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Zhang Y, Zang C, Mao M, Zhang M, Tang Z, Chen W, Zhu W. Advances in RNA therapy for the treatment of autoimmune diseases. Autoimmun Rev 2025; 24:103753. [PMID: 39842534 DOI: 10.1016/j.autrev.2025.103753] [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: 01/15/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/24/2025]
Abstract
Autoimmune diseases (ADs) are a group of complex, chronic conditions characterized by disturbance of immune tolerance, with examples including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. These diseases have unclear pathogenesis, and traditional therapeutic approaches remain limited. However, advances in high-throughput histology technology and scientific discoveries have led to the identification of various pathogenic factors contributing to ADs. Coupled with improvements in RNA nucleic acid-based drug synthesis, design, and delivery, RNA-based therapies have been extensively investigated for their potential in treating ADs. This paper reviews the progress in the use of miRNAs, lncRNAs, circRNAs, siRNAs, antisense oligonucleotides (ASOs), aptamers, mRNAs, and other RNA-based therapies in ADs, focusing on their therapeutic potential and application prospects, providing insights for future research and clinical treatment of autoimmune diseases.
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Affiliation(s)
- Ying Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Chenyang Zang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Manyun Mao
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Mi Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Zhenwei Tang
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wangqing Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China.
| | - Wu Zhu
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China.
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Sarvepalli S, Vadarevu S. Non-antiviral therapies for viral infections: Harnessing host mechanisms. Int Immunopharmacol 2025; 153:114521. [PMID: 40139096 DOI: 10.1016/j.intimp.2025.114521] [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: 01/14/2025] [Revised: 03/01/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Despite advancements in the field of directly acting anti-viral (DAA) therapies, viral infections still continue to pose significant global health challenges. The efficacy of DAAs are often hindered by mutations, origin of new strains, development of resistance and lack of broad spectrum effectiveness. Furthermore, patients with advanced-stage diseases may require higher doses and combinations of different DAA therapies, raising concerns about tolerability and safety. To overcome all these constraints, non-antiviral therapies that focuses on host mechanisms (also known as host-focused therapies) are emerging as an innovative approach. Host focused therapy aims to target the host molecules and pathways that are essential for viral infection and disease progression. Along with addressing the above mentioned challenges, these host focused therapies can also modulate excessive inflammatory responses. Recent advancements in understanding host-virus interactions and the pathways involved in the pathogenesis of severe viral infections from viral entry and replication to disease progression, have accelerated the development of host-focused therapies aimed at combating these infections. This review explores the growing rationale and various opportunities for host-focused therapies for severe viral infections including zika virus, dengue, HIV, influenza, and covid-19 to name a few. In addition, current clinical trial information on various classes of host focused therapies are presented, highlighting their therapeutic potential and significance in the field.
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Affiliation(s)
- Sruthi Sarvepalli
- College of Pharmacy and Health Sciences, St John's University, United States.
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Wang J, Xia A, Tang M, Yang S, Shen Y, Dao J, Tao R, Yue W. Integrative analysis of serum proteomics and transcriptomics in hepatitis C. Virol J 2025; 22:73. [PMID: 40082995 PMCID: PMC11905632 DOI: 10.1186/s12985-025-02690-1] [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: 12/02/2024] [Accepted: 03/03/2025] [Indexed: 03/16/2025] Open
Abstract
OBJECT Hepatitis C is a contagious disease caused by infection with the hepatitis C virus (HCV) through blood and mother-to-child routes. This study intends to characterize the serum molecular features of hepatitis C using proteomics and transcriptomics. METHODS Ctrl (normal population), HCV (population with previous HCV infection), and chronic HCV (patients with persistent HCV infection) groups were set up, and the expression profiles of the proteomes and transcriptomes of serum samples were identified using TMT and RNA-seq. Bioinformatics was applied to perform enrichment analysis and PPI network construction of differentially expressed proteins/genes (DEPs/DEGs). RT-qPCR and western blot verified the expression differences of DEPs/DEGs. RESULTS Compared to the Ctrl group, the HCV group had 356 DEPs in serum; compared to the HCV group, the chronic HCV group had 381 DEPs in serum. DEPs are predominantly immunoglobulins and exosomal proteins that regulate carbon dioxide transport, initiation of transcription, immune responses, and bacterial and viral infections. HSPA4, HSPD1, COPS5, PSMD2 and TCP1 are key HCV-associated proteins in DEPs. The HCV group had 684 DEGs compared to the Ctrl group, and the chronic HCV group had 350 DEGs compared to the HCV group. DEGs primarily encode the extracellular matrix and regulate wound healing, cellular communication, oxidative stress, cell adhesion, viral infection, and immunity. KIF11, CENPE, TTK, CDC20 and ASPM are HCV-related hub genes in DEGs. Combined analyses revealed interactions between DEPs and DEGs, especially EIF4A3, MNAT1, and UBE2D1. Moreover, the expression patterns of EIF4A3, EIF2B1, MNAT1, SNRNP70, and UBE2D1 in DEPs/DEGs from Ctrl, HCV, and chronic HCV groups were consistent with the sequencing results. CONCLUSION EIF4A3, EIF2B1, MNAT1, SNRNP70, and UBE2D1 are involved in the process of HCV infection and pathogenesis, and they may be potential biomarkers for the treatment of patients with hepatitis C.
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Affiliation(s)
- Jianqiong Wang
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Andong Xia
- Department of Infectious Diseases and Liver Diseases, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Min Tang
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Shengjun Yang
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Yandi Shen
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Jinhua Dao
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China
| | - Rui Tao
- Department of Clinical Laboratory, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China.
| | - Wei Yue
- Department of Infectious Diseases and Liver Diseases, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No.157 Jinbi Road, Kunming, Yunnan, China.
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Liu M, Wang Y, Zhang Y, Hu D, Tang L, Zhou B, Yang L. Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines. Signal Transduct Target Ther 2025; 10:73. [PMID: 40059188 PMCID: PMC11891339 DOI: 10.1038/s41392-024-02112-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/23/2024] [Accepted: 12/13/2024] [Indexed: 03/17/2025] Open
Abstract
The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously "undruggable" targets, suggesting that they could be useful for guiding the development of additional clinical candidates.
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Affiliation(s)
- Mohan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yusi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yibing Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Die Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bailing Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Casadémont I, Ayala-Suárez R, Modhiran N, Tawfik A, Prot M, Paul R, Simon-Lorière E, Díez-Fuertes F, Ubol S, Alcamí J, Sakuntabhai A. miRNome analysis reveals mir-155-5p as a protective factor to dengue infection in a resistant Thai cohort. Med Microbiol Immunol 2025; 214:13. [PMID: 39976655 PMCID: PMC11842423 DOI: 10.1007/s00430-025-00821-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 02/10/2025] [Indexed: 02/23/2025]
Abstract
Dengue virus (DENV) is a global health threat, with approximately 390 million infections annually, ranging from mild dengue fever to severe dengue hemorrhagic fever and shock syndrome. MicroRNA (miRNA) are crucial post-transcriptional regulators which may regulate host resistance to DENV infection. This study aimed to identify miRNAs involved in natural resistance to DENV infection. Individuals from a dengue-endemic area were classified as susceptible (SD) or resistant (RD) according to their anti-DENV antibody status. RD individuals were seronegative despite high local DENV infection prevalence. Monocytes susceptibility to DENV infection was assessed in vitro. The miRNome profiles of the monocytes from 7 individuals per group were assessed upon mock or DENV-2 infection. The antiviral effect of differentially expressed miRNAs was analyzed using miRNA mimics in HeLa cells followed by infection with DENV-1, DENV-2, DENV-3, and DENV-4 serotypes. We performed RNA-seq on miRNA mimic-transfected cells to identify miRNA-targeted genes interacting with DENV proteins. Monocytes from RD individuals exhibit lower DENV-2 production in vitro. The miRNAs miR-155, miR-132-3p, miR-576-5p were overexpressed in monocytes from RD group upon DENV-2 infection. The transfection of miR-155-5p mimic reduced DENV infection and viral production in HeLa cells, regulating 18 genes interacting with DENV proteins and downregulating target genes involved in interferon response, TP53 regulation, apoptosis, and vesicle trafficking (e.g. HSD17B12, ANXA2). Therefore, we show that monocytes from RD individuals show a distinct miRNA expression profile and reduced viral production. In vitro miR-155-5p upregulation induces an antiviral state, revealing potential therapeutic targets to treat dengue.
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Affiliation(s)
- Isabelle Casadémont
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France
| | - Rubén Ayala-Suárez
- AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Spain
- Spanish Consortium for Research in Infectious Diseases (CIBERINFEC), Madrid, Spain
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Alcalá de Henares, Spain
| | - Naphak Modhiran
- School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, Brisbane, Australia
| | - Ahmed Tawfik
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France
| | - Matthieu Prot
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France
| | - Richard Paul
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France
| | - Etienne Simon-Lorière
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France
| | - Francisco Díez-Fuertes
- AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Spain
- Spanish Consortium for Research in Infectious Diseases (CIBERINFEC), Madrid, Spain
| | - Sukathida Ubol
- Faculty of Science, Department of Microbiology, Mahidol University, Bangkok, Thailand
| | - José Alcamí
- AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Spain
- Spanish Consortium for Research in Infectious Diseases (CIBERINFEC), Madrid, Spain
- AIDS and HIV Infection Group (VIH-Clínic), Fundació de Recerca Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
| | - Anavaj Sakuntabhai
- Institut Pasteur, Université Paris-Cité, CNRS UMR 2000, 28 rue du Dr Roux, Paris, France.
