether hepatitis B e antigen seroconversion occurred at week 48. Serum microRNAs were dynamically detected. RESULTS At baseline, the responder group had lower miR-122-5p (P = 0.006) and higher miR-1307-3p (P = 0.018) than the non-responder group. After therapy, miR-320a-3p and miR-320c were higher in the responder group than the non-responder group (P = 0.043 and 0.031, respectively). In the responder group, 9 microRNAs-let-7d-5p, let-7f-5p, let-7i-5p, miR-126-3p, miR-1307-3p, miR-181a-5p, miR-21-5p, miR-425-5p and miR-652-3p-were significantly lower at week 48 than at baseline (P < 0.05); however, miR-320a-3p was significantly elevated after therapy (P < 0.001). In the non-responder group, miR-122-5p significantly decreased after therapy compared with baseline (P = 0.005). Finally, miR-122-5p was positively correlated with titer of hepatitis B virus DNA (r = 0.438, P = 0.008) and hepatitis B e antigen (r = 0.610, P < 0.001), and miR-320a-3p was negatively correlated with hepatitis B virus DNA titer (r = -0.366, P = 0.028) at baseline. CONCLUSIONS The dynamic fluctuations of serum microRNAs might predict the efficacy of antiviral therapy for CHB.
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Affiliation(s)
- Bingqin Tan
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China; Department of Infectious Diseases, Weifang People's Hospital, Weifang, Shandong 261000, PR China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China
| | - Jinhuan Wang
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Fang Xiong
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Xuli Bao
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Yao Gao
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Lele Yu
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Jun Lu
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China.
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Lu MY, Chen CT, Shih YL, Tsai PC, Hsieh MH, Huang CF, Yeh ML, Huang CI, Wang SC, Tsai YS, Ko YM, Lin CC, Chen KY, Wei YJ, Hsu PY, Hsu CT, Jang TY, Liu TW, Liang PC, Hsieh MY, Lin ZY, Chen SC, Huang JF, Dai CY, Chuang WL, Yu ML, Chang WY. Changing epidemiology and viral interplay of hepatitis B, C and D among injecting drug user-dominant prisoners in Taiwan. Sci Rep 2021; 11:8554. [PMID: 33879825 PMCID: PMC8058093 DOI: 10.1038/s41598-021-87975-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/06/2021] [Indexed: 02/07/2023] Open
Abstract
The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10-0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13-0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04-40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.
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Affiliation(s)
- Ming-Ying Lu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Chun-Ting Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yu-Lueng Shih
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Meng-Hsuan Hsieh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Health Management Center and Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ching-Chih Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Yu-Ju Wei
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Po-Yao Hsu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Cheng-Ting Hsu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ta-Wei Liu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Health Management Center and Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
- Faculty of Internal Medicine and Hepatitis Research Center, College of Medicine and Center for Cohort Study and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
| | - Wen-Yu Chang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
- Taiwan Liver Research Foundation, Kaohsiung, Taiwan, ROC
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 286] [Impact Index Per Article: 71.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Abstract
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
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Mukhopadhyay U, Banerjee A, Chawla-Sarkar M, Mukherjee A. Rotavirus Induces Epithelial-Mesenchymal Transition Markers by Transcriptional Suppression of miRNA-29b. Front Microbiol 2021; 12:631183. [PMID: 33679655 PMCID: PMC7930342 DOI: 10.3389/fmicb.2021.631183] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/19/2021] [Indexed: 01/29/2023] Open
Abstract
Acute gastroenteritis (AGE) is a serious global health problem and has been known to cause millions of infant deaths every year. Rotavirus (RV), a member of the Reoviridae family, still majorly accounts for the AGE in children below 5 years of age in India and worldwide. The involvement of miRNAs in the pathogenesis of RV has been suggested to be of the proviral as well as the anti-viral nature. miRNAs that promote the RV pathogenesis are capable of targeting the cellular components to evade the host anti-viral strategies. On the other hand, miRNAs with anti-rotaviral properties are themselves incapacitated during the progression of the infection. The exploitation of the epithelial-mesenchymal transition (EMT) as a pro-rotaviral strategy has already been identified. Thus, miRNAs that proficiently target the intermediates of the EMT pathway may serve as anti-viral counterparts in the RV-host interactions. The role of microRNA-29b (miR-29b) in the majority of human cancers has been well demonstrated, but its significance in viral infections is yet to be elaborated. In this study, we have assessed the role of miR-29b in RV-induced EMT and RV replication. Our study on miR-29b provides evidence for the recruitment of RV non-structural protein NSP1 to control the trans-repression of miR-29b in a p53-dependent manner. The trans-repression of miR-29b modulates the EMT pathway by targeting tripartite motif-containing protein 44 (TRIM44) and cyclin E1 (CCNE1). SLUG and SNAIL transcription repressors (downstream of TRIM44 and CCNE1) regulate the expression of E-cadherin, an important marker of the EMT. Also, it is established that ectopic expression of miR-29b not only constrains the EMT pathway but also restricts RV replication. Therefore, miR-29b repression is a crucial event in the RV pathogenesis. Ectopic expression of miR-29b displays potential anti-viral properties against RV propagation.
