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1
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Ma Y, Mao Y, Luo S, Zuo W, Gao P, Ying B. Development and characterization of a miRNA-responsive circular RNA expression system with cell type specificity. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102450. [PMID: 39967851 PMCID: PMC11834102 DOI: 10.1016/j.omtn.2025.102450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/10/2025] [Indexed: 02/20/2025]
Abstract
Although microRNAs (miRNAs) binding to messenger RNAs (mRNAs) generally results in mRNA degradation and reduced protein expression, their interaction with the internal ribosome entry sites (IRES) of certain RNA viruses enhances viral amplification and expression. In this study, we utilized the natural hepatitis C cirus (HCV) 5' UTR region, which contains miR-122 binding sites, as the IRES of circular RNA (circRNAs) constructs. These circRNAs allowed inducible expression of downstream genes with high specificity in response to both exogenous and endogenous miR-122. Substituting the miR-122 binding sites with those for other miRNAs also resulted in the translational activation of circRNAs by their respective miRNAs in transfected cells. Furthermore, mouse models administered intravenously with lipid nanoparticle-formulated circRNAs containing miRNA binding sites (circRNA-LNP) exhibited higher expression in targeted tissues compared to those with mutated binding sites. Our research introduces a novel strategy for tissue-specific regulation of circRNA expression, potentially broadening the therapeutic applications of circRNAs and paving the way for more precise and effective treatments in gene therapy.
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Affiliation(s)
- Yu Ma
- Suzhou Abogen Biosciences Company, Suzhou 215123, China
| | - Yuqiao Mao
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Shirui Luo
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Wenjie Zuo
- Suzhou Abogen Biosciences Company, Suzhou 215123, China
| | - Peng Gao
- Suzhou Abogen Biosciences Company, Suzhou 215123, China
| | - Bo Ying
- Suzhou Abogen Biosciences Company, Suzhou 215123, China
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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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3
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Sharma P, Naqvi RA, Borase H, Kapoor D, Valverde A, Capistrano K, Yadavalli T, Naqvi AR, Shukla D. Global MicroRNA Profiling of HSV-1 Infected Cornea Identifies miR-329 as a Novel Regulator of Virus Infection. Invest Ophthalmol Vis Sci 2025; 66:61. [PMID: 39992671 PMCID: PMC11878248 DOI: 10.1167/iovs.66.2.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/02/2025] [Indexed: 02/26/2025] Open
Abstract
Purpose Although the mechanisms underlying herpes simplex virus type-1 (HSV-1) ocular infection have been extensively studied, the role of host microRNAs (miRNAs) in the pathobiology of herpetic keratitis (HK) is not well understood. The aim of this study was to identify endogenous miRNA regulators involved in the progression of HSV-1 ocular infection. Methods C57BL/6 mice were infected with HSV-1 strain McKrae following epithelial debridement, and corneal miRNA profiles were analyzed at various time points using miRNA sequencing (miRNA-seq). The miRNA expression was measured at 2, 4, 6, and 10 days post-infection. Ingenuity Pathway Analysis (IPA) was used to identify immune pathways potentially targeted by differentially expressed miRNAs. The role of selected miRNAs in viral entry and replication was assessed by overexpression in murine embryonic fibroblasts (MEFs) and human corneal epithelial cells (HCEs). Results A total of 32 miRNAs at 2 days post-infection, 21 miRNAs at 4 days post-infection, 140 miRNAs at 6 days post-infection, and 27 miRNAs at 10 days post-infection showed significant changes in expression. IPA revealed that differentially expressed miRNAs targeted several immune pathways, including TLR and interferon signaling. Notably, mmu-miR-184-3p and mmu-let-7d-5p were upregulated, whereas mmu-miR-329-3p was down-regulated during infection. Functional assays demonstrated that overexpression of miR-329, but not miR-184-3p or miR-let-7d-5p, increased HSV-1 viral entry and replication in a dose-dependent manner. In contrast, miR-329 inhibition reversed these effects, suggesting its role as a pro-viral miRNA. Increased plaque formation and viral gB expression further confirmed miR-329's pro-viral role. Conclusions Our findings suggest that miR-329 functions as a pro-viral miRNA by disrupting TLR9 signaling, thus facilitating HSV-1 replication. Inhibition of miR-329 enhances TLR9-mediated antiviral responses, highlighting the potential of targeting host miRNAs as a novel therapeutic strategy for managing viral keratitis.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/biosynthesis
- Animals
- Herpesvirus 1, Human/physiology
- Herpesvirus 1, Human/genetics
- Keratitis, Herpetic/genetics
- Keratitis, Herpetic/virology
- Keratitis, Herpetic/metabolism
- Mice, Inbred C57BL
- Mice
- Humans
- Virus Replication
- Gene Expression Profiling
- Epithelium, Corneal/virology
- Epithelium, Corneal/metabolism
- Disease Models, Animal
- Gene Expression Regulation/physiology
- Cornea/virology
- Cornea/metabolism
- Cells, Cultured
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Affiliation(s)
- Pankaj Sharma
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Hemant Borase
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Divya Kapoor
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
- Department of Microbiology and Immunology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Kristelle Capistrano
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Tejabhiram Yadavalli
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Afsar R. Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois - Chicago, Chicago, Illinois, United States
| | - Deepak Shukla
- Department of Ophthalmology, University of Illinois - Chicago, Chicago, Illinois, United States
- Department of Microbiology and Immunology, University of Illinois - Chicago, Chicago, Illinois, United States
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4
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Janga H, Schmerer N, Aznaourova M, Schulte LN. Non-coding RNA Networks in Infection. Methods Mol Biol 2025; 2883:53-77. [PMID: 39702704 DOI: 10.1007/978-1-0716-4290-0_3] [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: 12/21/2024]
Abstract
In the face of global health challenges posed by infectious diseases and the emergence of drug-resistant pathogens, the exploration of cellular non-coding RNA (ncRNA) networks has unveiled new dimensions in infection research. Particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as instrumental players in ensuring a balance between protection against hyper-inflammatory conditions and the effective elimination of pathogens. Specifically, ncRNAs, such as the miRNA miR-155 or the lncRNAs MaIL1 (macrophage interferon-regulatory lncRNA 1), and LUCAT1 (lung cancer-associated transcript 1) have been recurrently linked to infectious and inflammatory diseases. Together with other ncRNAs, discussed in this chapter, they form a complex regulatory network shaping the host response to pathogens. Additionally, some pathogens exploit these ncRNAs to establish and sustain infections, underscoring their dual roles in host protection and colonization. Despite the substantial progress made, the vast majority of ncRNA loci remains unexplored, with ongoing research likely to reveal novel ncRNA categories and expand our understanding of their roles in infections. This chapter consolidates current insights into ncRNA-mediated regulatory networks, highlighting their contributions to severe diseases and their potential as targets and biomarkers for innovative therapeutic strategies.
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Affiliation(s)
| | - Nils Schmerer
- Institute for Lung Research, Philipps University, Marburg, Germany
| | | | - Leon N Schulte
- Institute for Lung Research, Philipps University, Marburg, Germany.
- German Center for Lung Research, Giessen, Germany.
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5
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Shi L, Guo C, Fang M, Yang Y, Yin F, Shen Y. Cross-kingdom regulation of plant microRNAs: potential application in crop improvement and human disease therapeutics. FRONTIERS IN PLANT SCIENCE 2024; 15:1512047. [PMID: 39741676 PMCID: PMC11685121 DOI: 10.3389/fpls.2024.1512047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025]
Abstract
Plant microRNAs (miRNAs) are small non-coding RNA molecules that usually negatively regulate gene expression at the post-transcriptional level. Recent data reveal that plant miRNAs are not limited to individual plants but can transfer across different species, allowing for communication with the plant, animal, and microbial worlds in a cross-kingdom approach. This review discusses the differences in miRNA biosynthesis between plants and animals and summarizes the current research on the cross-species regulatory effects of plant miRNAs on nearby plants, pathogenic fungi, and insects, which can be applied to crop disease and pest resistance. In particular, this review highlights the latest findings regarding the function of plant miRNAs in the transboundary regulation of human gene expression, which may greatly expand the clinical applicability of plant miRNAs as intriguing tools in natural plant-based medicinal products in the future.
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Affiliation(s)
- Lei Shi
- International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, Xinxiang, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Chao Guo
- School of Pharmacy, Xinxiang Medical University, Xinxiang, China
| | - Miaomiao Fang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yingmei Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Fei Yin
- National Demonstration Center for Experimental (Aquaculture) Education, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Yuan Shen
- International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, Xinxiang, China
- School of Pharmacy, Xinxiang Medical University, Xinxiang, China
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Liu YY, Li N, Chen XY, Wang H, Zhu SW, Yang L, Quan FY, Ma JC, Dai JW, Jiang YL, Xiang ZF, Cheng Q, Zhang WH, Chen KH, Hou W, Xiong HR. MicroRNA let-7a regulation of Hantaan virus replication by Targeting FAS Signaling Pathways. Virology 2024; 600:110254. [PMID: 39383773 DOI: 10.1016/j.virol.2024.110254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/16/2024] [Accepted: 09/26/2024] [Indexed: 10/11/2024]
Abstract
Hantaan virus (HTNV) infection in humans can cause hemorrhagic fever and renal syndrome (HFRS). Understanding host responses to HTNV infection is crucial for developing effective disease intervention strategies. Previous RNA-sequencing studies have investigated the role of microRNAs (miRNAs) in the post-transcriptional regulation of host genes in response to HTNV infection. In this study, we demonstrated that HTNV infection induces let-7a expression in human umbilical vein endothelial cells (HUVEC) and that HTNV G protein upregulates the expression of let-7a. miRNA let-7a mimics and inhibitors validated the predicted targets, including cell apoptosis genes (FAS, caspase-8, and caspase-3) and inflammatory factors (IL-6 and its related factors). Modulation of miRNA let-7a levels by miRNA mimics and inhibitors affected HTNV replication, indicating that HTNV modulates host miRNA expression to affect the outcome of the antiviral host response.
