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De Clercq E. The magic bullet: a tribute to Fritz Eckstein. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2025:1-9. [PMID: 40326535 DOI: 10.1080/15257770.2025.2500048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
The first encounter I ever had with Fritz Eckstein was in 1969 at Stanford University to discuss a polyribonucleotide in which the phosphate was replaced by thiophosphate groups, engendering increased interferon induction (i.e. antiviral activity). His research work then focused on the versatility of oligonucleotides as potential therapeutics. Spanning a period of several decades, various other leads of research were undertaken, i.e. 2'- and 3'-amino or -azido-substituted deoxyribonucleoside analogs, hammerhead ribozymes, small non-coding mRNAs (siRNAs, miRNAs) for monitoring gene therapy, and thiophosphate-substituted nucleotide analogs to be used in RNA and DNA sequencing. This exemplary scientific career generated not one but a multitude of magic bullets for biomedical research and application.
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Affiliation(s)
- Erik De Clercq
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Leuven, Belgium
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2
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Li Z, Xu Q, Zhang Y, Zhong J, Zhang T, Xue J, Liu S, Gao H, Zhang ZZZ, Wu J, Shen EZ. Mechanistic insights into RNA cleavage by human Argonaute2-siRNA complex. Cell Res 2025:10.1038/s41422-025-01114-7. [PMID: 40240484 DOI: 10.1038/s41422-025-01114-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/14/2025] [Indexed: 04/18/2025] Open
Abstract
In animals, AGO-clade Argonaute proteins utilize small interfering RNAs (siRNAs) as guides to recognize target with complete complementarity, resulting in target RNA cleavage that is a critical step for target silencing. These proteins feature a constricted nucleic acid-binding channel that limits base pairing between the guide and target beyond the seed region. How the AGO-siRNA complexes overcome this structural limitation and achieve efficient target cleavage remains unclear. We performed cryo-electron microscopy of human AGO-siRNA complexes bound to target RNAs of increasing lengths to examine the conformational changes associated with target recognition and cleavage. Initially, conformational transition propagates from the opening of the PAZ domain and extends through a repositioning of the PIWI-L1-N domain toward the binding channel, facilitating the capture of siRNA-target duplex. Subsequent extension of base pairing drives the downward movement of the PIWI-L1-N domain to enable catalytic activation. Finally, further base pairing toward the 3' end of siRNA destabilizes the PAZ-N domain, resulting in a "uni-lobed" architecture, which might facilitate the multi-turnover action of the AGO-siRNA enzyme complex. In contrast to PIWI-clade Argonautes, the "uni-lobed" structure of the AGO complex makes multiple contacts with the target in the central region of the siRNA-target duplex, positioning it within the catalytic site. Our findings shed light on the stepwise mechanisms by which the AGO-siRNA complex executes target RNA cleavage and offer insights into the distinct operational modalities of AGO and PIWI proteins in achieving such cleavage.
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Affiliation(s)
- Zhenzhen Li
- Fudan University, Shanghai, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Qikui Xu
- Fudan University, Shanghai, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Yan Zhang
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Jing Zhong
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Tianxiang Zhang
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Junchao Xue
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Shuxian Liu
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Haishan Gao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Z Z Zhao Zhang
- Duke University School of Medicine, Department of Pharmacology and Cancer Biology, Durham, NC, USA
| | - Jianping Wu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
| | - En-Zhi Shen
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
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Hashemi M, Fard AA, Pakshad B, Asheghabadi PS, Hosseinkhani A, Hosseini AS, Moradi P, Mohammadbeygi Niye M, Najafi G, Farahzadi M, Khoushab S, Taheriazam A, Farahani N, Mohammadi M, Daneshi S, Nabavi N, Entezari M. Non-coding RNAs and regulation of the PI3K signaling pathway in lung cancer: Recent insights and potential clinical applications. Noncoding RNA Res 2025; 11:1-21. [PMID: 39720352 PMCID: PMC11665378 DOI: 10.1016/j.ncrna.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 12/26/2024] Open
Abstract
Lung cancer (LC) is one of the most common causes of cancer-related death worldwide. It has been demonstrated that the prognosis of current drug treatments is affected by a variety of factors, including late stage, tumor recurrence, inaccessibility to appropriate treatments, and, most importantly, chemotherapy resistance. Non-coding RNAs (ncRNAs) contribute to tumor development, with some acting as tumor suppressors and others as oncogenes. The phosphoinositide 3-kinase (PI3Ks)/AKT serine/threonine kinase pathway is one of the most important common targets of ncRNAs in cancer, which is widely applied to modulate the cell cycle and a variety of biological processes, including cell growth, mobility survival, metabolic activity, and protein production. Discovering the biology of ncRNA-PI3K/AKT signaling may lead to advances in cancer diagnosis and treatment. As a result, we investigated the expression and role of PI3K/AKT-related ncRNAs in clinical characteristics of lung cancer, as well as their functions as potential biomarkers in lung cancer diagnosis, prognosis, and treatment.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Asal Abolghasemi Fard
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Bita Pakshad
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pezhman Shafiei Asheghabadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amineh Hosseinkhani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Atena Sadat Hosseini
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Parham Moradi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammadreza Mohammadbeygi Niye
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ghazal Najafi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohadeseh Farahzadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saloomeh Khoushab
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahya Mohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia, V8V 1P7, Canada
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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4
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Puchta-Jasińska M, Bolc P, Pietrusińska-Radzio A, Motor A, Boczkowska M. Small Interfering RNAs as Critical Regulators of Plant Life Process: New Perspectives on Regulating the Transcriptomic Machinery. Int J Mol Sci 2025; 26:1624. [PMID: 40004087 PMCID: PMC11855876 DOI: 10.3390/ijms26041624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/20/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Small interfering RNAs (siRNAs) are a distinct class of regulatory RNAs in plants and animals. Gene silencing by small interfering RNAs is one of the fundamental mechanisms for regulating gene expression. siRNAs are critical regulators during developmental processes. siRNAs have similar structures and functions to small RNAs but are derived from double-stranded RNA and may be involved in directing DNA methylation of target sequences. siRNAs are a less well-studied class than the miRNA group, and researchers continue to identify new classes of siRNAs that appear at specific developmental stages and in particular tissues, revealing a more complex mode of siRNA action than previously thought. This review characterizes the siRNA classes and their biogenesis process and focuses on presenting their known functions in the regulation of plant development and responses to biotic and abiotic stresses. The review also highlights the exciting potential for future research in this field, proposing methods for detecting plant siRNAs and a bioinformatic pathway for identifying siRNAs and their functions.
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Affiliation(s)
- Marta Puchta-Jasińska
- Plant Breeding and Acclimatization Institute—National Research Institute, 05-870 Radzików, Poland; (A.P.-R.); (A.M.); (M.B.)
| | - Paulina Bolc
- Plant Breeding and Acclimatization Institute—National Research Institute, 05-870 Radzików, Poland; (A.P.-R.); (A.M.); (M.B.)