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Frericks N, Klöhn M, Lange F, Pottkämper L, Carpentier A, Steinmann E. Host-targeting antivirals for chronic viral infections of the liver. Antiviral Res 2025; 234:106062. [PMID: 39716667 DOI: 10.1016/j.antiviral.2024.106062] [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: 11/29/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.
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Affiliation(s)
- Nicola Frericks
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Frauke Lange
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Lilli Pottkämper
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Arnaud Carpentier
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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Li X, Qian B, Chen X, Shen M, Zhao S, Zhang X, He J. The role of miR-152 in urological tumors: potential biomarkers and therapeutic targets. Front Immunol 2024; 15:1464327. [PMID: 39606232 PMCID: PMC11599204 DOI: 10.3389/fimmu.2024.1464327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Urological malignant tumors pose a significant threat to human health, with a high incidence rate each year. Prostate cancer, bladder cancer, and renal cell carcinoma are among the most prevalent and extensively researched urological malignancies. Despite advancements in research, the prognosis for these tumors remains unfavorable due to late detection, postoperative recurrence, and treatment resistance. A thorough investigation into their pathogenesis is crucial for early diagnosis and treatment. Recent studies have highlighted the close association between microRNAs (miRNAs) and cancer progression. miRNAs are small non-coding RNAs composed of 19-23 nucleotides that regulate gene expression by binding to the 3' untranslated region (3'UTR) of target mRNAs, impacting key cellular processes such as proliferation, differentiation, apoptosis, and migration. Dysregulation of miRNAs can disrupt the expression of oncogenes and tumor suppressor genes, contributing to cancer development. Among the various miRNAs studied, miR-152 has garnered attention for its role in urological malignancies. Several studies have indicated that dysregulation of miR-152 expression is significant in these cancers, warranting a comprehensive review of the evidence. This review focuses on the expression and function of miR-152 in prostate cancer, bladder cancer, and renal cell carcinoma, elucidating its mechanisms in cancer progression and exploring its potential as a therapeutic target and biomarker in urological malignancies.
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Affiliation(s)
- Xin Li
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Biao Qian
- Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xu Chen
- Department of Pathology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Maolei Shen
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Xinsheng Zhang
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Jian He
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
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Suvarnapathaki S, Serrano-Farias A, Dudley JC, Bettegowda C, Rincon-Torroella J. Unlocking the Potential of Circulating miRNAs as Biomarkers in Glioblastoma. Life (Basel) 2024; 14:1312. [PMID: 39459612 PMCID: PMC11509808 DOI: 10.3390/life14101312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
Using microRNAs (miRNAs) as potential circulating biomarkers in diagnosing and treating glioblastoma (GBM) has garnered a lot of scientific and clinical impetus in the past decade. As an aggressive primary brain tumor, GBM poses challenges in early detection and effective treatment with significant current diagnostic constraints and limited therapeutic strategies. MiRNA dysregulation is present in GBM. The intricate involvement of miRNAs in altering cell proliferation, invasion, and immune escape makes them prospective candidates for identifying and monitoring GBM diagnosis and response to treatment. These miRNAs could play a dual role, acting as both potential diagnostic markers and targets for therapy. By modulating the activity of various oncogenic and tumor-suppressive proteins, miRNAs create opportunities for precision medicine and targeted therapies in GBM. This review centers on the critical role and function of circulating miRNA biomarkers in GBM diagnosis and treatment. It highlights their significance in providing insights into disease progression, aiding in early diagnosis, and potential use as targets for novel therapeutic interventions. Ultimately, the study of miRNA would contribute to improving patient outcomes in the challenging landscape of GBM management.
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Affiliation(s)
- Sanika Suvarnapathaki
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (A.S.-F.); (J.C.D.); (C.B.)
| | - Antolin Serrano-Farias
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (A.S.-F.); (J.C.D.); (C.B.)
| | - Jonathan C. Dudley
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (A.S.-F.); (J.C.D.); (C.B.)
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (A.S.-F.); (J.C.D.); (C.B.)
| | - Jordina Rincon-Torroella
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (A.S.-F.); (J.C.D.); (C.B.)
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Ramadan YN, Kamel AM, Medhat MA, Hetta HF. MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clin Exp Med 2024; 24:217. [PMID: 39259390 PMCID: PMC11390904 DOI: 10.1007/s10238-024-01476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory illness of the gastrointestinal tract (GIT) triggered by an inappropriate immune response to environmental stimuli in genetically predisposed persons. Unfortunately, IBD patients' quality of life is negatively impacted by the symptoms associated with the disease. The exact etiology of IBD pathogenesis is not fully understood, but the emerging research indicated that the microRNA (miRNA) plays an important role. miRNAs have been documented to possess a significant role in regulating pro- and anti-inflammatory pathways, in addition to their roles in several physiological processes, including cell growth, proliferation, and apoptosis. Variations in the miRNA profiles might be a helpful prognostic indicator and a valuable tool in the differential diagnosis of IBD. Most interestingly, these miRNAs have a promising therapeutic target in several pre-clinical animal studies and phase 2 clinical studies to alleviate inflammation and improve patient's quality of life. This comprehensive review discusses the current knowledge about the significant physiological role of different miRNAs in the health of the intestinal immune system and addresses the role of the most relevant differentially expressed miRNAs in IBD, identify their potential targets, and emphasize their diagnostic and therapeutic potential for future research.
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Affiliation(s)
- Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Ayat M Kamel
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt
| | - Mohammed A Medhat
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
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Brillante S, Volpe M, Indrieri A. Advances in MicroRNA Therapeutics: From Preclinical to Clinical Studies. Hum Gene Ther 2024; 35:628-648. [PMID: 39150011 DOI: 10.1089/hum.2024.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2024] Open
Abstract
MicroRNAs (miRNAs) are crucial regulators of gene expression involved in various pathophysiological processes. Their ability to modulate multiple pathways simultaneously and their involvement in numerous diseases make miRNAs attractive tools and targets in therapeutic development. Significant efforts have been made to advance miRNA research in the preclinical stage, attracting considerable investment from biopharmaceutical companies. Consequently, an increasing number of miRNA-based therapies have entered clinical trials for both diagnostic and therapeutic applications across a wide range of diseases. While individual miRNAs can regulate a broad array of mRNA targets, this also complicates the management of adverse effects seen in clinical trials. Several candidates have been discontinued due to toxicity concerns, underscoring the need for comprehensive risk assessments of miRNA therapeutics. Despite no miRNA-based strategies have yet received approval from regulatory agencies, prominent progress in the miRNA modulation approaches and in the nano-delivery systems have been made in the last decade, leading to the development of novel safe and well-tolerated miRNA drug candidates. In this review, we present recent advances in the development of miRNA therapeutics currently in preclinical or clinical stages for treating both rare genetic disorders and multifactorial common conditions. We also address the challenges related to the safety and targeted delivery of miRNA therapies, as well as the identification of the most effective therapeutic candidates in preclinical and clinical trials.
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Affiliation(s)
- Simona Brillante
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
| | - Mariagrazia Volpe
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Alessia Indrieri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
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11
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Karthik S, Mohan S, Magesh I, Bharathy A, Kolipaka R, Ganesamoorthi S, Sathiya K, Shanmugavadivu A, Gurunathan R, Selvamurugan N. Chitosan nanocarriers for non-coding RNA therapeutics: A review. Int J Biol Macromol 2024; 263:130361. [PMID: 38395284 DOI: 10.1016/j.ijbiomac.2024.130361] [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: 10/05/2023] [Revised: 02/02/2024] [Accepted: 02/19/2024] [Indexed: 02/25/2024]
Abstract
Non-coding RNA (ncRNA)-based therapies entail delivering ncRNAs to cells to regulate gene expression and produce proteins that combat infections, cancer, neurological diseases, and bone abnormalities. Nevertheless, the therapeutic potential of these ncRNAs has been limited due to the difficulties in delivering them to specific cellular targets within the body. Chitosan (CS), a biocompatible cationic polymer, interacts with negatively charged RNA molecules to form stable complexes. It is a promising biomaterial to develop nanocarriers for ncRNA delivery, overcoming several disadvantages of traditional delivery systems. CS-based nanocarriers can protect ncRNAs from degradation and target-specific delivery by surface modifications and intracellular release profiles over an extended period. This review briefly summarizes the recent developments in CS nanocarriers' synthesis and design considerations and their applications in ncRNA therapeutics for treating various diseases. We also discuss the challenges and limitations of CS-based nanocarriers for ncRNA therapeutics and potential strategies for overcoming these challenges.
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Affiliation(s)
- S Karthik
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Sahithya Mohan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Induja Magesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Ashok Bharathy
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Rushil Kolipaka
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Srinidhi Ganesamoorthi
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - K Sathiya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Abinaya Shanmugavadivu
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Raghav Gurunathan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - N Selvamurugan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India.
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12
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Nappi F. Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review. Int J Mol Sci 2024; 25:3630. [PMID: 38612441 PMCID: PMC11011542 DOI: 10.3390/ijms25073630] [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: 01/23/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France
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13
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Shang M, Ma M, Su G, Xiao L. Application value of miRNA-182 as a biomarker for cancer diagnosis: a systematic review with meta-analysis. Biomark Med 2023; 17:907-918. [PMID: 38205594 DOI: 10.2217/bmm-2023-0176] [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] [Indexed: 01/12/2024] Open
Abstract
Aim: This study aims to establish the potential reliability and validity of miRNA-182 as a diagnostic tool in oncology, and hence to contribute to the decision-making process in clinical settings. Materials & methods: To further evaluate the role of miRNA-182 as a cancer biomarker, we conducted a search of the PubMed, Cochrane Library, Wanfang and China National Knowledge Infrastructure databases of existing literature. Conclusion: These results suggest that miRNA-182 could function as a potential molecular marker for cancer detection and diagnosis. The effect of miRNA-182 on tumor development should be further studied to confirm these results and add to the current understanding of its role in cancer.