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Affiliation(s)
- Yuan-Yuan Liu
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Ning Li
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China; Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China
| | - Xing-Yuan Chen
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Hui Wang
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China; School of Ecology and Environment, Tibet University, Lhasa, 850000, Tibet Autonomous Region, China
| | - Shao-Wei Zhu
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Lan Yang
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Fang-Yi Quan
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Jian-Chun Ma
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Jian-Wei Dai
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Ya-le Jiang
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China; Shenzhen Research Institute, Wuhan University, Shenzhen, 518057, Guangdong Province, China
| | - Zhou-Fu Xiang
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China; Shenzhen Research Institute, Wuhan University, Shenzhen, 518057, Guangdong Province, China
| | - Qi Cheng
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Wei-Hao Zhang
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China
| | - Ke-Han Chen
- School of Public Health, Wuhan University, Wuhan, 430071, Hubei Province, China
| | - Wei Hou
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China; School of Ecology and Environment, Tibet University, Lhasa, 850000, Tibet Autonomous Region, China; Shenzhen Research Institute, Wuhan University, Shenzhen, 518057, Guangdong Province, China; School of Public Health, Wuhan University, Wuhan, 430071, Hubei Province, China.
| | - Hai-Rong Xiong
- State Key Laboratory of Virology/ Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, 185 Donghu Road, Wuhan, 430071, Hubei Province, China.
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7
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Hassanin AAI, Ramos KS. Modulation of the Oncogenic LINE-1 Regulatory Network in Non-Small Cell Lung Cancer by Exosomal miRNAs. Int J Mol Sci 2024; 25:10674. [PMID: 39409003 PMCID: PMC11477113 DOI: 10.3390/ijms251910674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 09/26/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Several microRNAs (miRNAs), including miR-221-5p, Let-7b-5p, miR-21-5p, miR-9-5p, miR-126-3p, and miR-222-3p, were recently found to be enriched in circulating exosomes of patients with non-small cell lung cancers (NSCLCs). These miRNAs distinguished cancer cases from controls with high precision and were predicted to modulate the expression of genes within the oncogenic LINE-1 regulatory network. To test this hypothesis, plasma exosomes from controls, early, and late-stage NSCLC patients were co-cultured with non-tumorigenic lung epithelial cells for 72 h and processed for measurements of gene expression. Exosomes from late-stage NSCLC patients markedly increased the mRNA levels of LINE-1 ORF1 and ORF2, as well as the levels of target miRNAs in naïve recipient cells compared to saline or control exosomes. Late-stage exosomes also modulated the expression of oncogenic targets within the LINE-1 regulatory network, namely, ICAM1, AGL, RGS3, RGS13, VCAM1, and TGFβ1. In sharp contrast, exosomes from controls or early-stage NSCLC patients inhibited LINE-1 expression, along with many of the genetic targets within the LINE-1 regulatory network. Thus, late-stage NSCLC exosomes activate LINE-1 and miRNA-regulated oncogenic signaling in non-tumorigenic, recipient lung bronchial epithelial cells. These findings raise important questions regarding lung cancer progression and metastasis and open the door for the exploration of new therapeutic interventions.
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Affiliation(s)
- Abeer A. I. Hassanin
- Center for Genomic and Precision Medicine, Texas Medical Center, Texas A&M Institute of Biosciences and Technology, Houston, TX 77030, USA;
- Department of Animal Wealth Development, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Kenneth S. Ramos
- Center for Genomic and Precision Medicine, Texas Medical Center, Texas A&M Institute of Biosciences and Technology, Houston, TX 77030, USA;
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8
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Cousineau SE, Camargo C, Sagan SM. Poly(rC)-Binding Protein 2 Does Not Directly Participate in HCV Translation or Replication, but Rather Modulates Genome Packaging. Viruses 2024; 16:1220. [PMID: 39205194 PMCID: PMC11359930 DOI: 10.3390/v16081220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/22/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
The hepatitis C virus (HCV) co-opts many cellular factors-including proteins and microRNAs-to complete its life cycle. A cellular RNA-binding protein, poly(rC)-binding protein 2 (PCBP2), was previously shown to bind to the hepatitis C virus (HCV) genome; however, its precise role in the viral life cycle remained unclear. Herein, using the HCV cell culture (HCVcc) system and assays that isolate each step of the viral life cycle, we found that PCBP2 does not have a direct role in viral entry, translation, genome stability, or HCV RNA replication. Rather, our data suggest that PCBP2 depletion only impacts viral RNAs that can undergo genome packaging. Taken together, our data suggest that endogenous PCBP2 modulates the early steps of genome packaging, and therefore only has an indirect effect on viral translation and RNA replication, likely by increasing the translating/replicating pool of viral RNAs to the detriment of virion assembly.
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Affiliation(s)
- Sophie E. Cousineau
- Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Carolina Camargo
- Department of Microbiology & Immunology, University of British Columbia, 2350 Health Science Mall, Room 4.520, Vancouver, BC V6T 1Z3, Canada
| | - Selena M. Sagan
- Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 2B4, Canada
- Department of Microbiology & Immunology, University of British Columbia, 2350 Health Science Mall, Room 4.520, Vancouver, BC V6T 1Z3, Canada
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9
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Triebel S, Lamkiewicz K, Ontiveros N, Sweeney B, Stadler PF, Petrov AI, Niepmann M, Marz M. Comprehensive survey of conserved RNA secondary structures in full-genome alignment of Hepatitis C virus. Sci Rep 2024; 14:15145. [PMID: 38956134 PMCID: PMC11219754 DOI: 10.1038/s41598-024-62897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/22/2024] [Indexed: 07/04/2024] Open
Abstract
Hepatitis C virus (HCV) is a plus-stranded RNA virus that often chronically infects liver hepatocytes and causes liver cirrhosis and cancer. These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large 'cloud' of RNA genomes (quasispecies) which-by trial and error-comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements. Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies. Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches of Hepacivirus C are provided in the supplement.
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Affiliation(s)
- Sandra Triebel
- RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, 07743, Jena, Germany
- European Virus Bioinformatics Center, Friedrich Schiller University Jena, 07743, Jena, Germany
| | - Kevin Lamkiewicz
- RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, 07743, Jena, Germany
- European Virus Bioinformatics Center, Friedrich Schiller University Jena, 07743, Jena, Germany
| | - Nancy Ontiveros
- European Molecular Biology Laboratory, Wellcome Genome Campus, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, UK
| | - Blake Sweeney
- European Molecular Biology Laboratory, Wellcome Genome Campus, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, UK
| | - Peter F Stadler
- European Virus Bioinformatics Center, Friedrich Schiller University Jena, 07743, Jena, Germany
- Bioinformatics Group, Institute of Computer Science, and Interdisciplinary Center for Bioinformatics, University Leipzig, 04107, Leipzig, Germany
- German Center for Integrative Biodiversity Research (iDiv), 04103, Leipzig, Germany
| | | | - Michael Niepmann
- Institute for Biochemistry, Justus-Liebig-University Giessen, 35392, Giessen, Germany
| | - Manja Marz
- RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University Jena, 07743, Jena, Germany.
- European Virus Bioinformatics Center, Friedrich Schiller University Jena, 07743, Jena, Germany.
- Leibniz Institute on Aging-Fritz Lipmann Institute, 07745, Jena, Germany.
- German Center for Integrative Biodiversity Research (iDiv), 04103, Leipzig, Germany.
- Michael Stifel Center Jena, Friedrich Schiller University Jena, 07743, Jena, Germany.
- Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, 07743, Jena, Germany.
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10
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Fernández-Ruiz M, López-García Á, Valverde-Manso A, Parra P, Rodríguez-Goncer I, Ruiz-Merlo T, López-Medrano F, González E, Polanco N, San Juan R, Andrés A, Aguado JM, Redondo N. Human microRNA sequencing and cytomegalovirus infection risk after kidney transplantation. Am J Transplant 2024; 24:1180-1192. [PMID: 38311311 DOI: 10.1016/j.ajt.2024.01.028] [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: 10/03/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
Cytomegalovirus (CMV)-seropositive kidney transplant recipients (KTRs) with detectable CMV-specific cell-mediated immunity according to the QuantiFERON-CMV assay (QTF-CMV) are expected to have adequate immune protection. Nevertheless, a proportion of patients still develop CMV infection. Human microRNAs (hsa-miRNAs) are promising biomarkers owing to their high stability and easy detection. We performed whole blood miRNA sequencing in samples coincident with the first reactive QTF-CMV after transplantation or cessation of antiviral prophylaxis to investigate hsa-miRNAs differentially expressed according to the occurrence of CMV infection. One-year incidence of CMV viremia was 55.0% (median interval from miRNA sequencing sampling of 29 days). After qPCR validation, we found that hsa-miR-125a-5p was downregulated in KTRs developing CMV viremia within the next 90 days (ΔCt: 7.9 ± 0.9 versus 7.3 ± 1.0; P = .011). This difference was more evident among KTRs preemptively managed (8.2 ± 0.9 versus 6.9 ± 0.8; P < .001), with an area under the receiver operating characteristic curve of 0.865. Functional enrichment analysis identified hsa-miR-125a-5p targets involved in cell cycle regulation and apoptosis, including the BAK1 gene, which was significantly downregulated in KTRs developing CMV viremia. In conclusion, hsa-miR-125a-5p may serve as biomarker to identify CMV-seropositive KTRs at risk of CMV reactivation despite detectable CMV-CMI.