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Affiliation(s)
- Urbi Mukhopadhyay
- Division of Molecular Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Anwesha Banerjee
- Division of Virology, ICMR-National AIDS Research Institute, Pune, India
| | - Mamta Chawla-Sarkar
- Division of Molecular Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Anupam Mukherjee
- Division of Molecular Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
- Division of Virology, ICMR-National AIDS Research Institute, Pune, India
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int J Mol Sci 2020; 21:ijms21218362. [PMID: 33171811 PMCID: PMC7664704 DOI: 10.3390/ijms21218362] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and therapeutic targets.
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The assessment of selected MiRNAs profile in HIV, HBV, HCV, HIV/HCV, HIV/HBV Co-infection and elite controllers for determination of biomarker. Microb Pathog 2020; 147:104355. [DOI: 10.1016/j.micpath.2020.104355] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/14/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023]
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Zhang BY, Chai DP, Wu YH, Qiu LP, Zhang YY, Ye ZH, Yu XP. Potential Drug Targets Against Hepatitis B Virus Based on Both Virus and Host Factors. Curr Drug Targets 2020; 20:1636-1651. [PMID: 31362671 DOI: 10.2174/1389450120666190729115646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatitis B is a very harmful and epidemic disease caused by hepatitis B virus (HBV). Although an effective anti-HBV vaccine is available, chronic infection poses still a huge health burden in the whole world. The present anti-HBV drugs including nucleoside analogues and interferonalpha have their limitations without exception. There is no effective drug and therapeutic method that can really and truly cure hepatitis B so far. The variability of HBV genome results in that a significant number of patients develop drug resistance during the long-term use of anti-HBV drugs. Hence, it is urgently needed to discover novel targets and develop new drugs against hepatitis B. OBJECTIVE The review aims to provide the theory support for designing of the anti-HBV innovative drugs by offering a summary of the current situation of antiviral potential targets. RESULTS AND CONCLUSION Since HBV is obligate intracellular parasite, and as such it depends on host cellular components and functions to replicate itself. The targeting both virus and host might be a novel therapeutic option for hepatitis B. Accordingly, we analyse the advances in the study of the potential drug targets for anti-HBV infection, focusing on targeting virus genome, on targeting host cellular functions and on targeting virus-host proteins interactions, respectively. Meanwhile, the immune targets against chronic hepatitis B are also emphasized. In short, the review provides a summary of antiviral therapeutic strategies to target virus factors, host factors and immune factors for future designing of the innovative drug against HBV infection.
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Affiliation(s)
- Bing-Yi Zhang
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Dan-Ping Chai
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Yi-Hang Wu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Li-Peng Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Yong-Yong Zhang
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Zi-Hong Ye
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Xiao-Ping Yu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
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Chang S, Wang LHC, Chen BS. Investigating Core Signaling Pathways of Hepatitis B Virus Pathogenesis for Biomarkers Identification and Drug Discovery via Systems Biology and Deep Learning Method. Biomedicines 2020; 8:biomedicines8090320. [PMID: 32878239 PMCID: PMC7555687 DOI: 10.3390/biomedicines8090320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B Virus (HBV) infection is a major cause of morbidity and mortality worldwide. However, poor understanding of its pathogenesis often gives rise to intractable immune escape and prognosis recurrence. Thus, a valid systematic approach based on big data mining and genome-wide RNA-seq data is imperative to further investigate the pathogenetic mechanism and identify biomarkers for drug design. In this study, systems biology method was applied to trim false positives from the host/pathogen genetic and epigenetic interaction network (HPI-GEN) under HBV infection by two-side RNA-seq data. Then, via the principal network projection (PNP) approach and the annotation of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, significant biomarkers related to cellular dysfunctions were identified from the core cross-talk signaling pathways as drug targets. Further, based on the pre-trained deep learning-based drug-target interaction (DTI) model and the validated pharmacological properties from databases, i.e., drug regulation ability, toxicity, and sensitivity, a combination of promising multi-target drugs was designed as a multiple-molecule drug to create more possibility for the treatment of HBV infection. Therefore, with the proposed systems medicine discovery and repositioning procedure, we not only shed light on the etiologic mechanism during HBV infection but also efficiently provided a potential drug combination for therapeutic treatment of Hepatitis B.