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5
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Wang J, Gao J, Ding L, Yang X, Zheng D, Zeng Y, Zhu J, Lei W, Chen C, Liu Z, Huang JA. Circular RNA-Cacna1d Plays a Critical Role in Sepsis-induced Lung Injury by Sponging microRNA-185-5p. Am J Respir Cell Mol Biol 2025; 72:181-194. [PMID: 39236286 DOI: 10.1165/rcmb.2024-0067oc] [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: 02/14/2024] [Accepted: 09/05/2024] [Indexed: 09/07/2024] Open
Abstract
The role of circular RNAs (circRNAs) in sepsis-induced lung injury is not clear. This study investigated the role and molecular mechanism of a novel circRNA in sepsis-induced lung injury and explored its prognostic value in patients with sepsis. In this study, aberrant circRNA expression profiling in lung tissues from mice with sepsis-induced lung injury was analyzed using high-throughput sequencing. circRNA-Cacna1d was verified by qRT-PCR, and its biological function in sepsis-induced lung injury was validated in vitro and in vivo. The interactions among circRNA-Cacna1d, microRNAs (miRNAs), and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from patients with sepsis was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of mice with sepsis and in microvascular endothelial cells after LPS challenge. circRNA-Cacna1d knockdown alleviated inflammatory response and ameliorated the permeability of vascular endothelium, thereby mitigating sepsis-induced lung injury and significantly improving the survival rate of mice with sepsis. Mechanistically, circRNA-Cacna1d directly interacted with miRNA-185-5p and functioned as a miRNA sponge to regulate the RhoA/ROCK1 signaling pathway. The expression level of circRNA-Cacna1d in patients with early sepsis was significantly higher than that in the healthy control subjects. Higher levels of circRNA-Cacna1d in patients with sepsis were associated with increased disease severity and poorer outcomes. In conclusions, circRNA-Cacna1d may play a role in sepsis-induced lung injury by regulating the RhoA/ROCK1 axis by acting as a miRNA-185-5p sponge. circRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.
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Affiliation(s)
- Jiajia Wang
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Jinhui Gao
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Ling Ding
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Xuanzhe Yang
- Suzhou Medical College, Soochow University, Suzhou, China
| | - Dong Zheng
- Center of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China; and
| | - Yuanyuan Zeng
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Jianjie Zhu
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Wei Lei
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Cheng Chen
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Zeyi Liu
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
| | - Jian-An Huang
- Department of Pulmonary and Critical Care Medicine and
- Institute of Respiratory Diseases and
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6
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Pallathadka H, Jabir M, Rasool KH, Hanumanthaiah M, Sharma N, Pramanik A, Rab SO, Jawad SF, Oghenemaro EF, Mustafa YF. siRNA-based therapy for overcoming drug resistance in human solid tumours; molecular and immunological approaches. Hum Immunol 2025; 86:111221. [PMID: 39700968 DOI: 10.1016/j.humimm.2024.111221] [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: 08/10/2024] [Revised: 11/25/2024] [Accepted: 12/09/2024] [Indexed: 12/21/2024]
Abstract
RNA interference (RNAi) is a primordial biological process that protects against external intrusion. SiRNA has the potential to selectively silence disease-related genes in a sequence-specific way, thus offering a promising therapeutic approach. The efficacy of siRNA-based therapies in cancer treatment has gained significant recognition due to multiple studies demonstrating its ability to effectively suppress cancer cells' growth and multiplication. Moreover, siRNA-based medicines have shown considerable promise in enhancing the sensitivity of cancer cells to chemotherapy and other treatment methods by suppressing genes that play a role in the development of drug resistance. Exploring and identifying functional genes linked to cancer cell characteristics and drug resistance is crucial for developing effective siRNAs for cancer treatment and advancing targeted and personalized therapeutics. Targeting and silencing genes in charge of resistance mechanisms, such as those involved in drug efflux, cell survival, or DNA repair, is possible with siRNA therapy in the context of drug resistance, especially cancer. Through inhibiting these genes, siRNA therapy can prevent resistance and restore the efficacy of traditional medications. This review addresses the potential of siRNAs in addressing drug resistance in human tumours, opening up new possibilities in cancer therapy. This review article offers a non-systematic summary of how different siRNA types contribute to cancer cells' treatment resistance. Using pertinent keywords, sources were chosen from reliable databases, including PubMed, Scopus, and Google Scholar. The review covered essential papers in this area and those that mainly addressed the function of siRNA in drug resistance. The articles examined in connection with the title of this review were primarily published from 2020 onward and are based on in vitro studies. Furthermore, this article examines the potential barriers and prospective perspectives of siRNA therapies.
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Affiliation(s)
| | - Majid Jabir
- Department of Applied Sciences, University of Technology, Iraq
| | | | - Malathi Hanumanthaiah
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri - 140307, Mohali, Punjab, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University Dehradun, Uttarakhand, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Sabrean Farhan Jawad
- Department of Biochemistry, College of Science, Al-Mustaqbal University, 51001 Babil, Iraq.
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Delta State University, Faculty of Pharmacy, PMB 1 Abraka, Delta State, Nigeria
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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Ji M, Li L, Yu J, Wu Z, Sheng Y, Wang F. New insights into the function and therapeutic potential of RNA-binding protein TRBP in viral infection, chronic metabolic diseases, brain disorders and cancer. Life Sci 2024; 358:123159. [PMID: 39447729 DOI: 10.1016/j.lfs.2024.123159] [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: 08/20/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP.
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Affiliation(s)
- Minghui Ji
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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Fajardo C, De Donato M, Macedo M, Charoonnart P, Saksmerprome V, Yang L, Purton S, Mancera JM, Costas B. RNA Interference Applied to Crustacean Aquaculture. Biomolecules 2024; 14:1358. [PMID: 39595535 PMCID: PMC11592254 DOI: 10.3390/biom14111358] [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: 09/20/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/28/2024] Open
Abstract
RNA interference (RNAi) is a powerful tool that can be used to specifically knock-down gene expression using double-stranded RNA (dsRNA) effector molecules. This approach can be used in aquaculture as an investigation instrument and to improve the immune responses against viral pathogens, among other applications. Although this method was first described in shrimp in the mid-2000s, at present, no practical approach has been developed for the use of dsRNA in shrimp farms, as the limiting factor for farm-scale usage in the aquaculture sector is the lack of cost-effective and simple dsRNA synthesis and administration procedures. Despite these limitations, different RNAi-based approaches have been successfully tested at the laboratory level, with a particular focus on shrimp. The use of RNAi technology is particularly attractive for the shrimp industry because crustaceans do not have an adaptive immune system, making traditional vaccination methods unfeasible. This review summarizes recent studies and the state-of-the-art on the mechanism of action, design, use, and administration methods of dsRNA, as applied to shrimp. In addition, potential constraints that may hinder the deployment of RNAi-based methods in the crustacean aquaculture sector are considered.
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Affiliation(s)
- Carlos Fajardo
- Department of Biology, Faculty of Marine and Environmental Sciences, Instituto Universitario de Investigación Marina (INMAR), Campus de Excelencia Internacional del Mar (CEI-MAR), University of Cadiz (UCA), 11510 Puerto Real, Spain;
- Interdisciplinary Centre of Marine and Environmental Research, The University of Porto (CIIMAR), 4450-208 Matosinhos, Portugal; (M.M.); (B.C.)
| | - Marcos De Donato
- Center for Aquaculture Technologies (CAT), San Diego, CA 92121, USA;
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Querétaro 76130, Mexico
| | - Marta Macedo
- Interdisciplinary Centre of Marine and Environmental Research, The University of Porto (CIIMAR), 4450-208 Matosinhos, Portugal; (M.M.); (B.C.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (UP), 4050-313 Porto, Portugal
| | - Patai Charoonnart
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (Centex Shrimp), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.C.); (V.S.)