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Affiliation(s)
- Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Ángela López-García
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Andrea Valverde-Manso
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Patricia Parra
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Isabel Rodríguez-Goncer
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Tamara Ruiz-Merlo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Francisco López-Medrano
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Esther González
- Department of Nephrology, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Rafael San Juan
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Amado Andrés
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain; Department of Nephrology, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Natalia Redondo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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11
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Tripathi SK, Aneja A, Borgaonkar T, Das S. PSPC1 Binds to HCV IRES and Prevents Ribosomal Protein S5 Binding, Inhibiting Viral RNA Translation. Viruses 2024; 16:738. [PMID: 38793620 PMCID: PMC11126058 DOI: 10.3390/v16050738] [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: 04/10/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatitis C virus (HCV) infects the human liver, and its chronic infection is one of the major causes of Hepatocellular carcinoma. Translation of HCV RNA is mediated by an Internal Ribosome Entry Site (IRES) element located in the 5'UTR of viral RNA. Several RNA Binding proteins of the host interact with the HCV IRES and modulate its function. Here, we demonstrate that PSPC1 (Paraspeckle Component 1), an essential paraspeckle component, upon HCV infection is relocalized and interacts with HCV IRES to prevent viral RNA translation. Competition UV-crosslinking experiments showed that PSPC1 interacts explicitly with the SLIV region of the HCV IRES, which is known to play a vital role in ribosomal loading to the HCV IRES via interaction with Ribosomal protein S5 (RPS5). Partial silencing of PSPC1 increased viral RNA translation and, consequently, HCV replication, suggesting a negative regulation by PSPC1. Interestingly, the silencing of PSPC1 protein leads to an increased interaction of RPS5 at the SLIV region, leading to an overall increase in the viral RNA in polysomes. Overall, our results showed how the host counters viral infection by relocalizing nuclear protein to the cytoplasm as a survival strategy.
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Affiliation(s)
- Sachin Kumar Tripathi
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India
| | - Ashish Aneja
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India
| | - Teji Borgaonkar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India
- National Institute of Biomedical Genomics, Kalyani 741251, West Bengal, India
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12
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Shi R, Gao S, Huang H, Jiang K, Wang D. Integrating network pharmacology with microRNA microarray analysis to identify the role of miRNAs in thrombosis treated by the Dahuang Zhechong pill. Comput Biol Med 2024; 173:108338. [PMID: 38531252 DOI: 10.1016/j.compbiomed.2024.108338] [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: 11/28/2023] [Revised: 03/15/2024] [Accepted: 03/17/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND Thrombotic diseases are the leading causes of death worldwide, urging for improvements in treatment strategies. Dahuang Zhechong pill (DHZCP) is a traditional Chinese medicine widely used for treating thrombotic diseases; however, the underlying mechanisms remain unclear. This study aimed to explore the potential mechanisms of DHZCP in treating thrombosis with a focus on bioinformatics and miRNAs. METHODS We used network pharmacology to explore the targets of thrombosis treated with DHZCP and performed microarray analysis to acquire miRNA profiles and predict the target genes in thrombin-stimulated MEG-01 cells treated with DHZCP. Based on the overlapping of targets, we carried out a component-target-miRNA network and enrichment analysis and validated the selected miRNAs and mRNAs using quantitative reverse transcription-polymerase chain reaction. RESULTS Our data showed 850 targets of 230 active ingredients of DHZCP and 1214 thrombosis-related genes; 235 targets were common. We identified 32 miRNAs that were regulated by thrombin stimulation but regulated reversely by DHZCP treatment in MEG-01 cells, and predicted 1846 targets with function annotation. We analyzed conjointly 23 integrating targets from network pharmacology and microarray. HIF1A, PIK3CA, MAPK1 and BCL2L1 emerged as key nodes in the network diagrams. We confirmed the differential expression of seven miRNAs, one mRNA (BCL2L1) and platelet surface protein. CONCLUSIONS This study showed that miRNAs and their targets, such as BCL2L1, played crucial roles in platelet activation during DHZCP intervention in thrombosis, highlighting their potential to alleviate platelet activation and increase cell apoptosis. The study's findings could help develop new strategies for improving thrombosis treatment.
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Affiliation(s)
- Rui Shi
- Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China.
| | - Shan Gao
- Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China
| | - Huichao Huang
- Department of Infectious Disease, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ke Jiang
- Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China
| | - Dongsheng Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China.
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13
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Huang YJ, Cheng TL, Wang YT, Chen CS, Leu YL, Chang CS, Ho CH, Chao SW, Li CT, Chuang CH. Exploring the therapeutic potential of DV-B-120 as an inhibitor of dengue virus infection. J Virol 2024; 98:e0125823. [PMID: 38546211 PMCID: PMC11019862 DOI: 10.1128/jvi.01258-23] [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: 01/25/2024] [Accepted: 03/06/2024] [Indexed: 04/17/2024] Open
Abstract
Dengue fever, an infectious disease prevalent in subtropical and tropical regions, currently lacks effective small-molecule drugs as treatment. In this study, we used a fluorescence peptide cleavage assay to screen seven compounds to assess their inhibition of the dengue virus (DENV) NS2B-NS3 protease. DV-B-120 demonstrated superior inhibition of NS2B-NS3 protease activity and lower toxicity compared to ARDP0006. The selectivity index of DV-B-120 was higher than that of ARDP0006. In vivo assessments of the antiviral efficacy of DV-B-120 against DENV replication demonstrated delayed mortality of suckling mice treated with the compound, with 60-80% protection against life-threatening effects, compared to the outcomes of DENV-infected mice treated with saline. The lower clinical scores of DENV-infected mice treated with DV-B-120 indicated a reduction in acute-progressive illness symptoms, underscoring the potential therapeutic impact of DV-B-120. Investigations of DV-B-120's ability to restore the antiviral type I IFN response in the brain tissue of DENV-infected ICR suckling mice demonstrated its capacity to stimulate IFN and antiviral IFN-stimulated gene expression. DV-B-120 not only significantly delayed DENV-2-induced mortality and illness symptoms but also reduced viral numbers in the brain, ultimately restoring the innate antiviral response. These findings strongly suggest that DV-B-120 holds promise as a therapeutic agent against DENV infection and highlight its potential contribution in addressing the current lack of effective treatments for this infectious disease.IMPORTANCEThe prevalence of dengue virus (DENV) infection in tropical and subtropical regions is escalating due to factors like climate change and mosquito vector expansion. With over 300 million annual infections and potentially fatal outcomes, the urgent need for effective treatments is evident. While the approved Dengvaxia vaccine has variable efficacy, there are currently no antiviral drugs for DENV. This study explores seven compounds targeting the NS2B-NS3 protease, a crucial protein in DENV replication. These compounds exhibit inhibitory effects on DENV-2 NS2B-NS3, holding promise for disrupting viral replication and preventing severe manifestations. However, further research, including animal testing, is imperative to assess therapeutic efficacy and potential toxicity. Developing safe and potent treatments for DENV infection is critical in addressing the rising global health threat posed by this virus.
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Affiliation(s)
- Yi-Jung Huang
- Department of Biochemistry, School of Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Department of Biochemistry, School of Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yen-Tseng Wang
- Department of Biochemistry, School of Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chien-Shu Chen
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ling Leu
- Department of Pharmacy, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
| | - Chih-Shiang Chang
- School of Pharmacy, China Medical University, Taichung, Taiwan
- Drug Development Center, China Medical University, Taichung, Taiwan
| | - Cheng-Han Ho
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shi-Wei Chao
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Tse Li
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Hung Chuang
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
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14
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Chakraborty C, Bhattacharya M, Lee SS. Regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses: A comprehensive review. Rev Med Virol 2024; 34:e2526. [PMID: 38446531 DOI: 10.1002/rmv.2526] [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: 01/16/2024] [Revised: 02/11/2024] [Accepted: 02/22/2024] [Indexed: 03/07/2024]
Abstract
miRNAs are single-stranded ncRNAs that act as regulators of different human body processes. Several miRNAs have been noted to control the human immune and inflammatory response during severe acute respiratory infection syndrome (SARS-CoV-2) infection. Similarly, many miRNAs were upregulated and downregulated during different respiratory virus infections. Here, an attempt has been made to capture the regulatory role of miRNAs in the human immune and inflammatory response during the infection of SARS-CoV-2 and other respiratory viruses. Firstly, the role of miRNAs has been depicted in the human immune and inflammatory response during the infection of SARS-CoV-2. In this direction, several significant points have been discussed about SARS-CoV-2 infection, such as the role of miRNAs in human innate immune response; miRNAs and its regulation of granulocytes; the role of miRNAs in macrophage activation and polarisation; miRNAs and neutrophil extracellular trap formation; miRNA-related inflammatory response; and miRNAs association in adaptive immunity. Secondly, the miRNAs landscape has been depicted during human respiratory virus infections such as human coronavirus, respiratory syncytial virus, influenza virus, rhinovirus, and human metapneumovirus. The article will provide more understanding of the miRNA-controlled mechanism of the immune and inflammatory response during COVID-19, which will help more therapeutics discoveries to fight against the future pandemic.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal, India
| | | | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopaedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Gangwon-do, Republic of Korea
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15
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Jawad SF, Altalbawy FMA, Hussein RM, Fadhil AA, Jawad MA, Zabibah RS, Taraki TY, Mohan CD, Rangappa KS. The strict regulation of HIF-1α by non-coding RNAs: new insight towards proliferation, metastasis, and therapeutic resistance strategies. Cancer Metastasis Rev 2024; 43:5-27. [PMID: 37552389 DOI: 10.1007/s10555-023-10129-8] [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: 02/11/2023] [Accepted: 07/21/2023] [Indexed: 08/09/2023]
Abstract
The hypoxic environment is prominently witnessed in most solid tumors and is associated with the promotion of cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, metabolic reprogramming, therapeutic resistance, and metastasis of tumor cells. All the effects are mediated by the expression of a transcription factor hypoxia-inducible factor-1α (HIF-1α). HIF-1α transcriptionally modulates the expression of genes responsible for all the aforementioned functions. The stability of HIF-1α is regulated by many proteins and non-coding RNAs (ncRNAs). In this article, we have critically discussed the crucial role of ncRNAs [such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), Piwi-interacting RNAs (piRNAs), and transfer RNA (tRNA)-derived small RNAs (tsRNAs)] in the regulation of stability and expression of HIF-1α. We have comprehensively discussed the molecular mechanisms and relationship of HIF-1α with each type of ncRNA in either promotion or repression of human cancers and therapeutic resistance. We have also elaborated on ncRNAs that are in clinical examination for the treatment of cancers. Overall, the majority of aspects concerning the relationship between HIF-1α and ncRNAs have been discussed in this article.