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Affiliation(s)
- Mengyu Shang
- School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Mengdan Ma
- Shantou University Medical College, Shantou, 515041, China
| | - Ganglin Su
- Shantou University Medical College, Shantou, 515041, China
| | - Liang Xiao
- Department of Surgery and Oncology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China
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14
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Ranjbar S, Zhong XB, Manautou J, Lu X. A holistic analysis of the intrinsic and delivery-mediated toxicity of siRNA therapeutics. Adv Drug Deliv Rev 2023; 201:115052. [PMID: 37567502 PMCID: PMC10543595 DOI: 10.1016/j.addr.2023.115052] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/15/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Small interfering RNAs (siRNAs) are among the most promising therapeutic platforms in many life-threatening diseases. Owing to the significant advances in siRNA design, many challenges in the stability, specificity and delivery of siRNA have been addressed. However, safety concerns and dose-limiting toxicities still stand among the reasons for the failure of clinical trials of potent siRNA therapies, calling for a need of more comprehensive understanding of their potential mechanisms of toxicity. This review delves into the intrinsic and delivery related toxicity mechanisms of siRNA drugs and takes a holistic look at the safety failure of the clinical trials to identify the underlying causes of toxicity. In the end, the current challenges, and potential solutions for the safety assessment and high throughput screening of investigational siRNA and delivery systems as well as considerations for design strategies of safer siRNA therapeutics are outlined.
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Affiliation(s)
- Sheyda Ranjbar
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA
| | - José Manautou
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA
| | - Xiuling Lu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
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15
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Bailey S, Ferraresso M, Alonso-Crisostomo L, Ward D, Smith S, Nicholson JC, Saini H, Enright AJ, Scarpini CG, Coleman N, Murray MJ. Targeting oncogenic microRNAs from the miR-371~373 and miR-302/367 clusters in malignant germ cell tumours causes growth inhibition through cell cycle disruption. Br J Cancer 2023; 129:1451-1461. [PMID: 37789102 PMCID: PMC10628203 DOI: 10.1038/s41416-023-02453-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 09/13/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND MiR-371~373 and miR-302/367 cluster over-expression occurs in all malignant germ cell tumours (GCTs), regardless of age (paediatric/adult), site (gonadal/extragonadal), or subtype [seminoma, yolk sac tumour (YST), embryonal carcinoma (EC)]. Six of eight microRNAs from these clusters contain the seed sequence 'AAGUGC', determining mRNA targeting. Here we sought to identify the significance of these observations by targeting these microRNAs functionally. METHODS We targeted miR-371~373 and/or miR-302/367 clusters in malignant GCT cell lines, using CRISPR-Cas9, gapmer primary miR-302/367 transcript inhibition, and peptide nucleic acid (PNA) or locked nucleic acid (LNA)-DNA inhibition targeting miR-302a-d-3p, and undertook relevant functional assays. RESULTS MiR-302/367 cluster microRNAs made the largest contribution to AAGUGC seed abundance in malignant GCT cells, regardless of subtype (seminoma/YST/EC). Following the unsuccessful use of CRISPR-Cas9, gapmer, and PNA systems, LNA-DNA-based targeting resulted in growth inhibition in seminoma and YST cells. This was associated with the de-repression of multiple mRNAs targeted by AAGUGC seed-containing microRNAs, with pathway analysis confirming predominant disruption of Rho-GTPase signalling, vesicle organisation/transport, and cell cycle regulation, findings corroborated in clinical samples. Further LNA-DNA inhibitor studies confirmed direct cell cycle effects, with an increase of cells in G0/G1-phase and a decrease in S-phase. CONCLUSION Targeting of specific miR-371~373 and miR-302/367 microRNAs in malignant GCTs demonstrated their functional significance, with growth inhibition mediated through cell cycle disruption.
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Affiliation(s)
- Shivani Bailey
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
- Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Marta Ferraresso
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
| | | | - Dawn Ward
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
| | - Stephen Smith
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
| | - James C Nicholson
- Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
- Department of Paediatrics, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Harpreet Saini
- EMBL-European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Anton J Enright
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
| | - Cinzia G Scarpini
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK
| | - Nicholas Coleman
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
| | - Matthew J Murray
- Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
- Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
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16
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Nappi F, Avtaar Singh SS, Jitendra V, Alzamil A, Schoell T. The Roles of microRNAs in the Cardiovascular System. Int J Mol Sci 2023; 24:14277. [PMID: 37762578 PMCID: PMC10531750 DOI: 10.3390/ijms241814277] [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: 07/25/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The discovery of miRNAs and their role in disease represent a significant breakthrough that has stimulated and propelled research on miRNAs as targets for diagnosis and therapy. Cardiovascular disease is an area where the restrictions of early diagnosis and conventional pharmacotherapy are evident and deserve attention. Therefore, miRNA-based drugs have significant potential for development. Research and its application can make considerable progress, as seen in preclinical and clinical trials. The use of miRNAs is still experimental but has a promising role in diagnosing and predicting a variety of acute coronary syndrome presentations. Its use, either alone or in combination with currently available biomarkers, might be adopted soon, particularly if there is diagnostic ambiguity. In this review, we examine the current understanding of miRNAs as possible targets for diagnosis and treatment in the cardiovascular system. We report on recent advances in recognising and characterising miRNAs with a focus on clinical translation. The latest challenges and perspectives towards clinical application are discussed.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
| | | | - Vikram Jitendra
- Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK;
| | - Almothana Alzamil
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
| | - Thibaut Schoell
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
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17
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Mirzaei R, Karampoor S, Korotkova NL. The emerging role of miRNA-122 in infectious diseases: Mechanisms and potential biomarkers. Pathol Res Pract 2023; 249:154725. [PMID: 37544130 DOI: 10.1016/j.prp.2023.154725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
microRNAs (miRNAs) are small, non-coding RNA molecules that play crucial regulatory roles in numerous cellular processes. Recent investigations have highlighted the significant involvement of miRNA-122 (miR-122) in the pathogenesis of infectious diseases caused by diverse pathogens, encompassing viral, bacterial, and parasitic infections. In the context of viral infections, miR-122 exerts regulatory control over viral replication by binding to the viral genome and modulating the host's antiviral response. For instance, in hepatitis B virus (HBV) infection, miR-122 restricts viral replication, while HBV, in turn, suppresses miR-122 expression. Conversely, miR-122 interacts with the hepatitis C virus (HCV) genome, facilitating viral replication. Regarding bacterial infections, miR-122 has been found to regulate host immune responses by influencing inflammatory cytokine production and phagocytosis. In Vibrio anguillarum infections, there is a significant reduction in miR-122 expression, contributing to the pathophysiology of bacterial infections. Toll-like receptor 14 (TLR14) has been identified as a novel target gene of miR-122, affecting inflammatory and immune responses. In the context of parasitic infections, miR-122 plays a crucial role in regulating host lipid metabolism and immune responses. For example, during Leishmania infection, miR-122-containing extracellular vesicles from liver cells are unable to enter infected macrophages, leading to a suppression of the inflammatory response. Furthermore, miR-122 exhibits promise as a potential biomarker for various infectious diseases. Its expression level in body fluids, particularly in serum and plasma, correlates with disease severity and treatment response in patients affected by HCV, HBV, and tuberculosis. This paper also discusses the potential of miR-122 as a biomarker in infectious diseases. In summary, this review provides a comprehensive and insightful overview of the emerging role of miR-122 in infectious diseases, detailing its mechanism of action and potential implications for the development of novel therapeutic strategies.
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Affiliation(s)
- Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Nadezhda Lenoktovna Korotkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Russia; Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation (FSBEI HE PRMU MOH Russia), Russia
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18
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Baumeier C, Harms D, Aleshcheva G, Gross U, Escher F, Schultheiss HP. Advancing Precision Medicine in Myocarditis: Current Status and Future Perspectives in Endomyocardial Biopsy-Based Diagnostics and Therapeutic Approaches. J Clin Med 2023; 12:5050. [PMID: 37568452 PMCID: PMC10419903 DOI: 10.3390/jcm12155050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
The diagnosis and specific and causal treatment of myocarditis and inflammatory cardiomyopathy remain a major clinical challenge. Despite the rapid development of new imaging techniques, endomyocardial biopsies remain the gold standard for accurate diagnosis of inflammatory myocardial disease. With the introduction and continued development of immunohistochemical inflammation diagnostics in combination with viral nucleic acid testing, myocarditis diagnostics have improved significantly since their introduction. Together with new technologies such as miRNA and gene expression profiling, quantification of specific immune cell markers, and determination of viral activity, diagnostic accuracy and patient prognosis will continue to improve in the future. In this review, we summarize the current knowledge on the pathogenesis and diagnosis of myocarditis and inflammatory cardiomyopathies and highlight future perspectives for more in-depth and specialized biopsy diagnostics and precision, personalized medicine approaches.
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Affiliation(s)
- Christian Baumeier
- Institute of Cardiac Diagnostics and Therapy, IKDT GmbH, 12203 Berlin, Germany; (D.H.); (G.A.); (U.G.); (H.-P.S.)
| | - Dominik Harms
- Institute of Cardiac Diagnostics and Therapy, IKDT GmbH, 12203 Berlin, Germany; (D.H.); (G.A.); (U.G.); (H.-P.S.)
- Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany
| | - Ganna Aleshcheva
- Institute of Cardiac Diagnostics and Therapy, IKDT GmbH, 12203 Berlin, Germany; (D.H.); (G.A.); (U.G.); (H.-P.S.)
| | - Ulrich Gross
- Institute of Cardiac Diagnostics and Therapy, IKDT GmbH, 12203 Berlin, Germany; (D.H.); (G.A.); (U.G.); (H.-P.S.)
| | - Felicitas Escher
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Virchow Klinikum, 13353 Berlin, Germany;
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany
| | - Heinz-Peter Schultheiss
- Institute of Cardiac Diagnostics and Therapy, IKDT GmbH, 12203 Berlin, Germany; (D.H.); (G.A.); (U.G.); (H.-P.S.)
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19
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Zhu Y, Tan JK, Wong SK, Goon JA. Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:ijms24119168. [PMID: 37298120 DOI: 10.3390/ijms24119168] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/12/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.
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Affiliation(s)
- Yuezhi Zhu
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Sok Kuan Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jo Aan Goon
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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20
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Arman K, Dalloul Z, Bozgeyik E. Emerging role of microRNAs and long non-coding RNAs in COVID-19 with implications to therapeutics. Gene 2023; 861:147232. [PMID: 36736508 PMCID: PMC9892334 DOI: 10.1016/j.gene.2023.147232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which is commonly known as COVID-19 (COronaVIrus Disease 2019) has creeped into the human population taking tolls of life and causing tremendous economic crisis. It is indeed crucial to gain knowledge about their characteristics and interactions with human host cells. It has been shown that the majority of our genome consists of non-coding RNAs. Non-coding RNAs including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs) display significant roles in regulating gene expression in almost all cancers and viral diseases. It is intriguing that miRNAs and lncRNAs remarkably regulate the function and expression of major immune components of SARS-CoV-2. MiRNAs act via RNA interference mechanism in which they bind to the complementary sequences of the viral RNA strand, inducing the formation of silencing complex that eventually degrades or inhibits the viral RNA and viral protein expression. LncRNAs have been extensively shown to regulate gene expression in cytokine storm and thus emerges as a critical target for COVID-19 treatment. These lncRNAs also act as competing endogenous RNAs (ceRNAs) by sponging miRNAs and thus affecting the expression of downstream targets during SARS-CoV-2 infection. In this review, we extensively discuss the role of miRNAs and lncRNAs, describe their mechanism of action and their different interacting human targets cells during SARS-CoV-2 infection. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new therapies against SARS-CoV-2.
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Affiliation(s)
- Kaifee Arman
- Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
| | - Zeinab Dalloul
- Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada
| | - Esra Bozgeyik
- Department of Medical Services and Techniques, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey
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21
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Behnia M, Bradfute SB. The Host Non-Coding RNA Response to Alphavirus Infection. Viruses 2023; 15:v15020562. [PMID: 36851776 PMCID: PMC9967650 DOI: 10.3390/v15020562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
Alphaviruses are important human and animal pathogens that can cause a range of debilitating symptoms and are found worldwide. These include arthralgic diseases caused by Old-World viruses and encephalitis induced by infection with New-World alphaviruses. Non-coding RNAs do not encode for proteins, but can modulate cellular response pathways in a myriad of ways. There are several classes of non-coding RNAs, some more well-studied than others. Much research has focused on the mRNA response to infection against alphaviruses, but analysis of non-coding RNA responses has been more limited until recently. This review covers what is known regarding host cell non-coding RNA responses in alphavirus infections and highlights gaps in the knowledge that future research should address.
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22
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Putting the "mi" in omics: discovering miRNA biomarkers for pediatric precision care. Pediatr Res 2023; 93:316-323. [PMID: 35906312 PMCID: PMC9884316 DOI: 10.1038/s41390-022-02206-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/27/2022] [Indexed: 01/31/2023]
Abstract
In the past decade, growing interest in micro-ribonucleic acids (miRNAs) has catapulted these small, non-coding nucleic acids to the forefront of biomarker research. Advances in scientific knowledge have made it clear that miRNAs play a vital role in regulating cellular physiology throughout the human body. Perturbations in miRNA signaling have also been described in a variety of pediatric conditions-from cancer, to renal failure, to traumatic brain injury. Likewise, the number of studies across pediatric disciplines that pair patient miRNA-omics with longitudinal clinical data are growing. Analyses of these voluminous, multivariate data sets require understanding of pediatric phenotypic data, data science, and genomics. Use of machine learning techniques to aid in biomarker detection have helped decipher background noise from biologically meaningful changes in the data. Further, emerging research suggests that miRNAs may have potential as therapeutic targets for pediatric precision care. Here, we review current miRNA biomarkers of pediatric diseases and studies that have combined machine learning techniques, miRNA-omics, and patient health data to identify novel biomarkers and potential therapeutics for pediatric diseases. IMPACT: In the following review article, we summarized how recent developments in microRNA research may be coupled with machine learning techniques to advance pediatric precision care.
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23
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Gjorgjieva M, Ay AS, Correia de Sousa M, Delangre E, Dolicka D, Sobolewski C, Maeder C, Fournier M, Sempoux C, Foti M. MiR-22 Deficiency Fosters Hepatocellular Carcinoma Development in Fatty Liver. Cells 2022; 11:cells11182860. [PMID: 36139435 PMCID: PMC9496902 DOI: 10.3390/cells11182860] [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: 08/03/2022] [Revised: 09/02/2022] [Accepted: 09/09/2022] [Indexed: 12/24/2022] Open
Abstract
MiR-22 is mostly considered as a hepatic tumor-suppressor microRNA based on in vitro analyses. Yet, whether miR-22 exerts a tumor-suppressive function in the liver has not been investigated in vivo. Herein, in silico analyses of miR-22 expression were performed in hepatocellular carcinomas from human patient cohorts and different mouse models. Diethylnitrosamine-induced hepatocellular carcinomas were then investigated in lean and diet-induced obese miR-22-deficient mice. The proteome of liver tissues from miR-22-deficient mice prior to hepatocellular carcinoma development was further analyzed to uncover miR-22 regulated factors that impact hepatocarcinogenesis with miR-22 deficiency. MiR-22 downregulation was consistently observed in hepatocellular carcinomas from all human cohorts and mouse models investigated. The time of appearance of the first tumors was decreased and the number of tumoral foci induced by diethylnitrosamine was significantly increased by miR-22-deficiency in vivo, two features which were further drastically exacerbated with diet-induced obesity. At the molecular level, we provide evidence that the loss of miR-22 significantly affects the energetic metabolism and mitochondrial functions of hepatocytes, and the expression of tumor-promoting factors such as thrombospondin-1. Our study demonstrates that miR-22 acts as a hepatic tumor suppressor in vivo by restraining pro-carcinogenic metabolic deregulations through pleiotropic mechanisms and the overexpression of relevant oncogenes.
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Affiliation(s)
- Monika Gjorgjieva
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Anne-Sophie Ay
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Marta Correia de Sousa
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Etienne Delangre
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Dobrochna Dolicka
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
- Translational Research Centre in Onco-Haematology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
- Correspondence:
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24
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Scholz J, Weil PP, Pembaur D, Koukou G, Aydin M, Hauert D, Postberg J, Kreppel F, Hagedorn C. An Adenoviral Vector as a Versatile Tool for Delivery and Expression of miRNAs. Viruses 2022; 14:1952. [PMID: 36146759 PMCID: PMC9504453 DOI: 10.3390/v14091952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Only two decades after discovering miRNAs, our understanding of the functional effects of deregulated miRNAs in the development of diseases, particularly cancer, has been rapidly evolving. These observations and functional studies provide the basis for developing miRNA-based diagnostic markers or new therapeutic strategies. Adenoviral (Ad) vectors belong to the most frequently used vector types in gene therapy and are suitable for strong short-term transgene expression in a variety of cells. Here, we report the set-up and functionality of an Ad-based miRNA vector platform that can be employed to deliver and express a high level of miRNAs efficiently. This vector platform allows fast and efficient vector production to high titers and the expression of pri-miRNA precursors under the control of a polymerase II promoter. In contrast to non-viral miRNA delivery systems, this Ad-based miRNA vector platform allows accurate dosing of the delivered miRNAs. Using a two-vector model, we showed that Ad-driven miRNA expression was sufficient in down-regulating the expression of an overexpressed and highly stable protein. Additional data corroborated the downregulation of multiple endogenous target RNAs using the system presented here. Additionally, we report some unanticipated synergistic effects on the transduction efficiencies in vitro when cells were consecutively transduced with two different Ad-vectors. This effect might be taken into consideration for protocols using two or more different Ad vectors simultaneously.
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Affiliation(s)
- Jonas Scholz
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Patrick Philipp Weil
- Centre for Biomedical Education & Research (ZBAF), Clinical Molecular Genetics and Epigenetics, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448 Witten, Germany
| | - Daniel Pembaur
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Georgia Koukou
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Malik Aydin
- Laboratory of Experimental Pediatric Pneumology and Allergology, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58448 Witten, Germany
| | - Dorota Hauert
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Jan Postberg
- Centre for Biomedical Education & Research (ZBAF), Clinical Molecular Genetics and Epigenetics, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448 Witten, Germany
| | - Florian Kreppel
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Claudia Hagedorn
- Chair for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
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25
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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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26
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He Q, Guo P, Bo Z, Yu H, Yang J, Wang Y, Chen G. Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma. Cancer Cell Int 2022; 22:249. [PMID: 35945536 PMCID: PMC9361533 DOI: 10.1186/s12935-022-02643-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/27/2022] [Indexed: 11/10/2022] Open
Abstract
Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.