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok 12120, Thailand
| | - Vanvimon Saksmerprome
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (Centex Shrimp), Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (P.C.); (V.S.)
- National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok 12120, Thailand
| | - Luyao Yang
- Department of Structural and Molecular Biology, University College London (UCL), London WC1E 6BT, UK; (L.Y.); (S.P.)
| | - Saul Purton
- Department of Structural and Molecular Biology, University College London (UCL), London WC1E 6BT, UK; (L.Y.); (S.P.)
| | - Juan Miguel Mancera
- Department of Biology, Faculty of Marine and Environmental Sciences, Instituto Universitario de Investigación Marina (INMAR), Campus de Excelencia Internacional del Mar (CEI-MAR), University of Cadiz (UCA), 11510 Puerto Real, Spain;
| | - Benjamin Costas
- Interdisciplinary Centre of Marine and Environmental Research, The University of Porto (CIIMAR), 4450-208 Matosinhos, Portugal; (M.M.); (B.C.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (UP), 4050-313 Porto, Portugal
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9
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Wu R, Chen B, Jia J, Liu J. Relationship between Protein, MicroRNA Expression in Extracellular Vesicles and Rice Seed Vigor. Int J Mol Sci 2024; 25:10504. [PMID: 39408833 PMCID: PMC11476841 DOI: 10.3390/ijms251910504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Plant extracellular vesicles are non-self-replicating particles released by living plant cells and delimited by a lipid bilayer. They contain a large amount of lipids, RNA, and proteins. Seed vigor plays an important role in agricultural production and preservation of germplasm resources. Extracellular vesicles with cross-species communication with bioactive molecules can resist pathogens, exhibit anti-aging properties, and perform other functions; however, its potential influence on seed vigor has not been reported. In this study, rice seeds with different germination percentages were used to extract extracellular vesicles, endogenous proteins, and RNA. Protein qualitative identification and miRNA differential analysis were performed to analyze the regulatory mechanism of extracellular vesicles on seed vigor. Results: The profiles of four miRNA families were found to be significantly different: osa-miR164, osa-miR168, osa-miR166, and osa-miR159. Protein correlation analysis predicted that extracellular vesicles might mediate the synthesis of the seed cell wall; glyoxic acid cycle and tricarboxylic acid cycle; non-specific lipid transfer; mitochondrial quality control; and other biological processes to regulate rice seed viability. In addition, cupin protein, phospholipase D, aldehyde dehydrogenase, seven heat shock proteins (especially BiP1 and BiP2), protein disulfide isomerase-like (PDI), thioredoxin, calnexin and calreticulin, glutathione transferase, and other proteins found in extracellular vesicles were closely related to seed vigor. This provides a novel direction for the study of the regulation mechanism of seed vigor.
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Affiliation(s)
- Rouxian Wu
- Guangdong Key Laboratory for Crop Germplasm Resources Preservation and Utilization, Agro-Biological Gene Research Center, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China; (B.C.); (J.J.)
| | | | | | - Jun Liu
- Guangdong Key Laboratory for Crop Germplasm Resources Preservation and Utilization, Agro-Biological Gene Research Center, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China; (B.C.); (J.J.)
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10
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Wu L, Wei G, Yan Y, Zhou X, Zhu X, Zhang Y, Li X. Effects of miR-306 Perturbation on Life Parameters in the English Grain Aphid, Sitobion avenae (Homoptera: Aphididae). Int J Mol Sci 2024; 25:5680. [PMID: 38891867 PMCID: PMC11171923 DOI: 10.3390/ijms25115680] [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: 04/25/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
MicroRNAs (miRNA) play a vital role in insects' growth and development and have significant potential value in pest control. Previously, we identified miR-306 from small RNA libraries within the English grain aphid, Sitobion avenae, a devasting insect pest for wheat. miR-306 not only involves in wing morphogenesis, but also is critically important for aphid survival. Its specific impacts on the life history traits, however, remain unclear. Here, we evaluate the impact of miR-306 perturbation on S. avenae populations using a two-sex life table approach. This comprehensive analysis revealed that miR-306 perturbation significantly prolongs the developmental stages (9.64% and 8.20%) and adult longevity of S. avenae, while decreasing pre-adult survival rate (41.45% and 38.74%) and slightly reducing average fecundity (5.80% and 13.05%). Overall, miR-306 perturbation negatively affects the life table parameters of the aphid population. The population prediction models show a significant decline in the aphid population 60 days post interference, compared to the control groups (98.14% and 97.76%). Our findings highlight the detrimental effects of miR-306 perturbation on S. avenae population growth and suggest potential candidate genes for the development of RNAi-based biopesticides targeted specifically at this pest species.
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Affiliation(s)
- Linyuan Wu
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
| | - Guohua Wei
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
| | - Yi Yan
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
| | - Xuguo Zhou
- Department of Entomology, School of Integrative Biology, College of Liberal Arts & Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA;
| | - Xun Zhu
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
| | - Yunhui Zhang
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
| | - Xiangrui Li
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (L.W.); (G.W.); (Y.Y.); (X.Z.)
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11
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Moazzam M, Zhang M, Hussain A, Yu X, Huang J, Huang Y. The landscape of nanoparticle-based siRNA delivery and therapeutic development. Mol Ther 2024; 32:284-312. [PMID: 38204162 PMCID: PMC10861989 DOI: 10.1016/j.ymthe.2024.01.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/01/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions.
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Affiliation(s)
- Muhammad Moazzam
- Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, UK
| | - Mengjie Zhang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, School of Medical Technology, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China
| | - Abid Hussain
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, School of Medical Technology, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China
| | - Xiaotong Yu
- Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology of Ministry of Health, Peking University, Beijing 100191, China.
| | - Jia Huang
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
| | - Yuanyu Huang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, School of Medical Technology, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China; Rigerna Therapeutics Co. Ltd., Suzhou 215127, China.
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12
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Kola NS, Patel D, Thakur A. RNA-Based Vaccines and Therapeutics Against Intracellular Pathogens. Methods Mol Biol 2024; 2813:321-370. [PMID: 38888787 DOI: 10.1007/978-1-0716-3890-3_21] [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: 06/20/2024]
Abstract
RNA-based vaccines have sparked a paradigm shift in the treatment and prevention of diseases by nucleic acid medicines. There has been a notable surge in the development of nucleic acid therapeutics and vaccines following the global approval of the two messenger RNA-based COVID-19 vaccines. This growth is fueled by the exploration of numerous RNA products in preclinical stages, offering several advantages over conventional methods, i.e., safety, efficacy, scalability, and cost-effectiveness. In this chapter, we provide an overview of various types of RNA and their mechanisms of action for stimulating immune responses and inducing therapeutic effects. Furthermore, this chapter delves into the varying delivery systems, particularly emphasizing the use of nanoparticles to deliver RNA. The choice of delivery system is an intricate process involved in developing nucleic acid medicines that significantly enhances their stability, biocompatibility, and site-specificity. Additionally, this chapter sheds light on the current landscape of clinical trials of RNA therapeutics and vaccines against intracellular pathogens.
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Affiliation(s)
- Naga Suresh Kola
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
| | - Dhruv Patel
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
| | - Aneesh Thakur
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada.