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Affiliation(s)
- Sabrean Farhan Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Farag M A Altalbawy
- National Institute of Laser Enhanced Sciences, University of Cairo, Giza, 12613, Egypt
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | | | - Ali Abdulhussain Fadhil
- College of Medical Technology, Medical Lab Techniques, Al-Farahidi University, Baghdad, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Chakrabhavi Dhananjaya Mohan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, 570006, India.
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226 001, India.
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16
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Tao L, Wang Y, Shen Z, Cai J, Zheng J, Xia S, Lin Z, Wan Z, Qi H, Jin R, Wang L, Xu J, Liang X. Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma. Hepatol Int 2024; 18:91-107. [PMID: 37349627 PMCID: PMC10858123 DOI: 10.1007/s12072-023-10552-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/13/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy. Although its incidence is lower than that of hepatocellular carcinoma (HCC), ICC has a worse prognosis, and it is more prone to recur and metastasize, resulting in a far greater level of malignancy. METHODS Bioinformatics analysis and qRT-PCR were applied to assess the level of miR-122-5p and IGFBP4. Western blot, transwell assays, wound-healing assays, real-time cellular invasion monitoring, in vivo study were applied to explore the function of miR-122-5p and IGFBP4. Dual luciferase reporter assays and chromatin isolation by RNA purification (ChiRP) were applied to explore the regulation of IGFBP4 by miR-122-5p. RESULTS Using The Cancer Genome Atlas (TCGA) data set, Sir Run Run Shaw hospital data set and bioinformatics analyses, we identified miR-122-5p as a potential tumor suppressor in ICC and validated its suppressive effect in metastasis and invasion of ICC. Transcriptome sequencing, rescue and complement experiments were used to identify insulin-like growth factor binding protein 4 (IGFBP4) as a target of miR-122-5p. The mechanism by which miR-122-5p regulates IGFBP4 was clarified by chromatin separation RNA purification technology, and dual-luciferase reporter assays. We discovered a rare novel mechanism by which miR-122-5p promotes IGFBP4 mRNA transcription by binding to its promoter region. Furthermore, in mouse orthotopic metastasis model, miR-122-5p inhibited the invasion of ICC. CONCLUSION In summary, our study revealed a novel mechanism of miR-122-5p and function of the miR-122-5p/IGFBP4 axis in the metastasis of ICC. We also highlighted the clinical value of miR-122-5p and IGFBP4 in inhibiting ICC invasion and metastasis.
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Affiliation(s)
- Liye Tao
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yali Wang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Zefeng Shen
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Jingwei Cai
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Junhao Zheng
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Shunjie Xia
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Zhongjie Lin
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Zhe Wan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Haiou Qi
- Nursing Department and Nurse of Operating Room, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Renan Jin
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Ling Wang
- School of Automation, Hangzhou Dianzi University, Hangzhou, China.
- Key Laboratory of Medical Information and 3D Bioprinting of Zhejiang Province, Hangzhou, China.
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
| | - Xiao Liang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
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Yao J, Zhu Y, Zhang G, Zhou X, Shang H, Li L, Xu T. Action mechanisms and characteristics of miRNAs to regulate virus replication. Virology 2024; 590:109966. [PMID: 38100983 DOI: 10.1016/j.virol.2023.109966] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/05/2023] [Indexed: 12/17/2023]
Abstract
MicroRNAs (miRNAs) have the potential to be explored as antiviral products. It is known that miRNAs have different kinds of target mRNAs and different target sites in mRNAs, and that the action-modes of miRNAs at different target sites may be different. But there is no evidence demonstrating the significance of the differences for the regulation of viruses by miRNAs, which might be crucial for the exploration of miRNA-based antiviral products. Here the experimental studies about the antiviral effects of miRNAs, with validated target mRNAs and target sites in the mRNAs, were systematically collected, based on which the mechanisms whereby miRNAs regulated virus replication were systematically reviewed. And miRNAs' down-regulation rates on target mRNAs and antiviral rates were compared among the miRNAs with different target sites, to analyze the characteristics of action-modes of miRNAs at different target sites during virus replication.
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Affiliation(s)
- Jia Yao
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
| | - Yating Zhu
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
| | - Genrong Zhang
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
| | - Xianfeng Zhou
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
| | - Hongcai Shang
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China; Shang Hongcai, Key Laboratory of Chinese Internal Medicine of MOE and Beijing University of Chinese Medicine, 11 Eastern Section of the North Third Ring Road, Chaoyang District, Beijing, 100029, PR China.
| | - Longxue Li
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
| | - Tielong Xu
- Jiangxi University of Chinese Medicine, 1688 Mei Ling Avenue, Nanchang, 330004, PR China.
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18
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Vaucheret H, Voinnet O. The plant siRNA landscape. THE PLANT CELL 2024; 36:246-275. [PMID: 37772967 PMCID: PMC10827316 DOI: 10.1093/plcell/koad253] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 09/12/2023] [Accepted: 09/28/2023] [Indexed: 09/30/2023]
Abstract
Whereas micro (mi)RNAs are considered the clean, noble side of the small RNA world, small interfering (si)RNAs are often seen as a noisy set of molecules whose barbarian acronyms reflect a large diversity of often elusive origins and functions. Twenty-five years after their discovery in plants, however, new classes of siRNAs are still being identified, sometimes in discrete tissues or at particular developmental stages, making the plant siRNA world substantially more complex and subtle than originally anticipated. Focusing primarily on the model Arabidopsis, we review here the plant siRNA landscape, including transposable elements (TE)-derived siRNAs, a vast array of non-TE-derived endogenous siRNAs, as well as exogenous siRNAs produced in response to invading nucleic acids such as viruses or transgenes. We primarily emphasize the extraordinary sophistication and diversity of their biogenesis and, secondarily, the variety of their known or presumed functions, including via non-cell autonomous activities, in the sporophyte, gametophyte, and shortly after fertilization.
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Affiliation(s)
- Hervé Vaucheret
- Université Paris-Saclay, INRAE, AgroParisTech, Institut Jean-Pierre Bourgin (IJPB), 78000 Versailles, France
| | - Olivier Voinnet
- Department of Biology, Swiss Federal Institute of Technology (ETH-Zurich), 8092 Zürich, Switzerland
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19
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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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20
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Li X, Han Y, Meng Y, Yin L. Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases. RNA Biol 2024; 21:1-20. [PMID: 38174992 PMCID: PMC10773649 DOI: 10.1080/15476286.2023.2293343] [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] [Revised: 09/21/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.
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Affiliation(s)
- Xiaqing Li
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, China
| | - Yi Han
- Traditional Chinese Medicine Department, People’s Hospital of Yanjiang District, Ziyang, Sichuan, China
| | - Yu Meng
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
- Nephrology department, The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, China
| | - Lianghong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
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21
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Scott S, Li Y, Bermek O, Griffith JD, Lemon SM, Choi K. Binding of microRNA-122 to the hepatitis C virus 5' untranslated region modifies interactions with poly(C) binding protein 2 and the NS5B viral polymerase. Nucleic Acids Res 2023; 51:12397-12413. [PMID: 37941151 PMCID: PMC10711565 DOI: 10.1093/nar/gkad1000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 11/10/2023] Open
Abstract
Hepatitis C virus (HCV) requires two cellular factors, microRNA-122 (miR-122) and poly(C) binding protein 2 (PCBP2), for optimal replication. These host factors compete for binding to the 5' end of the single-stranded RNA genome to regulate the viral replication cycle. To understand how they interact with the RNA, we measured binding affinities of both factors for an RNA probe representing the 5' 45 nucleotides of the HCV genome (HCV45). Isothermal titration calorimetry revealed two, unequal miR-122 binding sites in HCV45, high-affinity (S1) and low-affinity (S2), differing roughly 100-fold in binding affinity. PCBP2 binds a site overlapping S2 with affinity similar to miR-122 binding to S2. PCBP2 circularizes the genome by also binding to the 3' UTR, bridging the 5' and 3' ends of the genome. By competing with PCBP2 for binding at S2, miR-122 disrupts PCBP2-mediated genome circularization. We show that the viral RNA-dependent RNA polymerase, NS5B, also binds to HCV45, and that the binding affinity of NS5B is increased in the presence of miR-122, suggesting miR-122 promotes recruitment of the polymerase. We propose that competition between miR-122 and PCBP2 for HCV45 functions as a translation-to-replication switch, determining whether the RNA genome templates protein synthesis or RNA replication.