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Affiliation(s)
- Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315199, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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27
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Saengchoowong S, Nimsamer P, Khongnomnan K, Poomipak W, Praianantathavorn K, Rattanaburi S, Poovorawan Y, Zhang Q, Payungporn S. Enhancing the yield of seasonal influenza viruses through manipulation of microRNAs in Madin-Darby canine kidney cells. Exp Biol Med (Maywood) 2022; 247:1335-1349. [PMID: 35666095 PMCID: PMC9442458 DOI: 10.1177/15353702221098340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Annual influenza vaccine is recommended to reduce the occurrence of seasonal influenza and its complications. Thus far, Madin-Darby canine kidney (MDCK) cell line has been used to manufacture cell-based influenza vaccines. Even though host microRNAs may facilitate viral replication, the interaction between MDCK cells-derived microRNAs and seasonal influenza viruses has been less frequently investigated. Therefore, this study highlighted microRNA profiles of MDCK cells to increase the yield of seasonal influenza virus production by manipulating cellular microRNAs. MDCK cells were infected with influenza A or B virus at a multiplicity of infection (MOI) of 0.01, and microRNA collections were then subjected to MiSeq (Illumina) Sequencing. The validated profiles revealed that cfa-miR-340, cfa-miR-146b, cfa-miR-197, and cfa-miR-215 were the most frequently upregulated microRNAs. The effect of candidate microRNA inhibition and overexpression on viral replication was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). The hybridization pattern between candidate miRNAs and viral genes was performed using miRBase and RNAhybrid web-based programs. Moreover, the predicted microRNA-binding sites were validated by a 3'-UTR reporter assay. The results indicated that cfa-miR-146b could directly target the PB1 gene of A/pH1N1 and the PA gene of B/Yamagata. Furthermore, cfa-miR-215 could silence the PB1 gene of A/pH1N1 and the PB1 gene of B/Victoria. However, the PB2 gene of the A/H3N2 virus was silenced by cfa-miR-197. In addition, the HA and NA sequences of influenza viruses harvested from the cell cultures treated with microRNA inhibitors were analyzed. The sequencing results revealed no difference in the antigenic HA and NA sequences between viruses isolated from the cells treated with microRNA inhibitors and the parental viruses. In conclusion, these findings suggested that MDCK cell-derived microRNAs target viral genes in a strain-specific manner for suppressing viral replication. Conversely, the use of such microRNA inhibitors may facilitate the production of influenza viruses.
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Affiliation(s)
- Suthat Saengchoowong
- Joint Chulalongkorn
University-University of Liverpool Doctoral Program in Biomedical Sciences and
Biotechnology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330,
Thailand,Faculty of Veterinary Medicine and
Applied Zoology, HRH Princess Chulabhorn College of Medical Science, Chulabhorn
Royal Academy, Bangkok 10210, Thailand
| | - Pattaraporn Nimsamer
- Research Unit of Systems Microbiology,
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, Thailand
| | - Kritsada Khongnomnan
- Research Unit of Systems Microbiology,
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, Thailand
| | - Witthaya Poomipak
- Research Affairs, Faculty of Medicine,
Chulalongkorn University, Bangkok 10330, Thailand
| | - Kesmanee Praianantathavorn
- Research Unit of Systems Microbiology,
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, Thailand
| | - Somruthai Rattanaburi
- Research Unit of Systems Microbiology,
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical
Virology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330,
Thailand
| | - Qibo Zhang
- Department of Clinical Infection,
Microbiology and Immunology, Institute of Infection, Veterinary and Ecological
Sciences, University of Liverpool, Liverpool L69 7BE, UK
| | - Sunchai Payungporn
- Research Unit of Systems Microbiology,
Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, Thailand,Sunchai Payungporn.
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28
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Abstract
The discovery of microRNAs and their role in diseases was a breakthrough that inspired research into microRNAs as drug targets. Cardiovascular diseases are an area in which limitations of conventional pharmacotherapy are highly apparent and where microRNA-based drugs have appreciably progressed into preclinical and clinical testing. In this Review, we summarize the current state of microRNAs as therapeutic targets in the cardiovascular system. We report recent advances in the identification and characterization of microRNAs, their manipulation and clinical translation, and discuss challenges and perspectives toward clinical application.
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Affiliation(s)
- Bernhard Laggerbauer
- Institute of Pharmacology and Toxicology, Technical University of Munich (TUM), Munich, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technical University of Munich (TUM), Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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29
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Zeng Q, Qi X, Ma J, Hu F, Wang X, Qin H, Li M, Huang S, Yang Y, Li Y, Bai H, Jiang M, Ren D, Kang Y, Zhao Y, Chen X, Ding X, Ye D, Wang Y, Jiang J, Li D, Chen X, Hu K, Zhang B, Shi B, Zhang C. Distinct miRNAs associated with various clinical presentations of SARS-CoV-2 infection. iScience 2022; 25:104309. [PMID: 35502319 PMCID: PMC9044631 DOI: 10.1016/j.isci.2022.104309] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/04/2022] [Accepted: 04/22/2022] [Indexed: 01/08/2023] Open
Abstract
MicroRNAs (miRNAs) have been shown to play important roles in viral infections, but their associations with SARS-CoV-2 infection remain poorly understood. Here, we detected 85 differentially expressed miRNAs (DE-miRNAs) from 2,336 known and 361 novel miRNAs that were identified in 233 plasma samples from 61 healthy controls and 116 patients with COVID-19 using the high-throughput sequencing and computational analysis. These DE-miRNAs were associated with SASR-CoV-2 infection, disease severity, and viral persistence in the patients with COVID-19, respectively. Gene ontology and KEGG pathway analyses of the DE-miRNAs revealed their connections to viral infections, immune responses, and lung diseases. Finally, we established a machine learning model using the DE-miRNAs between various groups for classification of COVID-19 cases with different clinical presentations. Our findings may help understand the contribution of miRNAs to the pathogenesis of COVID-19 and identify potential biomarkers and molecular targets for diagnosis and treatment of SARS-CoV-2 infection.
2,336 known and 361 novel miRNAs identified in this study 85 miRNAs associated with COVID-19 A panel of miRNAs targeting the viral or cellular genes Machine learning using miRNAs for classification of COVID-19
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Affiliation(s)
- Qiqi Zeng
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Xin Qi
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Junpeng Ma
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Fang Hu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Xiaorui Wang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Hongyu Qin
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Mengyang Li
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Shaoxin Huang
- SpecAlly Life Technology Co, Ltd, Wuhan East Lake High-tech Development Zone, 666 Gaoxin Road, Wuhan 430075, China
| | - Yong Yang
- SpecAlly Life Technology Co, Ltd, Wuhan East Lake High-tech Development Zone, 666 Gaoxin Road, Wuhan 430075, China
| | - Yixin Li
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Han Bai
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Meng Jiang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Doudou Ren
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Ye Kang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China
| | - Yang Zhao
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, China
| | - Xiaobei Chen
- Department of Infectious Diseases, The Renmin Hospital of Wuhan University, East Campus, East Lake New Technology Development Zone, Gaoxin 6th Road, Wuhan 430040, China
| | - Xi Ding
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China
| | - Di Ye
- Department of Rehabilitation, The Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan 430060, China
| | - Yankui Wang
- Dialysis Center, The Renmin Hospital of Wuhan University, East Campus, East Lake New Technology Development Zone, Gaoxin 6th Road, Wuhan 430040, China
| | - Jianguo Jiang
- LC-Bio Technologies (Hangzhou) Co., Ltd., Hanghzhou 310000, China
| | - Dong Li
- Department of Clinical Laboratory, The Renmin Hospital of Wuhan University, East Campus, East Lake New Technology Development Zone, Gaoxin 6th Road, Wuhan 430040, China
| | - Xi Chen
- SpecAlly Life Technology Co, Ltd, Wuhan East Lake High-tech Development Zone, 666 Gaoxin Road, Wuhan 430075, China.,Wuhan Institute of Biotechnology, Wuhan East Lake High-tech Development Zone, 666 Gaoxin Road, Wuhan 430040, China
| | - Ke Hu
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, China
| | - Binghong Zhang
- The Renmin Hospital of Wuhan University, East Campus, East Lake New Technology Development Zone, Gaoxin 6th Road, Wuhan 430040, China
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China
| | - Chengsheng Zhang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Western China Science and Technology Innovation Harbor, Building 21, Xi'an 710000, China.,Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China.,The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
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30
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The emerging role of bacterial regulatory RNAs in disease. Trends Microbiol 2022; 30:959-972. [DOI: 10.1016/j.tim.2022.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 03/02/2022] [Accepted: 03/09/2022] [Indexed: 02/02/2023]
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31
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Sun R, Zhang PP, Weng XQ, Gao XD, Huang CX, Wang L, Hu XX, Xu PP, Cheng L, Jiang L, Fu D, Qu B, Zhao Y, Feng Y, Dou HJ, Zheng Z, Zhao WL. Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells. Signal Transduct Target Ther 2022; 7:80. [PMID: 35301282 PMCID: PMC8931122 DOI: 10.1038/s41392-022-00895-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 01/06/2022] [Accepted: 01/18/2022] [Indexed: 11/09/2022] Open
Abstract
MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.