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Affiliation(s)
- Shen Chang
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan;
| | - Bor-Sen Chen
- Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan;
- Correspondence:
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Xia Y, Guo H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Res 2020; 180:104824. [PMID: 32450266 PMCID: PMC7387223 DOI: 10.1016/j.antiviral.2020.104824] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/03/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide with about 257 million individuals chronically infected. Current therapies can effectively control HBV replication and slow down disease progress, but cannot cure HBV infection. Upon infection, HBV establishes a pool of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The cccDNA exists as a minichromosome and resists to antivirals, thus a therapeutic eradication of cccDNA from the infected cells remains unattainable. In this review, we summarize the state of knowledge on the mechanisms underlying cccDNA formation and regulation, and discuss the possible strategies that may contribute to the eradication of HBV through targeting cccDNA.
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Affiliation(s)
- Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
| | - Haitao Guo
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol 2020; 10:1271. [PMID: 32850386 PMCID: PMC7399632 DOI: 10.3389/fonc.2020.01271] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that can function as gene regulators and are involved in tumorigenesis. We review the commonly dysregulated miRNAs in liver tumor tissues and plasma/serum of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The frequently reported up-regulated miRNAs in liver tumor tissues include miR-18a, miR-21, miR-221, miR-222, and miR-224, whereas down-regulated miRNAs include miR-26a, miR-101, miR-122, miR-125b, miR-145, miR-199a, miR-199b, miR-200a, and miR-223. For a subset of these miRNAs (up-regulated miR-222 and miR-224, down-regulated miR-26a and miR-125b), the pattern of dysregulated circulating miRNAs in plasma/serum is mirrored in tumor tissue based on multiple independent studies. Dysregulated miRNAs target oncogenes or tumor suppressor genes involved in hepatocarcinogenesis. Normalization of dysregulated miRNAs by up- or down-regulation has been shown to inhibit HCC cell proliferation or sensitize liver cancer cells to chemotherapeutic treatment. miRNAs hold as yet unrealized potential as biomarkers for early detection of HCC and as precision therapeutic targets, but further studies in diverse populations and across all stages of HCC are needed.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Ping An
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Cheryl A. Winkler
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Yanyan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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Fornes D, Heinecke F, Roberti SL, White V, Capobianco E, Jawerbaum A. Proinflammation in maternal and fetal livers and circulating miR-122 dysregulation in a GDM rat model induced by intrauterine programming. Mol Cell Endocrinol 2020; 510:110824. [PMID: 32315718 DOI: 10.1016/j.mce.2020.110824] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/05/2020] [Accepted: 04/11/2020] [Indexed: 12/11/2022]
Abstract
In gestational diabetes mellitus (GDM) pregnancies, a compromised fetal liver may impact offspring's metabolic health. Here, we aimed to address prooxidant, proinflammatory and profibrotic markers in the livers from GDM rats and their fetuses, and to analyze the expression of miR-122 (a relevant microRNA in liver pathophysiology) in fetal and maternal plasma of GDM rats, as well as in the fetal livers of neonatal streptozotocin-induced (nSTZ) diabetic rats, the rats that generate GDM through intrauterine programming. GDM and nSTZ rats were evaluated on day 21 of pregnancy. We found increased nitric oxide production and lipoperoxidation in the livers from GDM rats and their fetuses compared to controls. Livers from GDM fetuses also showed increased levels of connective tissue growth factor and matrix metalloproteinase-2. The expression of miRNA-122 was downregulated in the plasma from GDM rats and their male fetuses, as well as in the livers from male fetuses of nSTZ diabetic rats. miR-122 levels were regulated both in vitro through PPARγ activation and in vivo through a maternal diet enriched in PPAR ligands. Our findings revealed a prooxidant/proinflammatory environment in the livers from GDM rats and their fetuses and a dysregulation of miR-122, likely relevant in the programming of offspring's diseases.