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Affiliation(s)
- Seth Scott
- Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - You Li
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
| | - Oya Bermek
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
| | - Jack D Griffith
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
| | - Stanley M Lemon
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA
| | - Kyung H Choi
- Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA
- Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA
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22
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Wu Y, Yue Y, Xiong S. Cardiac miR-19a/19b was induced and hijacked by CVB3 to facilitate virus replication via targeting viral genomic RdRp-encoding region. Antiviral Res 2023; 217:105702. [PMID: 37604350 DOI: 10.1016/j.antiviral.2023.105702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023]
Abstract
Coxsackievirus B3 (CVB3) is one of the major pathogens of viral myocarditis, lacking specific anti-virus therapeutic options. Increasing evidence has shown an important involvement of the miR-17-92 cluster both in virus infection and cardiovascular development and diseases, while its role in CVB3-induced viral myocarditis remains unclear. In this study, we found that miR-19a and miR-19b were significantly up-regulated in heart tissues of CVB3-infected mice and exerted a significant facilitatory impact on CVB3 biosynthesis and replication, with a more pronounced effect observed in miR-19b, by targeting the encoding region of viral RNA-dependent RNA polymerase 3D (RdRp, 3Dpol) to increase viral genomic RNA stability. The virus-promoting effects were nullified by the synonymous mutations in the viral 3Dpol-encoding region, which corresponded to the seed sequence shared by miR-19a and miR-19b. In parallel, treatment with miR-19b antagomir not only resulted in a noteworthy suppression of CVB3 replication and infection in infected cells, but also demonstrated a significant reduction in the cardiac viral load of CVB3-infected mice, resulting in a considerable alleviation of myocarditis. Collectively, our study showed that CVB3-induced cardiac miR-19a/19b contributed to viral myocarditis via facilitating virus biosynthesis and replication, and targeting miR-19a/19b might represent a novel therapeutic target for CVB3-induced viral myocarditis.
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Affiliation(s)
- Yingchun Wu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Yan Yue
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
| | - Sidong Xiong
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
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23
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Nail HM, Chiu CC, Leung CH, Ahmed MMM, Wang HMD. Exosomal miRNA-mediated intercellular communications and immunomodulatory effects in tumor microenvironments. J Biomed Sci 2023; 30:69. [PMID: 37605155 PMCID: PMC10440907 DOI: 10.1186/s12929-023-00964-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
Extracellular communication, in other words, crosstalk between cells, has a pivotal role in the survival of an organism. This communication occurs by different methods, one of which is extracellular vesicles. Exosomes, which are small lipid extracellular vesicles, have recently been discovered to have a role in signal transduction between cells inside the body. These vesicles contain important bioactive molecules including lipids, proteins, DNA, mRNA, and noncoding RNAs such as microRNAs (miRNAs). Exosomes are secreted by all cells including immune cells (macrophages, lymphocytes, granulocytes, dendritic cells, mast cells) and tumor cells. The tumor microenvironment (TME) represents a complex network that supports the growth of tumor cells. This microenvironment encompasses tumor cells themselves, the extracellular matrix, fibroblasts, endothelial cells, blood vessels, immune cells, and non-cellular components such as exosomes and cytokines. This review aims to provide insights into the latest discoveries concerning how the immune system communicates internally and with other cell types, with a specific focus on research involving exosomal miRNAs in macrophages, dendritic cells, B lymphocytes, and T lymphocytes. Additionally, we will explore the role of exosomal miRNA in the TME and the immunomodulatory effect.
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Affiliation(s)
- Howida M Nail
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, No. 145, Xingda Rd., South Dist., Taichung City, 402, Taiwan
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, 999078, Macao, China
| | - Mahmoud M M Ahmed
- Department of Soil and Environmental Sciences, National Chung Hsing University, 404, Taichung City, Taiwan
| | - Hui-Min David Wang
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, No. 145, Xingda Rd., South Dist., Taichung City, 402, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, 404, Taiwan.
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24
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Rao G, Peng X, Tian Y, Fu X, Zhang Y. Circular RNAs in hepatocellular carcinoma: biogenesis, function, and pathology. Front Genet 2023; 14:1106665. [PMID: 37485335 PMCID: PMC10361733 DOI: 10.3389/fgene.2023.1106665] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Both genetic and environmental factors through a multitude of underlying molecular mechanisms participate in the pathogenesis of HCC. Recently, numerous studies have shown that circular RNAs (circRNAs), an emerging class of non-coding RNAs characterized by the presence of covalent bonds linking 3' and 5' ends, play an important role in the initiation and progression of cancers, including HCC. In this review, we outline the current status of the field of circRNAs, with an emphasis on the functions and mechanisms of circRNAs in HCC and its microenvironment. We also summarize and discuss recent advances of circRNAs as biomarkers and therapeutic targets. These efforts are anticipated to throw new insights into future perspectives about circRNAs in basic, translational and clinical research, eventually advancing the diagnosis, prevention and treatment of HCC.
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Affiliation(s)
- Guocheng Rao
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Xi Peng
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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25
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Panigrahi M, Palmer MA, Wilson JA. Enhanced Virus Translation Enables miR-122-Independent Hepatitis C Virus Propagation. J Virol 2023:e0085821. [PMID: 37338370 PMCID: PMC10373559 DOI: 10.1128/jvi.00858-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome forms RNA structures that regulate virus replication and translation. The region contains an internal ribosomal entry site (IRES) and a 5'-terminal region. Binding of the liver-specific microRNA (miRNA) miR-122 to two binding sites in the 5'-terminal region regulates viral replication, translation, and genome stability and is essential for efficient virus replication, but its precise mechanism of action is still unresolved. A current hypothesis is that miR-122 binding stimulates viral translation by facilitating the viral 5' UTR to form the translationally active HCV IRES RNA structure. While miR-122 is essential for detectable replication of wild-type HCV genomes in cell culture, several viral variants with 5' UTR mutations exhibit low-level replication in the absence of miR-122. We show that HCV mutants capable of replicating independently of miR-122 display an enhanced translation phenotype that correlates with their ability to replicate independently of miR-122. Further, we provide evidence that translation regulation is the major role for miR-122 and show that miR-122-independent HCV replication can be rescued to miR-122-dependent levels by the combined impacts of 5' UTR mutations that stimulate translation and by stabilizing the viral genome by knockdown of host exonucleases and phosphatases that degrade the genome. Finally, we show that HCV mutants capable of replicating independently of miR-122 also replicate independently of other microRNAs generated by the canonical miRNA synthesis pathway. Thus, we provide a model suggesting that translation stimulation and genome stabilization are the primary roles for miR-122 in promoting HCV. IMPORTANCE The unusual and essential role of miR-122 in promoting HCV propagation is incompletely understood. To better understand its role, we have analyzed HCV mutants capable of replicating independently of miR-122. Our data show that the ability of viruses to replicate independently of miR-122 correlates with enhanced virus translation but that genome stabilization is required to restore efficient HCV replication. This suggests that viruses must gain both abilities to escape the need for miR-122 and impacts the possibility that HCV can evolve to replicate outside the liver.
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Affiliation(s)
- Mamata Panigrahi
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Michael A Palmer
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Joyce A Wilson
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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26
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Rheault M, Cousineau SE, Fox DR, Abram QH, Sagan S. Elucidating the distinct contributions of miR-122 in the HCV life cycle reveals insights into virion assembly. Nucleic Acids Res 2023; 51:2447-2463. [PMID: 36807979 PMCID: PMC10018354 DOI: 10.1093/nar/gkad094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 01/20/2023] [Accepted: 02/18/2023] [Indexed: 02/23/2023] Open
Abstract
Efficient hepatitis C virus (HCV) RNA accumulation is dependent upon interactions with the human liver-specific microRNA, miR-122. MiR-122 has at least three roles in the HCV life cycle: it acts as an RNA chaperone, or 'riboswitch', allowing formation of the viral internal ribosomal entry site; it provides genome stability; and promotes viral translation. However, the relative contribution of each role in HCV RNA accumulation remains unclear. Herein, we used point mutations, mutant miRNAs, and HCV luciferase reporter RNAs to isolate each of the roles and evaluate their contribution to the overall impact of miR-122 in the HCV life cycle. Our results suggest that the riboswitch has a minimal contribution in isolation, while genome stability and translational promotion have similar contributions in the establishment phase of infection. However, in the maintenance phase, translational promotion becomes the dominant role. Additionally, we found that an alternative conformation of the 5' untranslated region, termed SLIIalt, is important for efficient virion assembly. Taken together, we have clarified the overall importance of each of the established roles of miR-122 in the HCV life cycle and provided insight into the regulation of the balance between viral RNAs in the translating/replicating pool and those engaged in virion assembly.