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13
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Fu K, Wu Q, Jiang N, Hu S, Ye H, Hu Y, Li L, Li T, Sun Z. Identification and Expressional Analysis of siRNAs Responsive to Fusarium graminearum Infection in Wheat. Int J Mol Sci 2023; 24:16005. [PMID: 37958988 PMCID: PMC10650599 DOI: 10.3390/ijms242116005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
The outbreak of Fusarium head blight (FHB) poses a serious threat to wheat production as it leads to both significant yield losses and accumulation of several mycotoxins including deoxynivalenol (DON) in the grains, which are harmful to human and livestock. To date, hundreds of FHB-resistance-related quantitative trait loci (QTLs) have been reported, but only a few of them have been cloned and used for breeding. Small interfering RNAs (siRNA) have been reported in plants to mediate host defense against pathogens, but they have rarely been reported in wheat-FHB interaction. In order to identify the key siRNAs that can potentially be used in the improvement of resistance to FHB, siRNAs from the spikes of an FHB-resistant variety Sumai 3 and an FHB-susceptible variety of Chinese Spring (CS) were sequenced after F. graminearum infection and mock inoculation, respectively. The expression patterns of the siRNAs of interest were analyzed. A total of 4019 siRNAs of high-confidence were identified, with 131 being CS-specific, 309 Sumai 3-specific and 3071 being common in both varieties. More than 87% of these siRNAs were 24 nt in length. An overall down-regulation trend was found for siRNAs in the spikes of both varieties after being infected with F. graminearum. The expression patterns for Triticum aestivum Dicer-like 3 (TaDCL3) that synthesizes 24 nt siRNAs were validated by qRT-PCR, which were positively correlated with those of the siRNAs. A total of 85% of the differentially expressed genes putatively targeted by the siRNAs were significantly up-regulated after infection, showing a negative correlation with the overall down-regulated expression of siRNAs. Interestingly, the majority of the up-regulated genes are annotated as disease resistance. These results suggested that the inhibition of siRNA by F. graminearum up-regulated the disease resistance genes, which were putatively suppressed by siRNAs through RNA-directed DNA methylation (RdDM). Consequently, the resistant capability to F. graminearum infection was enhanced. This study provides novel clues for investigating the function of siRNA in wheat-F. graminearum interaction.
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Affiliation(s)
- Kai Fu
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Qianhui Wu
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Ning Jiang
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Sijia Hu
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Hongyan Ye
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Yi Hu
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Lei Li
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Tao Li
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
| | - Zhengxi Sun
- Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Jiangsu Key Laboratory of Crop Genetics and Physiology, Agricultural College of Yangzhou University, Yangzhou 225009, China; (K.F.); (Q.W.); (N.J.); (S.H.); (H.Y.); (Y.H.); (L.L.); (T.L.)
- Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China
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14
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Zhang W, Jiang Y, He Y, Boucetta H, Wu J, Chen Z, He W. Lipid carriers for mRNA delivery. Acta Pharm Sin B 2023; 13:4105-4126. [PMID: 37799378 PMCID: PMC10547918 DOI: 10.1016/j.apsb.2022.11.026] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/26/2022] [Accepted: 11/03/2022] [Indexed: 12/05/2022] Open
Abstract
Messenger RNA (mRNA) is the template for protein biosynthesis and is emerging as an essential active molecule to combat various diseases, including viral infection and cancer. Especially, mRNA-based vaccines, as a new type of vaccine, have played a leading role in fighting against the current global pandemic of COVID-19. However, the inherent drawbacks, including large size, negative charge, and instability, hinder its use as a therapeutic agent. Lipid carriers are distinguishable and promising vehicles for mRNA delivery, owning the capacity to encapsulate and deliver negatively charged drugs to the targeted tissues and release cargoes at the desired time. Here, we first summarized the structure and properties of different lipid carriers, such as liposomes, liposome-like nanoparticles, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanoemulsions, exosomes and lipoprotein particles, and their applications in delivering mRNA. Then, the development of lipid-based formulations as vaccine delivery systems was discussed and highlighted. Recent advancements in the mRNA vaccine of COVID-19 were emphasized. Finally, we described our future vision and perspectives in this field.
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Affiliation(s)
- Wanting Zhang
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yuxin Jiang
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yonglong He
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Hamza Boucetta
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jun Wu
- Department of Geriatric Cardiology, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China
| | - Wei He
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China
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15
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Huang J, Lei L, Cui M, Cheng A, Wang M, Liu M, Zhu D, Chen S, Zhao X, Yang Q, Wu Y, Zhang S, Ou X, Mao S, Gao Q, Sun D, Tian B, Yin Z, Jia R. miR-146b-5p promotes duck Tembusu virus replication by targeting RPS14. Poult Sci 2023; 102:102890. [PMID: 37441905 PMCID: PMC10362356 DOI: 10.1016/j.psj.2023.102890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/12/2023] [Accepted: 06/17/2023] [Indexed: 07/15/2023] Open
Abstract
Duck Tembusu virus (DTMUV), belonging to the Flaviviridae family, is a major virus that affects duck health in China. MicroRNAs (miRNAs) play an important role in viral replication. However, little is known about the function of miRNAs during DTMUV infection. Here, the host miR-146b-5p was found to regulate DTMUV replication. When DTMUV infected duck embryo fibroblasts (DEFs), the expression levels of miR-146b-5p increased significantly over time. Moreover, the viral RNA copies, E protein expression levels and virus titers were all upregulated when miR-146b-5p was overexpressed in DEFs. The opposite results were also observed upon knockdown of miR-146b-5p in DEFs. To explore the mechanism by which miR-146b-5p promoted DTMUV replication, mass spectrometry, and RNA pull-down assays were employed. Ribosomal protein S14 (RPS14), a component of 40S ribosomal proteins, was identified to interact with miR-146b-5p. In addition, the relative mRNA expression levels of RPS14 gene were negatively modulated by miR-146b-5p. Subsequently, it was found that overexpression of RPS14 could decrease the replication of DTMUV, and the reverse results were also detected by knockdown of RPS14. In conclusion, this study revealed that miR-146b-5p promoted DTMUV replication by targeting RPS14, which provides a new mechanism by which DTMUV evades host defenses and a new direction for further antiviral strategies development.
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Affiliation(s)
- Juan Huang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Lin Lei
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Min Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Mafeng Liu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Dekang Zhu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Shun Chen
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Xinxin Zhao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Qiao Yang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Ying Wu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Shaqiu Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Xumin Ou
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Sai Mao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Qun Gao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Di Sun
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Bin Tian
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China.
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16
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Felekkis K, Pieri M, Papaneophytou C. Exploring the Feasibility of Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Osteoarthritis: Challenges and Opportunities. Int J Mol Sci 2023; 24:13144. [PMID: 37685951 PMCID: PMC10487837 DOI: 10.3390/ijms241713144] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage degradation and joint inflammation. As the most common aging-related joint disease, OA is marked by inadequate extracellular matrix synthesis and the breakdown of articular cartilage. However, traditional diagnostic methods for OA, relying on clinical assessments and radiographic imaging, often need to catch up in detecting early-stage disease or i accurately predicting its progression. Consequently, there is a growing interest in identifying reliable biomarkers that can facilitate early diagnosis and prognosis of OA. MicroRNAs (miRNAs) have emerged as potential candidates due to their involvement in various cellular processes, including cartilage homeostasis and inflammation. This review explores the feasibility of circulating miRNAs as diagnostic and prognostic biomarkers in OA, focusing on knee OA while shedding light on the challenges and opportunities associated with their implementation in clinical practice.