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Affiliation(s)
- Daiana Fornes
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Florencia Heinecke
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Sabrina Lorena Roberti
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Verónica White
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Evangelina Capobianco
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Universidad de Buenos Aires, Facultad de Medicina and CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina.
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Non-Coding RNAs in Lung Tumor Initiation and Progression. Int J Mol Sci 2020; 21:ijms21082774. [PMID: 32316322 PMCID: PMC7215285 DOI: 10.3390/ijms21082774] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.
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Chen L, Huang W, Wang L, Zhang Z, Zhang F, Zheng S, Kong D. The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism. Expert Rev Gastroenterol Hepatol 2020; 14:259-270. [PMID: 32124651 DOI: 10.1080/17474124.2020.1736042] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Epigenetic modification is a type of gene expression and regulation that does not involve changes in DNA sequences. An increasing number of studies have proven that epigenetic modifications play an important role in the occurrence and progression of liver diseases through the gene regulation and protein expressions of hepatocellular lipid metabolism, inflammatory reaction, cell proliferation, and activation, etc.Areas covered: In this study, we elaborated and analyzed the underlying functional mechanism of epigenetic modification in alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver fibrosis (LF), viral hepatitis, hepatocellular carcinoma (HCC), and research progress of recent years.Expert opinion: The further understanding of epigenetic mechanisms that can regulate gene expression and cell phenotype leads to new insights in epigenetic control of chronic liver disease. Currently, hepatologists are exploring the role of DNA methylation, histone/chromatin modification, and non-coding RNA in specific liver pathology. These findings have led to advances in direct epigenetic biomarker testing of patient tissue or body fluid specimens, as well as quantitative analysis. Based on these findings, drug validation of some targets involved in the epigenetic mechanism of liver disease is gradually being carried out clinically.
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Affiliation(s)
- Liping Chen
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weifang Huang
- Department of Pharmacology, School of Integral Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Barbu MG, Condrat CE, Thompson DC, Bugnar OL, Cretoiu D, Toader OD, Suciu N, Voinea SC. MicroRNA Involvement in Signaling Pathways During Viral Infection. Front Cell Dev Biol 2020; 8:143. [PMID: 32211411 PMCID: PMC7075948 DOI: 10.3389/fcell.2020.00143] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
The study of miRNAs started in 1993, when Lee et al. observed their involvement in the downregulation of a crucial protein known as LIN-14 in the nematode Caenorhabditis elegans. Since then, great progress has been made regarding research on microRNAs, which are now known to be involved in the regulation of various physiological and pathological processes in both animals and humans. One such example is represented by their interaction with various signaling pathways during viral infections. It has been observed that these pathogens can induce the up-/downregulation of various host miRNAs in order to elude the host's immune system. In contrast, some miRNAs studied could have an antiviral effect, enabling the defense mechanisms to fight the infection or, at the very least, they could induce the pathogen to enter a latent state. At the same time, some viruses encode their own miRNAs, which could further modulate the host's signaling pathways, thus favoring the survival and replication of the virus. The goal of this extensive literature review was to present how miRNAs are involved in the regulation of various signaling pathways in some of the most important and well-studied human viral infections. Further on, knowing which miRNAs are involved in various viral infections and what role they play could aid in the development of antiviral therapeutic agents for certain diseases that do not have a definitive cure in the present. The clinical applications of miRNAs are extremely important, as miRNAs targeted inhibition may have substantial therapeutic impact. Inhibition of miRNAs can be achieved through many different methods, but chemically modified antisense oligonucleotides have shown the most prominent effects. Though scientists are far from completely understanding all the molecular mechanisms behind the complex cross-talks between miRNA pathways and viral infections, the general knowledge is increasing on the different roles played by miRNAs during viral infections.