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Affiliation(s)
- Marylin Rheault
- Department of Microbiology & Immunology, McGill University, Montréal, Canada
| | - Sophie E Cousineau
- Department of Microbiology & Immunology, McGill University, Montréal, Canada
| | - Danielle R Fox
- Department of Microbiology & Immunology, McGill University, Montréal, Canada
- Department of Physiology, McGill University, Montréal, Canada
| | - Quinn H Abram
- Department of Biochemistry, McGill University, Montréal, Canada
| | - Selena M Sagan
- Department of Microbiology & Immunology, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
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27
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Rangel-Ramírez VV, González-Sánchez HM, Lucio-García C. Exosomes: from biology to immunotherapy in infectious diseases. Infect Dis (Lond) 2023; 55:79-107. [PMID: 36562253 DOI: 10.1080/23744235.2022.2149852] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Exosomes are extracellular vesicles derived from the endosomal compartment, which are released by all kinds of eukaryotic and prokaryotic organisms. These vesicles contain a variety of biomolecules that differ both in quantity and type depending on the origin and cellular state. Exosomes are internalized by recipient cells, delivering their content and thus contributing to cell-cell communication in health and disease. During infections exosomes may exert a dual role, on one hand, they can transmit pathogen-related molecules mediating further infection and damage, and on the other hand, they can protect the host by activating the immune response and reducing pathogen spread. Selective packaging of pathogenic components may mediate these effects. Recently, quantitative analysis of samples by omics technologies has allowed a deep characterization of the proteins, lipids, RNA, and metabolite cargoes of exosomes. Knowledge about the content of these vesicles may facilitate their therapeutic application. Furthermore, as exosomes have been detected in almost all biological fluids, pathogenic or host-derived components can be identified in liquid biopsies, making them suitable for diagnosis and prognosis. This review attempts to organize the recent findings on exosome composition and function during viral, bacterial, fungal, and protozoan infections, and their contribution to host defense or to pathogen spread. Moreover, we summarize the current perspectives and future directions regarding the potential application of exosomes for prophylactic and therapeutic purposes.
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Affiliation(s)
| | | | - César Lucio-García
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, México
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28
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Evers P, Pezacki JP. Unraveling Complex MicroRNA Signaling Pathways with Activity‐Based Protein Profiling to Guide Therapeutic Discovery**. Isr J Chem 2023. [DOI: 10.1002/ijch.202200088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Parrish Evers
- Department of Chemistry and Biomolecular Sciences University of Ottawa 150 Louis-Pasteur Pvt. K1N 6N5 Ottawa Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences University of Ottawa 150 Louis-Pasteur Pvt. K1N 6N5 Ottawa Canada
- Department of Biochemistry Microbiology, and Immunology University of Ottawa 451 Smyth Rd. K1H 8M5 Ottawa Canada
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29
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Subversion of a protein-microRNA signaling pathway by hepatitis C virus. Proc Natl Acad Sci U S A 2023; 120:e2220406120. [PMID: 36649406 PMCID: PMC9942813 DOI: 10.1073/pnas.2220406120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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30
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The Role of Non-Coding RNAs in Liver Disease, Injury, and Regeneration. Cells 2023; 12:cells12030359. [PMID: 36766701 PMCID: PMC9914052 DOI: 10.3390/cells12030359] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/04/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Non-coding RNAs (ncRNAs) have diverse functions in health and pathology in many tissues, including the liver. This review highlights important microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in liver disease and regeneration. Greater attention is given to more prevalent and well characterized RNAs, including: miR-122, miR-21, the let-7 family of miRs, miR-451a, miR-144, and MALAT1.
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Wang W, Sun L, Huang MT, Quan Y, Jiang T, Miao Z, Zhang Q. Regulatory circular RNAs in viral diseases: applications in diagnosis and therapy. RNA Biol 2023; 20:847-858. [PMID: 37882652 PMCID: PMC10730172 DOI: 10.1080/15476286.2023.2272118] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2023] [Indexed: 10/27/2023] Open
Abstract
Circular RNA (circRNA) forms closed loops via back-splicing in precursor mRNA, resisting exonuclease degradation. In higher eukaryotes, protein-coding genes create circRNAs through exon back-splicing. Unlike mRNAs, circRNAs possess unique production and structural traits, bestowing distinct cellular functions and biomedical potential. In this review, we explore the pivotal roles of viral circRNAs and associated RNA in various biological processes. Analysing the interactions between viral circRNA and host cellular machinery yields fresh insights into antiviral immunity, catalysing the development of potential therapeutics. Furthermore, circRNAs serve as enduring biomarkers in viral diseases due to their stable translation within specific tissues. Additionally, a deeper understanding of translational circRNA could expedite the establishment of circRNA-based expression platforms, meeting the rising demand for broad-spectrum viral vaccines. We also highlight the applications of circular RNA in biomarker studies as well as circRNA-based therapeutics. Prospectively, we expect a technological revolution in combating viral infections using circRNA.
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Affiliation(s)
- Wei Wang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Lei Sun
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Meng-Ting Huang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yun Quan
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Tao Jiang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
| | - Zhichao Miao
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qiong Zhang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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32
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Emanuelson C, Ankenbruck N, Kumbhare R, Thomas M, Connelly C, Baktash Y, Randall G, Deiters A. Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells. J Med Chem 2022; 65:16338-16352. [PMID: 36449366 PMCID: PMC9942140 DOI: 10.1021/acs.jmedchem.2c01141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
MicroRNAs (miRNAs) are noncoding RNA molecules of 22-24 nucleotides that are estimated to regulate thousands of genes in humans, and their dysregulation has been implicated in many diseases. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and has been linked to the development of hepatocellular carcinoma and hepatitis C virus (HCV) infection. Its role in these diseases renders miR-122 a potential target for small-molecule therapeutics. Here, we report the discovery of a new sulfonamide class of small-molecule miR-122 inhibitors from a high-throughput screen using a luciferase-based reporter assay. Structure-activity relationship (SAR) studies and secondary assays led to the development of potent and selective miR-122 inhibitors. Preliminary mechanism-of-action studies suggest a role in the promoter-specific transcriptional inhibition of miR-122 expression through direct binding to the liver-enriched transcription factor hepatocyte nuclear factor 4α. Importantly, the developed inhibitors significantly reduce HCV replication in human liver cells.
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Affiliation(s)
- Cole Emanuelson
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Nicholas Ankenbruck
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Rohan Kumbhare
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Meryl Thomas
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Colleen Connelly
- Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Yasmine Baktash
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Alexander Deiters
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
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Zhang J, Li F, Sun P, Wang J, Li K, Zhao Z, Bai X, Cao Y, Bao H, Li D, Zhang J, Liu Z, Lu Z. Downregulation of miR-122 by porcine reproductive and respiratory syndrome virus promotes viral replication by targeting SOCS3. Vet Microbiol 2022; 275:109595. [DOI: 10.1016/j.vetmic.2022.109595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/23/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
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miRNA Pathway Alteration in Response to Non-Coding RNA Delivery in Viral Vector-Based Gene Therapy. Int J Mol Sci 2022; 23:ijms232314954. [PMID: 36499289 PMCID: PMC9741442 DOI: 10.3390/ijms232314954] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022] Open
Abstract
Gene therapy is widely used to treat incurable disorders and has become a routine procedure in clinical practice. Since viruses can exhibit specific tropisms, effectively penetrate the cell, and are easy to use, most gene therapy approaches are based on viral delivery of genetic material. However, viral vectors have some disadvantages, such as immune response and cytotoxicity induced by a disturbance of cell metabolism, including miRNA pathways that are an important part of transcription regulation. Therefore, any viral-based gene therapy approach involves the evaluation of side effects and safety. It is possible for such effects to be caused either by the viral vectors themselves or by the delivered genetic material. Many gene therapy techniques use non-coding RNA delivery as an effective agent for gene expression regulation, with the risk of cellular miRNA pathways being affected due to the nature of the non-coding RNAs. This review describes the effect of viral vector entry and non-coding RNA delivery by these vectors on miRNA signaling pathways.
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35
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Kalkusova K, Taborska P, Stakheev D, Smrz D. The Role of miR-155 in Antitumor Immunity. Cancers (Basel) 2022; 14:5414. [PMID: 36358832 PMCID: PMC9659277 DOI: 10.3390/cancers14215414] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 09/19/2023] Open
Abstract
MicroRNAs belong to a group of short non-coding RNA molecules that are involved in the regulation of gene expression at multiple levels. Their function was described two decades ago, and, since then, microRNAs have become a rapidly developing field of research. Their participation in the regulation of cellular processes, such as proliferation, apoptosis, cell growth, and migration, made microRNAs attractive for cancer research. Moreover, as a single microRNA can simultaneously target multiple molecules, microRNAs offer a unique advantage in regulating multiple cellular processes in different cell types. Many of these cell types are tumor cells and the cells of the immune system. One of the most studied microRNAs in the context of cancer and the immune system is miR-155. MiR-155 plays a role in modulating innate and adaptive immune mechanisms in distinct immune cell types. As such, miR-155 can be part of the communication between the tumor and immune cells and thus impact the process of tumor immunoediting. Several studies have already revealed its effect on antitumor immune responses, and the targeting of this molecule is increasingly implemented in cancer immunotherapy. In this review, we discuss the current knowledge of miR-155 in the regulation of antitumor immunity and the shaping of the tumor microenvironment, and the plausible implementation of miR-155 targeting in cancer therapy.