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Affiliation(s)
| | | | - Christos Papaneophytou
- Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, 46 Makedonitissas Avenue, Nicosia 2417, Cyprus; (K.F.); (M.P.)
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17
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Asakura H, Tanaka M, Tamura T, Saito Y, Yamakawa T, Abe K, Asakura T. Genes related to cell wall metabolisms are targeted by miRNAs in immature tomato fruits under drought stress. Biosci Biotechnol Biochem 2023; 87:290-302. [PMID: 36572396 DOI: 10.1093/bbb/zbac209] [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: 10/17/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022]
Abstract
The metabolism of tomato fruits changes when plants experience drought stress. In this study, we investigated changes in microRNA (miRNA) abundance and detected 32 miRNAs whose expression changes in fruit. The candidate target genes for each miRNA were predicted from the differentially expressed genes identified by transcriptome analysis at the same fruit maturation stage. The predicted targeted genes were related to cell wall metabolisms, response to pathogens, and plant hormones. Among these, we focused on cell wall metabolism-related genes and performed a dual luciferase assay to assess the targeting of their mRNAs by their predicted miRNA. As a result, sly-miR10532 and sly-miR7981e suppress the expression of mRNAs of galacturonosyltransferase-10 like encoding the main enzyme of pectin biosynthesis, while sly-miR171b-5p targets β-1,3-glucosidase mRNAs involved in glucan degradation. These results will allow the systematic characterization of miRNA and their target genes in the tomato fruit under drought stress conditions.
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Affiliation(s)
- Hiroko Asakura
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Mayui Tanaka
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Tomoko Tamura
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1, Sakuragaoka, Setagaya-ku, Tokyo, Japan
| | - Yoshikazu Saito
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Takashi Yamakawa
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Keiko Abe
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan.,Kanagawa Institute of Industrial Science and Technology (KISTEC), Life Science & Environmental Research Center (LiSE), 705-1, Imaizumi, Ebina, Kanagawa, Japan
| | - Tomiko Asakura
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, Japan
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Tu MJ, Yu AM. Recent Advances in Novel Recombinant RNAs for Studying Post-transcriptional Gene Regulation in Drug Metabolism and Disposition. Curr Drug Metab 2023; 24:175-189. [PMID: 37170982 PMCID: PMC10825985 DOI: 10.2174/1389200224666230425232433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 05/13/2023]
Abstract
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/ pharmacodynamics (PK/PD) and further influence drug safety and therapeutic outcomes. ADME gene functions are controlled by diverse factors, such as genetic polymorphism, transcriptional regulation, and coadministered medications. MicroRNAs (miRNAs) are a superfamily of regulatory small noncoding RNAs that are transcribed from the genome to regulate target gene expression at the post-transcriptional level. The roles of miRNAs in controlling ADME gene expression have been demonstrated, and such miRNAs may consequently influence cellular drug metabolism and disposition capacity. Several types of miRNA mimics and small interfering RNA (siRNA) reagents have been developed and widely used for ADME research. In this review article, we first provide a brief introduction to the mechanistic actions of miRNAs in post-transcriptional gene regulation of drug-metabolizing enzymes, transporters, and transcription factors. After summarizing conventional small RNA production methods, we highlight the latest advances in novel recombinant RNA technologies and applications of the resultant bioengineered RNA (BioRNA) agents to ADME studies. BioRNAs produced in living cells are not only powerful tools for general biological and biomedical research but also potential therapeutic agents amenable to clinical investigations.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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Kalkusova K, Taborska P, Stakheev D, Smrz D. The Role of miR-155 in Antitumor Immunity. Cancers (Basel) 2022; 14:5414. [PMID: 36358832 PMCID: PMC9659277 DOI: 10.3390/cancers14215414] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 09/19/2023] Open
Abstract
MicroRNAs belong to a group of short non-coding RNA molecules that are involved in the regulation of gene expression at multiple levels. Their function was described two decades ago, and, since then, microRNAs have become a rapidly developing field of research. Their participation in the regulation of cellular processes, such as proliferation, apoptosis, cell growth, and migration, made microRNAs attractive for cancer research. Moreover, as a single microRNA can simultaneously target multiple molecules, microRNAs offer a unique advantage in regulating multiple cellular processes in different cell types. Many of these cell types are tumor cells and the cells of the immune system. One of the most studied microRNAs in the context of cancer and the immune system is miR-155. MiR-155 plays a role in modulating innate and adaptive immune mechanisms in distinct immune cell types. As such, miR-155 can be part of the communication between the tumor and immune cells and thus impact the process of tumor immunoediting. Several studies have already revealed its effect on antitumor immune responses, and the targeting of this molecule is increasingly implemented in cancer immunotherapy. In this review, we discuss the current knowledge of miR-155 in the regulation of antitumor immunity and the shaping of the tumor microenvironment, and the plausible implementation of miR-155 targeting in cancer therapy.
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Affiliation(s)
- Katerina Kalkusova
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
| | - Pavla Taborska
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
| | - Dmitry Stakheev
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
- Laboratory of Immunotherapy, Institute of Microbiology of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
| | - Daniel Smrz
- Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, 150 06 Prague, Czech Republic
- Laboratory of Immunotherapy, Institute of Microbiology of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
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20
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Wang J, Ye Z, Chen Y, Qiao X, Jin Y. MicroRNA-25-5p negatively regulates TXNIP expression and relieves inflammatory responses of brain induced by lipopolysaccharide. Sci Rep 2022; 12:17915. [PMID: 36289253 PMCID: PMC9605969 DOI: 10.1038/s41598-022-21169-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 09/23/2022] [Indexed: 01/20/2023] Open
Abstract
Sepsis is one of the most common causes of death in patients suffering from severe infection or injury. Currently, a specific effective therapy remains to be established. In the present study, miR-25-5p, miR-105, miR-106b-5p, miR-154-3p, miR-20b-5p, miR-295-3p, miR-291-3p, miR-301b, miR-352, and miR-93-5p were predicted to target TXNIP mRNA from the databases of miRDB, Targetscan, and microT-CDS. The luciferase reporter assay confirmed that miR-25-5p negatively regulates TXNIP expression. The ELISA analyses and western blotting demonstrated that miR-25-5p downregulated the production of IL-1β, IL-6, IL-8, and TNF-α in lipopolysaccharide (LPS)-stimulated cells or rats, as well as the protein levels of TXNIP, NLRP3, and cleaved caspase-1. In addition, miR-25-5p increased the cell viability and decreased the apoptosis in LPS-stimulated CTX TNA2 cells and reduced the abnormal morphology of the brain in LPS-stimulated rats. Besides, miR-25-5p decreased the relative mean fluorescence intensity of DCF in LPS-stimulated CTX TNA2 cell, apoptosis, and protein levels of MnSOD and catalase in LPS-stimulated brains. These findings indicate that miR-25-5p downregulated LPS-induced inflammatory responses, reactive oxygen species production, and brain damage, suggesting that miR-25-5p is a candidate treatment for septic encephalopathy.