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Affiliation(s)
- Madalina Gabriela Barbu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Carmen Elena Condrat
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Dana Claudia Thompson
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Oana Larisa Bugnar
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
| | - Dragos Cretoiu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Oana Daniela Toader
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, Bucharest, Romania
| | - Nicolae Suciu
- Alessandrescu-Rusescu National Institute for Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, Bucharest, Romania
| | - Silviu Cristian Voinea
- Department of Surgical Oncology, Institute of Oncology Prof. Dr. Alexandru Trestioreanu, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Chen L, Ming X, Li W, Bi M, Yan B, Wang X, Yang P, Yang B. The microRNA-155 mediates hepatitis B virus replication by reinforcing SOCS1 signalling-induced autophagy. Cell Biochem Funct 2020; 38:436-442. [PMID: 31930529 DOI: 10.1002/cbf.3488] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 12/05/2019] [Accepted: 12/17/2019] [Indexed: 12/19/2022]
Abstract
As small conserved RNAs without a coding function, microRNAs are expressed in multicellular organisms and contribute to the modulation of multiple cellular reactions, such as viral replication, as well as autophagy. microRNAs can regulate host gene expression and inhibit or reinforce hepatitis B virus (HBV) replication. Hepatic cells express miR-155 noticeably. Consequently, our study explored miR-155 modulation of HBV replication and investigated the potential mechanism involved. miR-155 was inhibited on HBV infection. miR-155 transfection remarkably reinforced HBV replication, antigen expression, and progeny secretion in HepG2215 cells. Moreover, miR-155 impaired the inhibition of the cytokine signalling 1 (SOCS1)/Akt/mTOR axis and reinforced HepG2215 autophagy. Additionally, the autophagy inhibitor (3-MA) eliminated HBsAg secretion triggered by miR-155. Taken together, miR-155 reinforced HBV replication by reinforcing SOCS1-triggered autophagy. SIGNIFICANCE OF THE STUDY: The research studied the potential mechanism involved in HBV replication and miR-155 that miR-155 reinforces HBV replication by reinforcing the SOCS1/Akt/mTOR axis-stimulated autophagy, and therefore, it can provide medical practitioners with the inspiration that chronic HBV might be cured or improved by regulating the activation of miR-155 in cells. In the study, the experiments show that autophagy inhibitors (3-MA) counteracted miR-155 contribution to HBV replication, and it might be a practicable way to improve HBV through some therapies that can repress the autophagy in related cells.
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Affiliation(s)
- Liyan Chen
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Xiaoyu Ming
- Department of Orthopedics, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Haerbin, China
| | - Wensong Li
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Manru Bi
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Bingzhu Yan
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Xiaoren Wang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Pengfei Yang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Baoshan Yang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
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Franck M, Schütte K, Malfertheiner P, Link A. Prognostic value of serum microRNA-122 in hepatocellular carcinoma is dependent on coexisting clinical and laboratory factors. World J Gastroenterol 2020; 26:86-96. [PMID: 31933516 PMCID: PMC6952302 DOI: 10.3748/wjg.v26.i1.86] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/04/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is ongoing search for new noninvasive biomarkers to improve management of patients with hepatocellular carcinoma (HCC). Studies, mostly from the Asian-Pacific region, demonstrated differential expression of liver-specific microRNA-122 (miR-122) in tissue as well as in sera of patients with hepatitis B virus- and hepatitis C virus-induced HCC. AIM To evaluate prognostic value of miR-122 in patients with HCC in a European population and determine potential factors related to alteration of miR-122 in sera. METHODS Patients with confirmed HCC (n = 91) were included in the study over a two-year period. Patients were characterized according to Child-Pugh score, Barcelona clinic liver cancer (BCLC) staging system, etiology of liver disease, laboratory parameters and overall survival. MiR-122 was measured in sera using TaqMan assay normalized to spiked-in cel-miR-39. RESULTS Serum miR-122 quantity was independent of the Child-Pugh score, the BCLC stage or the underlying etiology. Significant positive correlation was found between miR-122 and alanine aminotransferase (P < 0.0001), aspartate aminotransferase (P = 0.0001), alpha-fetoprotein (AFP) (P = 0.0034) and hemoglobin concentration (P = 0.076). Negative correlation was observed between miR-122 level and creatinine concentration (P = 0.0028). AFP, Child-Pugh score and BCLC staging system were associated with survival differences. In overall cohort low miR-122 in sera was only associated with a trend for a better overall survival without reaching statistical significance. Subgroup analysis revealed that low miR-122 was significantly associated with better prognosis in patients with advanced cirrhosis (Child-Pugh class B/C), advanced tumor stage (BCLC B/C/D) and normal AFP (< 7 ng/mL). CONCLUSION Our results strongly support the value of miR-122 as potential biomarker of liver injury and probably prognosis. Nevertheless, the value of miR-122 in prediction of prognosis of HCC patients was limited to certain patients' subgroups. Since circulating miR-122 may be influenced by impaired renal function, AFP and hemoglobin concentration, those factors need to be considered while interpreting miR-122 level.
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Affiliation(s)
- Martin Franck
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Kerstin Schütte
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück 49074, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
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