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Affiliation(s)
- Katerina Kalkusova
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
| | - Pavla Taborska
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
| | - Dmitry Stakheev
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
- Laboratory of Immunotherapy, Institute of Microbiology of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
| | - Daniel Smrz
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
- Laboratory of Immunotherapy, Institute of Microbiology of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
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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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37
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Panigrahi M, Palmer MA, Wilson JA. MicroRNA-122 Regulation of HCV Infections: Insights from Studies of miR-122-Independent Replication. Pathogens 2022; 11:1005. [PMID: 36145436 PMCID: PMC9504723 DOI: 10.3390/pathogens11091005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
Despite the advancement in antiviral therapy, Hepatitis C remains a global health challenge and one of the leading causes of hepatitis related deaths worldwide. Hepatitis C virus, the causative agent, is a positive strand RNA virus that requires a liver specific microRNA called miR-122 for its replication. Unconventional to the canonical role of miRNAs in translation suppression by binding to 3'Untranslated Region (UTR) of messenger RNAs, miR-122 binds to two sites on the 5'UTR of viral genome and promotes viral propagation. In this review, we describe the unique relationship between the liver specific microRNA and HCV, the current knowledge on the mechanisms by which the virus uses miR-122 to promote the virus life cycle, and how miR-122 impacts viral tropism and pathogenesis. We will also discuss the use of anti-miR-122 therapy and its impact on viral evolution of miR-122-independent replication. This review further provides insight into how viruses manipulate host factors at the initial stage of infection to establish a successful infection.
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Affiliation(s)
| | | | - Joyce A. Wilson
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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38
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Makowska M, Smolarz B, Romanowicz H. microRNAs in Subarachnoid Hemorrhage (Review of Literature). J Clin Med 2022; 11:jcm11154630. [PMID: 35956244 PMCID: PMC9369929 DOI: 10.3390/jcm11154630] [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] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/25/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Recently, many studies have shown that microRNAs (miRNAs) in extracellular bioliquids are strongly associated with subarachnoid hemorrhage (SAH) and its complications. The article presents issues related to the occurrence of subarachnoid hemorrhage (epidemiology, symptoms, differential diagnosis, examination, and treatment of the patient) and a review of current research on the correlation between miRNAs and the complications of SAH. The potential use of miRNAs as biomarkers in the treatment of SAH is presented.
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Affiliation(s)
- Marianna Makowska
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Beata Smolarz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
- Correspondence: ; Tel.: +48-42-271-12-90
| | - Hanna Romanowicz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
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39
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MicroRNA-Based Diagnosis and Therapy. Int J Mol Sci 2022; 23:ijms23137167. [PMID: 35806173 PMCID: PMC9266664 DOI: 10.3390/ijms23137167] [Citation(s) in RCA: 309] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.
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40
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Dogan S, Spahiu E, Cilic A. Structural Analysis of microRNAs in Myeloid Cancer Reveals Consensus Motifs. Genes (Basel) 2022; 13:genes13071152. [PMID: 35885935 PMCID: PMC9316571 DOI: 10.3390/genes13071152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/19/2022] [Accepted: 06/24/2022] [Indexed: 02/04/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that function in post-transcriptional gene silencing and mRNA regulation. Although the number of nucleotides of miRNAs ranges from 17 to 27, they are mostly made up of 22 nucleotides. The expression of miRNAs changes significantly in cancer, causing protein alterations in cancer cells by preventing some genes from being translated into proteins. In this research, a structural analysis of 587 miRNAs that are differentially expressed in myeloid cancer was carried out. Length distribution studies revealed a mean and median of 22 nucleotides, with an average of 21.69 and a variance of 1.65. We performed nucleotide analysis for each position where Uracil was the most observed nucleotide and Adenine the least observed one with 27.8% and 22.6%, respectively. There was a higher frequency of Adenine at the beginning of the sequences when compared to Uracil, which was more frequent at the end of miRNA sequences. The purine content of each implicated miRNA was also assessed. A novel motif analysis script was written to detect the most frequent 3–7 nucleotide (3–7n) long motifs in the miRNA dataset. We detected CUG (42%) as the most frequent 3n motif, CUGC (15%) as a 4n motif, AGUGC (6%) as a 5n motif, AAGUGC (4%) as a 6n motif, and UUUAGAG (4%) as a 7n motif. Thus, in the second part of our study, we further characterized the motifs by analyzing whether these motifs align at certain consensus sequences in our miRNA dataset, whether certain motifs target the same genes, and whether these motifs are conserved within other species. This thorough structural study of miRNA sequences provides a novel strategy to study the implications of miRNAs in health and disease. A better understanding of miRNA structure is crucial to developing therapeutic settings.
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Affiliation(s)
- Senol Dogan
- Faculty of Physics and Earth Sciences, Peter Debye Institute, Leipzig University, 04103 Leipzig, Germany
- Correspondence:
| | - Emrulla Spahiu
- Institute of Molecular and Cell Physiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;
| | - Anis Cilic
- Excellence Cluster Cardiopulmonary System, University of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University, 35392 Giessen, Germany;
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41
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Breuer J, Barth P, Noe Y, Shalamova L, Goesmann A, Weber F, Rossbach O. What goes around comes around: Artificial circular RNAs bypass cellular antiviral responses. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 28:623-635. [PMID: 35497503 PMCID: PMC9042720 DOI: 10.1016/j.omtn.2022.04.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022]
Abstract
Natural circular RNAs have been found to sequester microRNAs and suppress their function. We have used this principle as a molecular tool and produced artificial circular RNA sponges in a cell-free system by in vitro transcription and ligation. Formerly, we were able to inhibit hepatitis C virus propagation by applying a circular RNA decoy strategy against microRNA-122, which is essential for the viral life cycle. In another proof-of-principle study, we used circular RNAs to sequester microRNA-21, an oncogenic and pro-proliferative microRNA. This strategy slowed tumor growth in a 3D cell culture model system, as well as in xenograft mice upon systemic delivery. In the wake of the global use of an in vitro transcribed RNA in coronavirus disease 2019 (COVID-19) vaccines, the question arose whether therapeutic circular RNAs trigger cellular antiviral defense mechanisms when delivered systemically. In this study, we present data on the cellular innate immune response as a consequence of liposome-based transfection of the circular RNA sponges we previously used to inhibit microRNA function. We find that circular RNAs produced by the presented methodology do not trigger the antiviral response and do not activate innate immune-signaling pathways.
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MicroRNAs as messengers of liver diseases: has the message finally been decrypted? Clin Sci (Lond) 2022; 136:323-328. [PMID: 35234251 DOI: 10.1042/cs20211177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/17/2022]
Abstract
MicroRNAs (miRNAs), which are regarded as crucial regulators of gene expression and diverse aspects of cell biology, can be present in various body fluids as highly stable molecules. It is also known that miRNAs exert tissue-specific regulation of gene transcription. Large amount of clinical and experimental evidence provided the rationale for raising the intriguing question of whether miRNAs can mediate cell-cell communication. For those reasons, miRNAs have been considered as the 'Holy Grail' of biomarkers allowing non-invasive diagnostic screening and early detection of a variety of diseases, including solid and non-solid cancers. In a study published in Clin. Sci. (Lond.) (2011) 120(5):183-193 (https://doi.org/10.1042/CS20100297), Gui et al. investigated the hypothesis that circulating miRNAs could be used to identify patients with liver pathologies. Specifically, the authors profiled circulating miRNAs in patients with hepatocellular carcinoma (HCC), liver cirrhosis (LC), and healthy controls and found that serum miR-885-5p levels were significantly higher in samples of patients with HCC (6.5-fold increase) and LC (8.8-fold increase). In this commentary, we highlight biological aspects associated with mir-122-the 'liver-specific' miRNA, which has been associated with a diverse range of liver pathologies. In addition, we discuss the relevance of mir-885-5p as potential biomarker for detecting human cancers. Finally, we provide some clues about how presumably unrelated miRNAs such as miR-122 and miR-885-5p may act in similar biological processes (BPs), making the miRNA regulatory networks more complex than anticipated.
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43
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Zhao H, Yang J, Wang Q, Cui Z, Li D, Niu J, Guo Y, Zhang Q, Zhang S, Zhao Y, Wang K, Lian W, Hu G. Exosomal miRNA-328-3p targets ZO-3 and inhibits porcine epidemic diarrhea virus proliferation. Arch Virol 2022; 167:901-910. [PMID: 35147806 DOI: 10.1007/s00705-022-05364-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/06/2021] [Indexed: 11/02/2022]
Abstract
As essential transfer carriers for cell-to-cell communication and genetic material, exosomes carry microRNAs that participate in the regulation of various biological processes. MicroRNAs are a type of single-stranded noncoding RNA that bind to specific target gene mRNAs to degrade or inhibit their translation, thereby regulating target gene expression. Although it is known that a variety of microRNAs are involved in the viral infection process, there are few reports on specific microRNAs involved in porcine epidemic diarrhea virus (PEDV) infection. In this study, we isolated and identified exosomes in PEDV-infected Vero E6 cells. Using transcriptomics technology, we found that miRNA-328-3p was significantly downregulated in exosomes following PEDV infection. Moreover, exosomal miRNA-328-3p inhibited infection by PEDV by targeting and inhibiting tight junction protein 3 (TJP-3/ZO-3) in recipient cells. Our findings provide evidence that, after infecting cells, PEDV downregulates expression of miRNA-328-3p, and the resulting reduced inhibition of the target protein ZO-3 helps to enhance PEDV infection. These results provide new insight for understanding the regulatory mechanism of PEDV infection.
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Affiliation(s)
- Han Zhao
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Jinxin Yang
- Jilin Provincal Center for Animal Disease Control and Prevention, Changchun, 130117, Jilin, China
| | - Qian Wang
- Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Zhanding Cui
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, Gansu, China
| | - Dengliang Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang, 712100, Shanxi, China
| | - Jiangting Niu
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Yanbing Guo
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Qian Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Shuang Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Yanli Zhao
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China
| | - Kai Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China.
| | - Wei Lian
- Jilin ZhengYe Biological Products Co., Ltd., Jilin, 132101, Jilin, China.
| | - Guixue Hu
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130118, China.