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Affiliation(s)
- Jiabing Wang
- grid.440657.40000 0004 1762 5832Department of Pharmacy, Municipal Hospital Affiliated to Taizhou University, Taizhou, 318000 China
| | - Zhinan Ye
- grid.440657.40000 0004 1762 5832Department of Neurology, Municipal Hospital Affiliated to Taizhou University, Taizhou, 318000 China
| | - Yuan Chen
- grid.440657.40000 0004 1762 5832Department of Neurosurgery, Municipal Hospital Affiliated to Taizhou University, Taizhou, 318000 China
| | - Xinyu Qiao
- grid.440657.40000 0004 1762 5832Department of Neurology, Municipal Hospital Affiliated to Taizhou University, Taizhou, 318000 China
| | - Yong Jin
- grid.440657.40000 0004 1762 5832Department of Neurosurgery, Municipal Hospital Affiliated to Taizhou University, Taizhou, 318000 China
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21
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Prajzlerová K, Šenolt L, Filková M. Is there a potential of circulating miRNAs as biomarkers in rheumatic diseases? Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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22
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Teng XQ, Qu J, Li GH, Zhuang HH, Qu Q. Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery. Front Cell Dev Biol 2022; 10:824299. [PMID: 35874843 PMCID: PMC9304887 DOI: 10.3389/fcell.2022.824299] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are central nervous system tumors originating from glial cells, whose incidence and mortality rise in coming years. The current treatment of gliomas is surgery combined with chemotherapy or radiotherapy. However, developing therapeutic resistance is one of the significant challenges. Recent research suggested that small interfering RNA (siRNA) has excellent potential as a therapeutic to silence genes that are significantly involved in the manipulation of gliomas’ malignant phenotypes, including proliferation, invasion, metastasis, therapy resistance, and immune escape. However, it is challenging to deliver the naked siRNA to the action site in the cells of target tissues. Therefore, it is urgent to develop delivery strategies to transport siRNA to achieve the optimal silencing effect of the target gene. However, there is no systematic discussion about siRNAs’ clinical potential and delivery strategies in gliomas. This review mainly discusses siRNAs’ delivery strategies, especially nanotechnology-based delivery systems, as a potential glioma therapy. Moreover, we envisage the future orientation and challenges in translating these findings into clinical applications.
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Affiliation(s)
- Xin-Qi Teng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Guo-Hua Li
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Hai-Hui Zhuang
- Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Qiang Qu,
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Lodde V, Floris M, Muroni MR, Cucca F, Idda ML. Non-coding RNAs in malaria infection. WILEY INTERDISCIPLINARY REVIEWS. RNA 2022; 13:e1697. [PMID: 34651456 PMCID: PMC9286032 DOI: 10.1002/wrna.1697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/02/2021] [Accepted: 09/21/2021] [Indexed: 12/31/2022]
Abstract
Malaria is one of the most severe infectious diseases affecting humans and it is caused by protozoan pathogens of the species Plasmodium (spp.). The malaria parasite Plasmodium is characterized by a complex, multistage life cycle that requires tight gene regulation which allows for host invasion and defense against host immune responses. Unfortunately, the mechanisms regulating gene expression during Plasmodium infection remain largely elusive, though several lines of evidence implicate a major involvement of non-coding RNAs (ncRNAs). The ncRNAs have been found to play a key role in regulating transcriptional and post-transcriptional events in a broad range of organisms including Plasmodium. In Plasmodium ncRNAs have been shown to regulate key events in the multistage life cycle and virulence ability. Here we review recent progress involving ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) and their role as regulators of gene expression during Plasmodium infection in human hosts with focus on the possibility of using these molecules as biomarkers for monitoring disease status. We also discuss the surprising function of ncRNAs in mediating the complex interplay between parasite and human host and future perspectives of the field. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Valeria Lodde
- Department of Biomedical SciencesUniversity of SassariSassariItaly
| | - Matteo Floris
- Department of Biomedical SciencesUniversity of SassariSassariItaly
| | - Maria Rosaria Muroni
- Department of Medical, Surgical, and Experimental SciencesUniversity of SassariSassariItaly
| | - Francesco Cucca
- Department of Biomedical SciencesUniversity of SassariSassariItaly
| | - Maria Laura Idda
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)SassariItaly
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24
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Lei L, Cheng A, Wang M, Jia R. The Influence of Host miRNA Binding to RNA Within RNA Viruses on Virus Multiplication. Front Cell Infect Microbiol 2022; 12:802149. [PMID: 35531344 PMCID: PMC9069554 DOI: 10.3389/fcimb.2022.802149] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
microRNAs (miRNAs), non-coding RNAs about 22 nt long, regulate the post-transcription expression of genes to influence many cellular processes. The expression of host miRNAs is affected by virus invasion, which also affects virus replication. Increasing evidence has demonstrated that miRNA influences RNA virus multiplication by binding directly to the RNA virus genome. Here, the knowledge relating to miRNAs’ relationships between host miRNAs and RNA viruses are discussed.
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Affiliation(s)
- Lin Lei
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- *Correspondence: Renyong Jia,
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25
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Chen Z, Mai Q, Wang Q, Gou Q, Shi F, Mo Z, Cui W, Zhuang W, Li W, Xu R, Zhou Z, Chen X, Zhang J. CircPOLR2A promotes proliferation and impedes apoptosis of glioblastoma multiforme cells by up-regulating POU3F2 to facilitate SOX9 transcription. Neuroscience 2022; 503:118-130. [DOI: 10.1016/j.neuroscience.2022.03.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 10/31/2022]
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26
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The embryonic transcriptome of Parhyale hawaiensis reveals different dynamics of microRNAs and mRNAs during the maternal-zygotic transition. Sci Rep 2022; 12:174. [PMID: 34996916 PMCID: PMC8741983 DOI: 10.1038/s41598-021-03642-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/09/2021] [Indexed: 11/18/2022] Open
Abstract
Parhyale hawaiensis has emerged as the crustacean model of choice due to its tractability, ease of imaging, sequenced genome, and development of CRISPR/Cas9 genome editing tools. However, transcriptomic datasets spanning embryonic development are lacking, and there is almost no annotation of non-protein-coding RNAs, including microRNAs. We have sequenced microRNAs, together with mRNAs and long non-coding RNAs, in Parhyale using paired size-selected RNA-seq libraries at seven time-points covering important transitions in embryonic development. Focussing on microRNAs, we annotate 175 loci in Parhyale, 88 of which have no known homologs. We use these data to annotate the microRNAome of 37 crustacean genomes, and suggest a core crustacean microRNA set of around 61 sequence families. We examine the dynamic expression of microRNAs and mRNAs during the maternal-zygotic transition. Our data suggest that zygotic genome activation occurs in two waves in Parhyale with microRNAs transcribed almost exclusively in the second wave. Contrary to findings in other arthropods, we do not predict a general role for microRNAs in clearing maternal transcripts. These data significantly expand the available transcriptomics resources for Parhyale, and facilitate its use as a model organism for the study of small RNAs in processes ranging from embryonic development to regeneration.