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Affiliation(s)
- Rui Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Pei-Pei Zhang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang-Qin Weng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Xiao-Dong Gao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Chuan-Xin Huang
- Department of Immunobiology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Xiao-Xia Hu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Peng-Peng Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Lin Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Lu Jiang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Di Fu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Bin Qu
- Department of Laboratory Medicine, Shanghai RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
| | - Yan Feng
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Hong-Jing Dou
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University, Shanghai, China.
| | - Zhong Zheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.
| | - Wei-Li Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.
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32
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Liu X, Wen YZ, Huang ZL, Shen X, Wang JH, Luo YH, Chen WX, Lun ZR, Li HB, Qu LH, Shan H, Zheng LL. SARS-CoV-2 causes a significant stress response mediated by small RNAs in the blood of COVID-19 patients. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:751-762. [PMID: 35003892 PMCID: PMC8719421 DOI: 10.1016/j.omtn.2021.12.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 12/29/2021] [Indexed: 12/24/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a serious impact on the world. In this study, small RNAs from the blood of COVID-19 patients with moderate or severe symptoms were extracted for high-throughput sequencing and analysis. Interestingly, the levels of a special group of tRNA-derived small RNAs (tsRNAs) were found to be dramatically upregulated after SARS-CoV-2 infection, particularly in coronavirus disease 2019 (COVID-19) patients with severe symptoms. In particular, the 3′CCA tsRNAs from tRNA-Gly were highly consistent with the inflammation indicator C-reactive protein (CRP). In addition, we found that the majority of significantly changed microRNAs (miRNAs) were associated with endoplasmic reticulum (ER)/unfolded protein response (UPR) sensors, which may lead to the induction of proinflammatory cytokine and immune responses. This study found that SARS-CoV-2 infection caused significant changes in the levels of stress-associated small RNAs in patient blood and their potential functions. Our research revealed that the cells of COVID-19 patients undergo tremendous stress and respond, which can be reflected or regulated by small non-coding RNA (sncRNAs), thus providing potential thought for therapeutic intervention in COVID-19 by modulating small RNA levels or activities.
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Affiliation(s)
- Xi Liu
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, P. R. China
| | - Yan-Zi Wen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Zi-Liang Huang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Xia Shen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China.,Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511458, P. R. China.,Center for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh EH8 9AG, UK
| | - Jun-Hao Wang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Yi-Hai Luo
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Wen-Xin Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Zhao-Rong Lun
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Hui-Bin Li
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Liang-Hu Qu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
| | - Hong Shan
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, P. R. China.,Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, P. R. China.,Department of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, P. R. China
| | - Ling-Ling Zheng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China
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Panigrahi M, Thibault PA, Wilson JA. MicroRNA 122 Affects both the Initiation and the Maintenance of Hepatitis C Virus Infections. J Virol 2022; 96:e0190321. [PMID: 34908444 PMCID: PMC8865533 DOI: 10.1128/jvi.01903-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/08/2021] [Indexed: 11/20/2022] Open
Abstract
A liver-specific microRNA, miR-122, anneals to the hepatitis C virus (HCV) genomic 5' terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full-length RNAs with specific mutations in the 5' untranslated region (UTR) can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having encephalomyocarditis virus internal ribosomal entry site (EMCV IRES)-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by the amount of viral RNA delivered. HCV RNAs replicating independently of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of an miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication, suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection and also supports new replication complex formation during ongoing infection and after infected cell division. IMPORTANCE The mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as a potential HCV therapy.
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Affiliation(s)
- Mamata Panigrahi
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Patricia A. Thibault
- Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Joyce A. Wilson
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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34
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Gaddam RR, Dhuri K, Kim YR, Jacobs JS, Kumar V, Li Q, Irani K, Bahal R, Vikram A. γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet. J Med Chem 2022; 65:3332-3342. [PMID: 35133835 PMCID: PMC8883473 DOI: 10.1021/acs.jmedchem.1c01831] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
![]()
The blood levels
of microRNA-122 (miR-122) is associated with the
severity of cardiovascular disorders, and targeting it with efficient
and safer miR inhibitors could be a promising approach. Here, we report
the generation of a γ-peptide nucleic acid (γPNA)-based
miR-122 inhibitor (γP-122-I) that rescues vascular endothelial
dysfunction in mice fed a high-fat diet. We synthesized diethylene
glycol-containing γP-122-I and found that its systemic administration
counteracted high-fat diet (HFD)-feeding-associated increase in blood
and aortic miR-122 levels, impaired endothelial function, and reduced
glycemic control. A comprehensive safety analysis established that
γP-122-I affects neither the complete blood count nor biochemical
tests of liver and kidney functions during acute exposure. In addition,
long-term exposure to γP-122-I did not change the overall adiposity,
or histology of the kidney, liver, and heart. Thus, γP-122-I
rescues endothelial dysfunction without any evidence of toxicity in vivo and demonstrates the suitability of γPNA technology
in generating efficient and safer miR inhibitors.
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Affiliation(s)
- Ravinder Reddy Gaddam
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
| | - Karishma Dhuri
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Young-Rae Kim
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
| | - Julia S Jacobs
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
| | - Vikas Kumar
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Qiuxia Li
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
| | - Kaikobad Irani
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Ajit Vikram
- Department of Internal Medicine, Carver College of Medicine University of Iowa, Iowa City, Iowa 52242, United States
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35
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Kornmueller K, Amri EZ, Scheideler M, Prassl R. Delivery of miRNAs to the adipose organ for metabolic health. Adv Drug Deliv Rev 2022; 181:114110. [PMID: 34995679 DOI: 10.1016/j.addr.2021.114110] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 12/14/2021] [Accepted: 12/30/2021] [Indexed: 11/16/2022]
Abstract
Despite the increasing prevalence of obesity and diabetes, there is no efficient treatment to combat these epidemics. The adipose organ is the main site for energy storage and plays a pivotal role in whole body lipid metabolism and energy homeostasis, including remodeling and dysfunction of adipocytes and adipose tissues in obesity and diabetes. Thus, restoring and balancing metabolic functions in the adipose organ is in demand. MiRNAs represent a novel class of drugs and drug targets, as they are heavily involved in the regulation of many cellular and metabolic processes and diseases, likewise in adipocytes. In this review, we summarize key regulatory activities of miRNAs in the adipose organ, discuss various miRNA replacement and inhibition strategies, promising delivery systems for miRNAs and reflect the future of novel miRNA-based therapeutics to target adipose tissues with the ultimate goal to combat metabolic disorders.
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Affiliation(s)
- Karin Kornmueller
- Department of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | | | - Marcel Scheideler
- Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Ruth Prassl
- Department of Biophysics, Gottfried Schatz Research Center, Medical University of Graz, Austria.
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36
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Huang PS, Liao CJ, Huang YH, Yeh CT, Chen CY, Tang HC, Chang CC, Lin KH. Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer. Cancers (Basel) 2021; 13:5361. [PMID: 34771525 PMCID: PMC8582514 DOI: 10.3390/cancers13215361] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 11/27/2022] Open
Abstract
Liver cancer is the leading cause of cancer-related mortality in the world. This mainly reflects the lack of early diagnosis tools and effective treatment methods. MicroRNAs (miRNAs) are a class of non-transcribed RNAs, some of which play important regulatory roles in liver cancer. Here, we discuss microRNAs with key impacts on liver cancer, such as miR-122, miR-21, miR-214, and miR-199. These microRNAs participate in various physiological regulatory pathways of liver cancer cells, and their modulation can have non-negligible effects in the treatment of liver cancer. We discuss whether these microRNAs can be used for better clinical diagnosis and/or drug development. With the advent of novel technologies, fast, inexpensive, and non-invasive RNA-based biomarker research has become a new mainstream approach. However, the clinical application of microRNA-based markers has been limited by the high sequence similarity among them and the potential for off-target problems. Therefore, researchers particularly value microRNAs that are specific to or have special functions in liver cancer. These include miR-122, which is specifically expressed in the liver, and miR-34, which is necessary for the replication of the hepatitis C virus in liver cancer. Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (P.-S.H.); (C.-J.L.)
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Chia-Jung Liao
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (P.-S.H.); (C.-J.L.)
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-H.H.); (C.-T.Y.)
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-H.H.); (C.-T.Y.)
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
| | - Hui-Chi Tang
- Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Cheng-Chih Chang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia-yi, Chia-yi 613, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (P.-S.H.); (C.-J.L.)
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-H.H.); (C.-T.Y.)
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
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37
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Pandey M, Ojha D, Bansal S, Rode AB, Chawla G. From bench side to clinic: Potential and challenges of RNA vaccines and therapeutics in infectious diseases. Mol Aspects Med 2021; 81:101003. [PMID: 34332771 DOI: 10.1016/j.mam.2021.101003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/27/2021] [Accepted: 07/16/2021] [Indexed: 12/14/2022]
Abstract
The functional and structural versatility of Ribonucleic acids (RNAs) makes them ideal candidates for overcoming the limitations imposed by small molecule-based drugs. Hence, RNA-based biopharmaceuticals such as messenger RNA (mRNA) vaccines, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNA mimics, anti-miRNA oligonucleotides (AMOs), aptamers, riboswitches, and CRISPR-Cas9 are emerging as vital tools for the treatment and prophylaxis of many infectious diseases. Some of the major challenges to overcome in the area of RNA-based therapeutics have been the instability of single-stranded RNAs, delivery to the diseased cell, and immunogenicity. However, recent advancements in the delivery systems of in vitro transcribed mRNA and chemical modifications for protection against nucleases and reducing the toxicity of RNA have facilitated the entry of several exogenous RNAs into clinical trials. In this review, we provide an overview of RNA-based vaccines and therapeutics, their production, delivery, current advancements, and future translational potential in treating infectious diseases.