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44
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Burgess HM, Vink EI, Mohr I. Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells. Genes Dev 2022; 36:108-132. [PMID: 35193946 PMCID: PMC8887129 DOI: 10.1101/gad.349276.121] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With their categorical requirement for host ribosomes to translate mRNA, viruses provide a wealth of genetically tractable models to investigate how gene expression is remodeled post-transcriptionally by infection-triggered biological stress. By co-opting and subverting cellular pathways that control mRNA decay, modification, and translation, the global landscape of post-transcriptional processes is swiftly reshaped by virus-encoded factors. Concurrent host cell-intrinsic countermeasures likewise conscript post-transcriptional strategies to mobilize critical innate immune defenses. Here we review strategies and mechanisms that control mRNA decay, modification, and translation in animal virus-infected cells. Besides settling infection outcomes, post-transcriptional gene regulation in virus-infected cells epitomizes fundamental physiological stress responses in health and disease.
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Affiliation(s)
- Hannah M Burgess
- Department of Microbial Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
| | - Elizabeth I Vink
- Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA
| | - Ian Mohr
- Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA
- Laura and Isaac Perlmutter Cancer Institute, New York University School of Medicine, New York, New York 10016, USA
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45
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Kaur J, Rawat Y, Sood V, Periwal N, Rathore DK, Kumar S, Kumar N, Bhattacharyya S. Replication of Dengue Virus in K562-Megakaryocytes Induces Suppression in the Accumulation of Reactive Oxygen Species. Front Microbiol 2022; 12:784070. [PMID: 35087488 PMCID: PMC8787197 DOI: 10.3389/fmicb.2021.784070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/07/2021] [Indexed: 11/13/2022] Open
Abstract
Dengue virus can infect human megakaryocytes leading to decreased platelet biogenesis. In this article, we report a study of Dengue replication in human K562 cells undergoing PMA-induced differentiation into megakaryocytes. PMA-induced differentiation in these cells recapitulates steps of megakaryopoiesis including gene activation, expression of CD41/61 and CD61 platelet surface markers and accumulation of intracellular reactive oxygen species (ROS). Our results show differentiating megakaryocyte cells to support higher viral replication without any apparent increase in virus entry. Further, Dengue replication suppresses the accumulation of ROS in differentiating cells, probably by only augmenting the activity of the transcription factor NFE2L2 without influencing the expression of the coding gene. Interestingly pharmacological modulation of NFE2L2 activity showed a simultaneous but opposite effect on intracellular ROS and virus replication suggesting the former to have an inhibitory effect on the later. Also cells that differentiated while supporting intracellular virus replication showed reduced level of surface markers compared to uninfected differentiated cells.
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Affiliation(s)
- Jaskaran Kaur
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Yogita Rawat
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Vikas Sood
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Neha Periwal
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Deepak Kumar Rathore
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Shrikant Kumar
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Niraj Kumar
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
| | - Sankar Bhattacharyya
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
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46
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Gedefaw L, Ullah S, Lee TMH, Yip SP, Huang CL. Targeting Inflammasome Activation in COVID-19: Delivery of RNA Interference-Based Therapeutic Molecules. Biomedicines 2021; 9:1823. [PMID: 34944639 PMCID: PMC8698532 DOI: 10.3390/biomedicines9121823] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Mortality and morbidity associated with COVID-19 continue to be significantly high worldwide, owing to the absence of effective treatment strategies. The emergence of different variants of SARS-CoV-2 is also a considerable source of concern and has led to challenges in the development of better prevention and treatment strategies, including vaccines. Immune dysregulation due to pro-inflammatory mediators has worsened the situation in COVID-19 patients. Inflammasomes play a critical role in modulating pro-inflammatory cytokines in the pathogenesis of COVID-19 and their activation is associated with poor clinical outcomes. Numerous preclinical and clinical trials for COVID-19 treatment using different approaches are currently underway. Targeting different inflammasomes to reduce the cytokine storm, and its associated complications, in COVID-19 patients is a new area of research. Non-coding RNAs, targeting inflammasome activation, may serve as an effective treatment strategy. However, the efficacy of these therapeutic agents is highly dependent on the delivery system. MicroRNAs and long non-coding RNAs, in conjunction with an efficient delivery vehicle, present a potential strategy for regulating NLRP3 activity through various RNA interference (RNAi) mechanisms. In this regard, the use of nanomaterials and other vehicle types for the delivery of RNAi-based therapeutic molecules for COVID-19 may serve as a novel approach for enhancing drug efficacy. The present review briefly summarizes immune dysregulation and its consequences, the roles of different non-coding RNAs in regulating the NLRP3 inflammasome, distinct types of vectors for their delivery, and potential therapeutic targets of microRNA for treatment of COVID-19.
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Affiliation(s)
- Lealem Gedefaw
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Sami Ullah
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Thomas M. H. Lee
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China;
| | - Shea Ping Yip
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Chien-Ling Huang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China
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Aslani M, Mortazavi-Jahromi SS, Mirshafiey A. Cytokine storm in the pathophysiology of COVID-19: Possible functional disturbances of miRNAs. Int Immunopharmacol 2021; 101:108172. [PMID: 34601331 PMCID: PMC8452524 DOI: 10.1016/j.intimp.2021.108172] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.
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Affiliation(s)
- Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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48
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Natarelli L, Virgili F, Weber C. SARS-CoV-2, Cardiovascular Diseases, and Noncoding RNAs: A Connected Triad. Int J Mol Sci 2021; 22:12243. [PMID: 34830125 PMCID: PMC8620514 DOI: 10.3390/ijms222212243] [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: 10/06/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 12/23/2022] Open
Abstract
Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by important respiratory impairments frequently associated with severe cardiovascular damages. Moreover, patients with pre-existing comorbidity for cardiovascular diseases (CVD) often present a dramatic increase in inflammatory cytokines release, which increases the severity and adverse outcomes of the infection and, finally, mortality risk. Despite this evident association at the clinical level, the mechanisms linking CVD and COVID-19 are still blurry and unresolved. Noncoding RNAs (ncRNAs) are functional RNA molecules transcribed from DNA but usually not translated into proteins. They play an important role in the regulation of gene expression, either in relatively stable conditions or as a response to different stimuli, including viral infection, and are therefore considered a possible important target in the design of specific drugs. In this review, we introduce known associations and interactions between COVID-19 and CVD, discussing the role of ncRNAs within SARS-CoV-2 infection from the perspective of the development of efficient pharmacological tools to treat COVID-19 patients and taking into account the equally dramatic associated consequences, such as those affecting the cardiovascular system.
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Affiliation(s)
- Lucia Natarelli
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), 800336 Munich, Germany;
| | - Fabio Virgili
- Research Center for Food and Nutrition, Council for Agricultural Research and Economics, 00178 Rome, Italy;
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU), 800336 Munich, Germany;
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 HX Maastricht, The Netherlands
- Munich Cluster for Systems Neurology (SyNergy), Institute for Stroke and Dementia Research, 81377 Munich, Germany
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Hu J, Stojanović J, Yasamineh S, Yasamineh P, Karuppannan SK, Hussain Dowlath MJ, Serati-Nouri H. The potential use of microRNAs as a therapeutic strategy for SARS-CoV-2 infection. Arch Virol 2021; 166:2649-2672. [PMID: 34278528 PMCID: PMC8286877 DOI: 10.1007/s00705-021-05152-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/21/2021] [Indexed: 02/06/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, there is no effective therapeutic approach for treating SARS-CoV-2 infections. MicroRNAs (miRNAs) have been recognized to target the viral genome directly or indirectly, thereby inhibiting viral replication. Several studies have demonstrated that host miRNAs target different sites in SARS-CoV-2 RNA and constrain the production of essential viral proteins. Furthermore, miRNAs have lower toxicity, are more immunogenic, and are more diverse than protein-based and even plasmid-DNA-based therapeutic agents. In this review, we emphasize the role of miRNAs in viral infection and their potential use as therapeutic agents against COVID-19 disease. The potential of novel miRNA delivery strategies, especially EDV™ nanocells, for targeting lung tissue for treatment of SARS-CoV-2 infection is also discussed.
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Affiliation(s)
- Jiulue Hu
- Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang, 473004, Henan, China
| | - Jelena Stojanović
- Faculty of Mathematics and Computer Science in Belgrade, ALFA BK University, Belgrade, Serbia
| | - Saman Yasamineh
- Young Researcher and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
| | - Pooneh Yasamineh
- Young Researcher and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Sathish Kumar Karuppannan
- Center for Environmental Nuclear Research, Directorate of Research and Virtual Education, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603203, Kanchipuram, Chennai, Tamil Nadu, India
| | - Mohammed Junaid Hussain Dowlath
- Center for Environmental Nuclear Research, Directorate of Research and Virtual Education, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603203, Kanchipuram, Chennai, Tamil Nadu, India
| | - Hamed Serati-Nouri
- Stem cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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50
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RNA Structures and Their Role in Selective Genome Packaging. Viruses 2021; 13:v13091788. [PMID: 34578369 PMCID: PMC8472981 DOI: 10.3390/v13091788] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
To generate infectious viral particles, viruses must specifically select their genomic RNA from milieu that contains a complex mixture of cellular or non-genomic viral RNAs. In this review, we focus on the role of viral encoded RNA structures in genome packaging. We first discuss how packaging signals are constructed from local and long-range base pairings within viral genomes, as well as inter-molecular interactions between viral and host RNAs. Then, how genome packaging is regulated by the biophysical properties of RNA. Finally, we examine the impact of RNA packaging signals on viral evolution.
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