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27
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Joshi N, Liu D, Dickson KA, Marsh DJ, Ford CE, Stenzel MH. An organotypic model of high-grade serous ovarian cancer to test the anti-metastatic potential of ROR2 targeted Polyion complex nanoparticles. J Mater Chem B 2021; 9:9123-9135. [PMID: 34676865 DOI: 10.1039/d1tb01837j] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy. Most patients are diagnosed at late stages when the tumour has metastasised throughout the peritoneal cavity. The Wnt receptor ROR2 has been identified as a promising therapeutic target in HGSOC, with limited targeting therapeutic options currently available. Small interfering RNA (siRNA)-based therapeutics hold great potential for inhibiting the function of specific biomarkers, however major challenges remain in efficient delivery and stability. The aim of this study was to investigate the ability of nanoparticles to deliver ROR2 siRNA into HGSOC cells, including platinum resistant models, and estimate the anti-metastatic effect via a 3D organotypic model for ovarian cancer. The nanoparticles were generated by conjugating poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) of various chain length to bovine serum albumin (BSA), followed by the condensation of ROR2 siRNA into polyplexes, also termed polyion complex (PIC) nanoparticles. The toxicity and uptake of ROR2 siRNA PIC nanoparticles in two HGSOC cell lines, CaOV3 as well as its cisplatin resistant pair (CaOV3CisR), in addition to primary cells used for the 3D organotypic model were investigated. ROR2 knockdown at both transcriptional and translational levels were evaluated via real-time PCR and western blot analysis, respectively. Following 24 h incubation with the nanoparticles, functional assays were performed including proliferation (IncuCyte S3), transwell migration and 3D co-cultured transwell invasion assays. The PICs nanoparticles exhibited negligible toxicity in the paired CaOV3 cell lines or primary cells. Treating CaOV3 and CaOV3CisR cells with ROR2 siRNA containing PICs nanoparticles significantly inhibited migration and invasion ability. The biocompatible ROR2 siRNA conjugated PICs nanoparticles provide an innovative therapeutic option. ROR2 targeting therapy shows potential in treating HGSOC including platinum resistant forms.
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Affiliation(s)
- Nidhi Joshi
- School of Chemistry, University of New South Wales, Sydney, 2052, Australia.
| | - Dongli Liu
- School of Women's and Children's Health, Faculty of Medicine and Health, University of New South Wales, Australia.
| | - Kristie-Ann Dickson
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Deborah J Marsh
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.,Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia
| | - Caroline E Ford
- School of Women's and Children's Health, Faculty of Medicine and Health, University of New South Wales, Australia.
| | - Martina H Stenzel
- School of Chemistry, University of New South Wales, Sydney, 2052, Australia.
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Gutierrez J, Platt R, Opazo JC, Ray DA, Hoffmann F, Vandewege M. Evolutionary history of the vertebrate Piwi gene family. PeerJ 2021; 9:e12451. [PMID: 34760405 PMCID: PMC8574217 DOI: 10.7717/peerj.12451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 10/18/2021] [Indexed: 11/28/2022] Open
Abstract
PIWIs are regulatory proteins that belong to the Argonaute family. Piwis are primarily expressed in gonads and protect the germline against the mobilization and propagation of transposable elements (TEs) through transcriptional gene silencing. Vertebrate genomes encode up to four Piwi genes: Piwil1, Piwil2, Piwil3 and Piwil4, but their duplication history is unresolved. We leveraged phylogenetics, synteny and expression analyses to address this void. Our phylogenetic analysis suggests Piwil1 and Piwil2 were retained in all vertebrate members. Piwil4 was the result of Piwil1 duplication in the ancestor of gnathostomes, but was independently lost in ray-finned fishes and birds. Further, Piwil3 was derived from a tandem Piwil1 duplication in the common ancestor of marsupial and placental mammals, but was secondarily lost in Atlantogenata (Xenarthra and Afrotheria) and some rodents. The evolutionary rate of Piwil3 is considerably faster than any Piwi among all lineages, but an explanation is lacking. Our expression analyses suggest Piwi expression has mostly been constrained to gonads throughout vertebrate evolution. Vertebrate evolution is marked by two early rounds of whole genome duplication and many multigene families are linked to these events. However, our analyses suggest Piwi expansion was independent of whole genome duplications.
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Affiliation(s)
- Javier Gutierrez
- Department of Biology, Eastern New Mexico University, Portales, NM, United States of America
| | - Roy Platt
- Host Pathogen Interaction Program, Texas Biomedical Research Institute, San Antonio, TX, United States of America
| | - Juan C. Opazo
- Instituto de Ciencias Ambientales y Evolutivas, Universidad Austral de Chile, Valdivia, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Valdivia, Chile
- Integrative Biology Group, Universidad Austral de Chile, Valdivia, Chile
| | - David A. Ray
- Department of Biological Sciences, Texas Tech University, Lubbock, TX, United States of America
| | - Federico Hoffmann
- Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, Mississippi State University, Starkville, MS, United States of America
- Institute for Genomics, Biocomputing and Biotechnology, Mississippi State University, Starkville, MS, United States of America
| | - Michael Vandewege
- Department of Biology, Eastern New Mexico University, Portales, NM, United States of America
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Liu J, Zeng X, Han K, Jia X, Zhou M, Zhang Z, Wang Y. The expression regulation of Cyclins and CDKs in ovary via miR-9c and miR-263a of Scylla paramamosain. Comp Biochem Physiol B Biochem Mol Biol 2021; 254:110567. [PMID: 33548504 DOI: 10.1016/j.cbpb.2021.110567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 01/14/2021] [Accepted: 01/21/2021] [Indexed: 12/14/2022]
Abstract
Scylla paramamosain is an economically important cultured crab species in China. Cyclins and cyclin-dependent kinases (CDKs) play important roles in regulations of cell cycle and ovarian development. MiRNAs can negatively regulate gene expression at the post-transcriptional level through base-complementary pairing with the 3'-untranslated region (3-UTR) of the target gene. In this study, bioinformatics prediction showed that miR-9c and miR-263a identified from our group's gonad miRNAome of S. paramamosain may bind to the 3' UTR region of cyclin A, cyclin B, cyclin E, cyclin H, CDK1, and CDK2. Furthermore, the results of double luciferase reporter gene assay showed that the luciferase activities of HEK293T cells co-transfected with miR-9c mimics/miR-9c inhibitor and the 3'-UTR plasmid vectors of the five genes (cyclin A, cyclin B, cyclin H, CDK1, and CDK2) were significantly decreased/increased compared with those in the NC (negative control) and BC (blank control) groups. The results in miR-263a were similar to miR-9c, but all of the six genes could be regulated by miR-263a. In in vivo experiments, agomiR-9c (miR-9c enhancer) injection resulted in decreases of cyclin A and CDK1 expression level, and reverse effects were observed by injecting antagomiR-9c. AgomiR-263a decreased the expression of cyclin A, cyclin B, cyclin H, CDK1, and CDK2, but antagomiR-263a increased their expression. Both the in vitro and in vivo experiments confirmed functions of miR-9c and miR-263a in cell cycle progress of ovarian development by expression regulation of cyclin A, cyclin B, cyclin E, cyclin H, CDK1, and CDK2. The findings provide new insights into the reproductive regulation mechanism in mud crab and further enrich the knowledge of cell cycle and ovarian development regulation in invertebrates.
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Affiliation(s)
- Jianan Liu
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, China
| | - Xianyuan Zeng
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; School of Life Sciences, Ningde Normal University, Ningde 352100, China
| | - Kunhuang Han
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; School of Life Sciences, Ningde Normal University, Ningde 352100, China
| | - Xiwei Jia
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, China
| | - Mingcan Zhou
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; Key Laboratory of Marine Biotechnology of Fujian Province, Institute of Oceanology, College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Ziping Zhang
- Key Laboratory of Marine Biotechnology of Fujian Province, Institute of Oceanology, College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
| | - Yilei Wang
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen 361021, China; Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, China.