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Affiliation(s)
- Manish Pandey
- RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Divya Ojha
- Laboratory of Synthetic Biology, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Sakshi Bansal
- RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Ambadas B Rode
- Laboratory of Synthetic Biology, Regional Centre for Biotechnology, Faridabad, 121001, India.
| | - Geetanjali Chawla
- RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, 121001, India.
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38
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Pietropaolo V, Prezioso C, Moens U. Role of Virus-Induced Host Cell Epigenetic Changes in Cancer. Int J Mol Sci 2021; 22:ijms22158346. [PMID: 34361112 PMCID: PMC8346956 DOI: 10.3390/ijms22158346] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- Correspondence: (V.P.); (U.M.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-Degenerative Pathologies, 00161 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
- Correspondence: (V.P.); (U.M.)
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39
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Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov 2021; 20:629-651. [PMID: 34145432 PMCID: PMC8212082 DOI: 10.1038/s41573-021-00219-z] [Citation(s) in RCA: 942] [Impact Index Per Article: 235.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.
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Affiliation(s)
- Melanie Winkle
- Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research Division - Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences - National Research Centre, Cairo, Egypt
| | - Muller Fabbri
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - George A Calin
- Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA.
- The RNA Interference and Non-codingRNA Center, MD Anderson Cancer Center, Texas State University, Houston, TX, USA.
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40
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Douvris A, Burger D, Rodriguez RA, Clark EG, Viñas J, Lalu MM, Shorr R, Burns KD. MicroRNA in Human Acute Kidney Injury: A Systematic Review Protocol. Can J Kidney Health Dis 2021; 8:20543581211009999. [PMID: 33996109 PMCID: PMC8072838 DOI: 10.1177/20543581211009999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/12/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a common complication of hospitalization with high morbidity and mortality for which no effective treatments exist and for which current diagnostic tools have limitations for earlier identification. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in the pathogenesis of AKI, and some miRNAs have shown promise as therapeutic tools in animal models of AKI. However, less is known about the role of miRNAs in human AKI. OBJECTIVE To evaluate the role of miRNAs in human subjects with AKI. DESIGN Systematic review and meta-analysis. MEASUREMENTS Quantification of miRNA levels from human blood, urine, or kidney biopsy samples, and measures of renal function as defined in the study protocol. METHODS A comprehensive search strategy for Ovid MEDLINE All, Embase, Web of Science, and CENTRAL will be developed to identify investigational studies that evaluated the relationship between miRNA levels and human AKI. Primary outcomes will include measurements of kidney function and miRNA levels. Study screening, review and data extraction will be performed independently by 2 reviewers. Study quality and certainty of evidence will be assessed with validated tools. A narrative synthesis will be included and the possibility for meta-analysis will be assessed according to characteristics of clinical and statistical heterogeneity between studies. LIMITATIONS These include (1) lack of randomized trials of miRNAs for the prevention or treatment of human AKI, (2) quality of included studies, and (3) sources of clinical and statistical heterogeneity that may affect strength and reproducibility of results. CONCLUSION Previous studies of miRNAs in different animal models of AKI have generated strong interest on their use for the prevention and treatment of human AKI. This systematic review will characterize the most promising miRNAs for human research and will identify methodological constraints from miRNA research in human AKI to help inform the design of future studies. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020201253.
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Affiliation(s)
- Adrianna Douvris
- Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada
| | - Dylan Burger
- Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada
| | - Rosendo A. Rodriguez
- Department of Medicine, The University of Ottawa and The Ottawa Hospital, ON, Canada
| | - Edward G. Clark
- Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada
| | - Jose Viñas
- Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada
| | - Manoj M. Lalu
- Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada
- Department of Anesthesiology and Pain Medicine, Clinical Epidemiology and Regenerative Medicine Programs, Blueprint Translational Research Group, The Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, Canada
| | - Risa Shorr
- Department of Medicine, The University of Ottawa and The Ottawa Hospital, ON, Canada
| | - Kevin D. Burns
- Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada
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41
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Romano G, Acunzo M, Nana-Sinkam P. microRNAs as Novel Therapeutics in Cancer. Cancers (Basel) 2021; 13:1526. [PMID: 33810332 PMCID: PMC8037786 DOI: 10.3390/cancers13071526] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead.
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Affiliation(s)
| | | | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (G.R.); (M.A.)
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42
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Crooke ST, Liang XH, Baker BF, Crooke RM. Antisense technology: A review. J Biol Chem 2021; 296:100416. [PMID: 33600796 PMCID: PMC8005817 DOI: 10.1016/j.jbc.2021.100416] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/15/2022] Open
Abstract
Antisense technology is beginning to deliver on the broad promise of the technology. Ten RNA-targeted drugs including eight single-strand antisense drugs (ASOs) and two double-strand ASOs (siRNAs) have now been approved for commercial use, and the ASOs in phase 2/3 trials are innovative, delivered by multiple routes of administration and focused on both rare and common diseases. In fact, two ASOs are used in cardiovascular outcome studies and several others in very large trials. Interest in the technology continues to grow, and the field has been subject to a significant number of reviews. In this review, we focus on the molecular events that result in the effects observed and use recent clinical results involving several different ASOs to exemplify specific molecular mechanisms and specific issues. We conclude with the prospective on the technology.
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Affiliation(s)
- Stanley T Crooke
- Core Antisense Research, Ionis Pharmaceuticals, Inc, Carlsbad, California, USA.
| | - Xue-Hai Liang
- Core Antisense Research, Ionis Pharmaceuticals, Inc, Carlsbad, California, USA
| | - Brenda F Baker
- Development Communication, Ionis Pharmaceuticals, Inc, Carlsbad, California, USA
| | - Rosanne M Crooke
- Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, California, USA
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Widiasta A, Sribudiani Y, Nugrahapraja H, Hilmanto D, Sekarwana N, Rachmadi D. Potential role of ACE2-related microRNAs in COVID-19-associated nephropathy. Noncoding RNA Res 2020; 5:153-166. [PMID: 32923747 PMCID: PMC7480227 DOI: 10.1016/j.ncrna.2020.09.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 01/08/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease (COVID-19), potentially have severe kidney adverse effects. This organ expressed angiotensin-converting enzyme 2 (ACE2), the transmembrane protein which facilitate the entering of the virus into the cell. Therefore, early detection of the kidney manifestations of COVID-19 is crucial. Previous studies showed ACE2 role in various indications of this disease, especially in kidney effects. The MicroRNAs (miRNAs) in this organ affected ACE2 expression. Therefore, this review aims at summarizing the literature of a novel miRNA-based therapy and its potential applications in COVID-19-associated nephropathy. Furthermore, previous studies were analyzed for the kidney manifestations of COVID-19 and the miRNAs role that were published on the online databases, namely MEDLINE (PubMed) and Scopus. Several miRNAs, particularly miR-18 (which was upregulated in nephropathy), played a crucial role in ACE2 expression. Therefore, the antimiR-18 roles were summarized in various primate models that aided in developing the therapy for ACE2 related diseases.
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Affiliation(s)
- Ahmedz Widiasta
- Pediatric Nephrology Division, Child Health Department, Faculty of Medicine, Universitas Padjadjaran, Indonesia
- Medical Genetic Research Center, Faculty of Medicine, Universitas Padjadjaran, Indonesia
| | - Yunia Sribudiani
- Medical Genetic Research Center, Faculty of Medicine, Universitas Padjadjaran, Indonesia
- Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Indonesia
| | - Husna Nugrahapraja
- Life Science and Biotechnology, Bandung Institute of Technology, Indonesia
| | - Dany Hilmanto
- Pediatric Nephrology Division, Child Health Department, Faculty of Medicine, Universitas Padjadjaran, Indonesia
| | - Nanan Sekarwana
- Pediatric Nephrology Division, Child Health Department, Faculty of Medicine, Universitas Padjadjaran, Indonesia
| | - Dedi Rachmadi
- Pediatric Nephrology Division, Child Health Department, Faculty of Medicine, Universitas Padjadjaran, Indonesia
- Medical Genetic Research Center, Faculty of Medicine, Universitas Padjadjaran, Indonesia
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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis. Viruses 2020; 12:v12121364. [PMID: 33260407 PMCID: PMC7761224 DOI: 10.3390/v12121364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin's lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.
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Elbadawy HM, Mohammed Abdul MI, Aljuhani N, Vitiello A, Ciccarese F, Shaker MA, Eltahir HM, Palù G, Di Antonio V, Ghassabian H, Del Vecchio C, Salata C, Franchin E, Ponterio E, Bahashwan S, Thabet K, Abouzied MM, Shehata AM, Parolin C, Calistri A, Alvisi G. Generation of Combinatorial Lentiviral Vectors Expressing Multiple Anti-Hepatitis C Virus shRNAs and Their Validation on a Novel HCV Replicon Double Reporter Cell Line. Viruses 2020; 12:v12091044. [PMID: 32962117 PMCID: PMC7551853 DOI: 10.3390/v12091044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Despite the introduction of directly acting antivirals (DAAs), for the treatment of hepatitis C virus (HCV) infection, their cost, patient compliance, and viral resistance are still important issues to be considered. Here, we describe the generation of a novel JFH1-based HCV subgenomic replicon double reporter cell line suitable for testing different antiviral drugs and therapeutic interventions. This cells line allowed a rapid and accurate quantification of cell growth/viability and HCV RNA replication, thus discriminating specific from unspecific antiviral effects caused by DAAs or cytotoxic compounds, respectively. By correlating cell number and virus replication, we could confirm the inhibitory effect on the latter of cell over confluency and characterize an array of lentiviral vectors expressing single, double, or triple cassettes containing different combinations of short hairpin (sh)RNAs, targeting both highly conserved viral genome sequences and cellular factors crucial for HCV replication. While all vectors were effective in reducing HCV replication, the ones targeting viral sequences displayed a stronger antiviral effect, without significant cytopathic effects. Such combinatorial platforms as well as the developed double reporter cell line might find application both in setting-up anti-HCV gene therapy approaches and in studies aimed at further dissecting the viral biology/pathogenesis of infection.
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Affiliation(s)
- Hossein M. Elbadawy
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
| | - Mohi I. Mohammed Abdul
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
- Correspondence: (M.I.M.A.); (A.C.); (G.A.)
| | - Naif Aljuhani
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
| | - Adriana Vitiello
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Francesco Ciccarese
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Mohamed A. Shaker
- Pharmaceutics and Pharmaceutical Technology Department, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia;
- Pharmaceutics Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
| | - Heba M. Eltahir
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
| | - Giorgio Palù
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Veronica Di Antonio
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Hanieh Ghassabian
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Claudia Del Vecchio
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Cristiano Salata
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Elisa Franchin
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Eleonora Ponterio
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
- Fondazione Policlinico Universitario "A. Gemelli"—I.R.C.C.S., 00168 Rome, Italy
| | - Saleh Bahashwan
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
| | - Khaled Thabet
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Mekky M. Abouzied
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Ahmed M. Shehata
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 41477, Saudi Arabia; (H.M.E.); (N.A.); (H.M.E.); (S.B.); (M.M.A.); (A.M.S.)
- Department of Pharmacology and toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Cristina Parolin
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
| | - Arianna Calistri
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
- Correspondence: (M.I.M.A.); (A.C.); (G.A.)
| | - Gualtiero Alvisi
- Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; (A.V.); (F.C.); (G.P.); (V.D.A.); (H.G.); (C.D.V.); (C.S.); (E.F.); (E.P.); (C.P.)
- Correspondence: (M.I.M.A.); (A.C.); (G.A.)
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Antisense drug discovery and development technology considered in a pharmacological context. Biochem Pharmacol 2020; 189:114196. [PMID: 32800852 DOI: 10.1016/j.bcp.2020.114196] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023]
Abstract
When coined, the term "antisense" included oligonucleotides of any structure, with any chemical modification and designed to work through any post-RNA hybridization mechanism. However, in practice the term "antisense" has been used to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to RNAswhile the term "siRNA" has come to mean double stranded oligonucleotides designed to activate Ago2. However, the two approaches share many common features. The medicinal chemistry developed for ASOs greatly facilitated the development of siRNA technology and remains the chemical basis for both approaches. Many of challenges faced and solutions achieved share many common features. In fact, because ss ASOs can be designed to activate Ago2, the two approaches intersect at this remarkably important protein. There are also meaningful differences. The pharmacokinetic properties are quite different and thus potential routes of delivery differ. ASOs may be designedto use a variety of post-RNA binding mechanismswhile siRNAs depend solely on the robust activity of Ago2. However, siRNAs and ASOs are both used for therapeutic purposes and both must be and can be understood in a pharmacological context. Thus, the goals of this review are to put ASOs in pharmacological context and compare their behavior as pharmacological agents to the those of siRNAs.
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Gohir W, Klement W, Singer LG, Palmer SM, Mazzulli T, Keshavjee S, Husain S. Identifying host microRNAs in bronchoalveolar lavage samples from lung transplant recipients infected with Aspergillus. J Heart Lung Transplant 2020; 39:1228-1237. [PMID: 32771440 DOI: 10.1016/j.healun.2020.07.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/06/2020] [Accepted: 07/17/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides that play a crucial role in post-transcriptional regulation of gene expression. Dysregulation of miRNA expression has been shown during microbial infections. We sought to identify miRNAs that distinguish invasive aspergillosis (IA) from non-IA in lung transplant recipients (LTRs). METHODS We used NanoString nCounter Human miRNA, version 3, panel to measure miRNAs in bronchoalveolar lavage (BAL) samples from LTRs with Aspergillus colonization (ASP group) (n = 10), those with Aspergillus colonization and chronic lung allograft dysfunction (CLAD) (ASPCLAD group) (n = 7), those with IA without CLAD (IA group) (n = 10), those who developed IA with CLAD (IACLAD group) (n = 9), and control patients (controls) (n = 9). The miRNA profile was compared using the permutation test of 100,000 trials for each of the comparisons. We used mirDIP to obtain their gene targets and pathDIP to determine the pathway enrichment. RESULTS We performed pairwise comparisons between patient groups to identify differentially expressed miRNAs. A total of 5 miRNAs were found to be specific to IA, including 4 (miR-145-5p, miR-424-5p, miR-99b-5p, and miR-4488) that were upregulated and the pair (miR-4454 + miR-7975) that was downregulated in IA group vs controls. The expression change for these miRNAs was specific to patients with IA; they were not significantly differentiated between IACLAD and IA groups. Signaling pathways associated with an immunologic response to IA were found to be significantly enriched. CONCLUSIONS We report a set of 5 differentially expressed miRNAs in the BAL of LTRs with IA that might help in the development of diagnostic and prognostic tools for IA in LTRs. However, further investigation is needed in a larger cohort to validate the findings.
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Affiliation(s)
- Wajiha Gohir
- Transplant Infectious Diseases, Ajmera Family Transplant Centre
| | - William Klement
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Lianne G Singer
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Scott M Palmer
- Division of Pulmonary and Critical Care Medicine, Duke University, Durham, North Carolina; Duke Clinical Research Institute, Duke University, Durham, North Carolina
| | - Tony Mazzulli
- Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Shahid Husain
- Transplant Infectious Diseases, Ajmera Family Transplant Centre.
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Zhou LY, Qin Z, Zhu YH, He ZY, Xu T. Current RNA-based Therapeutics in Clinical Trials. Curr Gene Ther 2020; 19:172-196. [PMID: 31566126 DOI: 10.2174/1566523219666190719100526] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/26/2019] [Accepted: 07/09/2019] [Indexed: 02/08/2023]
Abstract
Long-term research on various types of RNAs has led to further understanding of diverse mechanisms, which eventually resulted in the rapid development of RNA-based therapeutics as powerful tools in clinical disease treatment. Some of the developing RNA drugs obey the antisense mechanisms including antisense oligonucleotides, small interfering RNAs, microRNAs, small activating RNAs, and ribozymes. These types of RNAs could be utilized to inhibit/activate gene expression or change splicing to provide functional proteins. In the meantime, some others based on different mechanisms like modified messenger RNAs could replace the dysfunctional endogenous genes to manage some genetic diseases, and aptamers with special three-dimensional structures could bind to specific targets in a high-affinity manner. In addition, the recent most popular CRISPR-Cas technology, consisting of a crucial single guide RNA, could edit DNA directly to generate therapeutic effects. The desired results from recent clinical trials indicated the great potential of RNA-based drugs in the treatment of various diseases, but further studies on improving delivery materials and RNA modifications are required for the novel RNA-based drugs to translate to the clinic. This review focused on the advances and clinical studies of current RNA-based therapeutics, analyzed their challenges and prospects.
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Affiliation(s)
- Ling-Yan Zhou
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Zhou Qin
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Yang-Hui Zhu
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.,State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Zhi-Yao He
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.,State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Ting Xu
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
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Coordinated AR and microRNA regulation in prostate cancer. Asian J Urol 2020; 7:233-250. [PMID: 32742925 PMCID: PMC7385519 DOI: 10.1016/j.ajur.2020.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 03/22/2020] [Accepted: 04/17/2020] [Indexed: 12/26/2022] Open
Abstract
The androgen receptor (AR) remains a key driver of prostate cancer (PCa) progression, even in the advanced castrate-resistant stage, where testicular androgens are absent. It is therefore of critical importance to understand the molecular mechanisms governing its activity and regulation during prostate tumourigenesis. MicroRNAs (miRs) are small ∼22 nt non-coding RNAs that regulate target gene, often through association with 3′ untranslated regions (3′UTRs) of transcripts. They display dysregulation during cancer progression, can function as oncogenes or tumour suppressors, and are increasingly recognised as targets or regulators of hormonal action. Thus, understanding factors which modulate miRs synthesis is essential. There is increasing evidence for complex and dynamic bi-directional cross-talk between the multi-step miR biogenesis cascade and the AR signalling axis in PCa. This review summarises the wealth of mechanisms by which miRs are regulated by AR, and conversely, how miRs impact AR's transcriptional activity, including that of AR splice variants. In addition, we assess the implications of the convergence of these pathways on the clinical employment of miRs as PCa biomarkers and therapeutic targets.
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50
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Ratti M, Lampis A, Ghidini M, Salati M, Mirchev MB, Valeri N, Hahne JC. MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside. Target Oncol 2020; 15:261-278. [PMID: 32451752 PMCID: PMC7283209 DOI: 10.1007/s11523-020-00717-x] [Citation(s) in RCA: 262] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.
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Affiliation(s)
- Margherita Ratti
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Medical Department, Division of Oncology, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimiliano Salati
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Milko B Mirchev
- Clinic of Gastroenterology, Medical University, Varna, Bulgaria
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
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