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30
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Gong Y, Zhang X. RNAi-based antiviral immunity of shrimp. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 115:103907. [PMID: 33122015 DOI: 10.1016/j.dci.2020.103907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/26/2020] [Accepted: 10/23/2020] [Indexed: 06/11/2023]
Abstract
As a kind of important economic marine crustaceans in aquaculture, shrimp can be infected by more than 20 viruses. To fight against the virus invasion, shrimp have developed the innate immunity, including RNA interference (RNAi). RNAi, mediated by short interfering RNAs (siRNAs) or microRNAs (miRNAs), plays important roles in virus-host interactions. At present, RNAi is considered to be an efficient antiviral response of shrimp. The siRNA-based RNAi, first recognized as an antiviral response of animals to resist RNA viruses, has emerged in animals as an efficient antiviral strategy against the invasion of DNA viruses and RNA viruses. In shrimp, as well as in other animals, siRNA contains a seed region (2nd-7th nt) and a supplementary region (12th-17th nt). Based on the findings in shrimp and other animals, miRNAs are essential regulators of virus-host interactions, such as virus infection/latency, and host apoptosis, autophagy and phagocytosis. Except for the seed sequence (2nd-7th), the complementary bases (to the target mRNA sequence) of a miRNA 9th-18th non-seed sequence are essential for the miRNA targeting. So far, rapidly growing evidences have supported the existence of functional RNAi machinery in shrimp. In this review, we summarize the progress of RNAi in the antiviral immune response of shrimp. The potential applications of RNAi to control shrimp diseases were also summarized.
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Affiliation(s)
- Yi Gong
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, 515063, People's Republic of China
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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31
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Abstract
Owing to the unique physical and chemical properties of carbon nanotubes, they have been widely explored as delivery vectors for proteins, and nucleic acid etc. after functionalization. Particularly, the modification of carbon nanotubes suited for the delivery of siRNA has been intensely studied over the past decade. The assay described in this chapter allows for realizable quantification of siRNA binding on carbon nanotube-based materials using gel electrophoresis and silencing by flow cytometry when the siRNA complexes are delivered in vitro.
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Affiliation(s)
- Danyang Li
- School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Khuloud T Al-Jamal
- School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
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Gong Y, Kong T, Ren X, Lin S, Li S. miR-9875 functions in antiviral immunity by targeting PDCD6 in mud crab ( Scylla paramamosain). Virulence 2020; 11:849-862. [PMID: 32597292 PMCID: PMC7549984 DOI: 10.1080/21505594.2020.1787078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/23/2020] [Accepted: 06/17/2020] [Indexed: 12/23/2022] Open
Abstract
Programmed cell death 6 (PDCD6) is a well-known apoptosis regulator that is involved in the immunity of mammals. However, the effects of miRNA-mediated regulation of PDCD6 expression on apoptosis and virus infection in organisms, especially in marine invertebrates, have not been extensively explored. In this study, PDCD6 of mud crab (Scylla paramamosain) (Sp-PDCD6) was characterized. The results showed that Sp-PDCD6 contains five EF-hands domains and could suppress virus infection via apoptosis promotion. It also presented that Sp-PDCD6 was directly targeted by miR-9875 in vitro and in vivo, miR-9875 served as a positive regulator during the virus invasion. The findings indicated that the miR-9875-PDCD6 pathway possessed fundamental effects on the immune response to virus infection in mud crab. Therefore, our research provided a novel insight into the roles of both miR-9875 and PDCD6 in the regulation of apoptosis and virus defense in mud crab.
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Affiliation(s)
- Yi Gong
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Tongtong Kong
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Xin Ren
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Shanmeng Lin
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Shengkang Li
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
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Biochemical characterization of the dicing activity of Dicer-like 2 in the model filamentous fungus Neurospora crassa. Fungal Genet Biol 2020; 146:103488. [PMID: 33276093 DOI: 10.1016/j.fgb.2020.103488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 11/24/2020] [Indexed: 11/23/2022]
Abstract
Dicing of double-stranded RNA (dsRNA) into small RNA is an essential process to trigger transcriptional and post-transcriptional gene silencing. Using cell-free extracts of the model filamentous fungus Neurospora crassa, we successfully detected the dicing activity of one of two N. crassa Dicers NcDCL2. The predominant 23-nucleotide (nt) cleavage product was always detected from 30-nt to 130-nt dsRNA substrates, and additional products of approximately 18 to 28 nt were occasionally produced. The enzymatic properties of NcDCL2 are different from those of insect and plant small interfering RNA (siRNA)-producing Dicers, Drosophila melanogaster Dicer-2 and Arabidopsis thaliana DCL3 and DCL4 (AtDCL3 and AtDCL4). Whereas AtDCL3 and AtDCL4 preferentially cleave short and long dsRNAs, respectively, NcDCL2 cleaved both short and long dsRNAs. These results suggest that N. crassa has a single siRNA-producing Dicer NcDCL2, which is a prototype of plant siRNA-producing Dicers with distinct functions in diverse RNA silencing pathways. The dicing assay reported here is convenient to detect and biochemically characterize the dicing activities of both plant and fungal Dicers, and is likely applicable to other organisms.
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Talebi A, Rahnema M, Bigdeli MR. The Positive Effect of MiR1 Antagomir on Ischemic Neurological Disorders Via Changing the Expression of Bcl-w and Bad Genes. Basic Clin Neurosci 2020; 11:811-820. [PMID: 33850618 PMCID: PMC8019842 DOI: 10.32598/bcn.11.6.324.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 03/10/2018] [Accepted: 10/15/2019] [Indexed: 12/04/2022] Open
Abstract
Introduction: MicroRNAs (miRNAs or miRs) are non-coding RNAs. Studies have shown that miRNAs are expressed aberrantly in stroke. The miR1 enhances ischemic damage, and a previous study has demonstrated that reduction of miR1 level has a neuroprotective effect on the Middle Cerebral Artery Occlusion (MCAO). Since apoptosis is one of the important processes in neural protection, the possible effect of miR1 on this pathway has been tested in this study. Post-ischemic administration of miR1 antagomir reduces infarct volume via bcl-w and bad expression. Methods: Rats were divided into four experimental groups: sham, control, positive control, and antagomir treatment group. One hour after MCAO surgery, the rats were received intravenously (Tail vein) 0.1 mL Normal Saline (NS), 0.1 mL rapamycin, and 300 pmol/g miR1 antagomir (soluble in 0.1 mL normal saline) in control, positive control, and treatment group, respectively. Twenty-four hours after reperfusion infarct volume was measured. The expression of miR1, bcl-w, and bad were analyzed using real-time PCR in sham, control, and treated groups. Results: Our results indicate that administration of miR1 antagomir reduces infarct volume significantly, it also decreases miR1 and bad expression while increases bcl-w expression. Conclusion: Understanding the precise neuroprotective mechanism of miR1 antagomir can make it a proper treatment and an innovative approach for stroke therapy.
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Affiliation(s)
- Anis Talebi
- Department of Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mehdi Rahnema
- Department of Biology, Faculty of Engineering and Basic Sciences, Zanjan Branch, Islamic Azad University, Zanjan, Iran
| | - Mohammad Reza Bigdeli
- Department of Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
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Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AA, Khadse SC, Satheeshkumar R, Satija S, Metha M, Chellappan DK, Shrivastava G, Gupta G, Negi P, Dua K, Zacconi FC. Small interfering RNA for cancer treatment: overcoming hurdles in delivery. Acta Pharm Sin B 2020; 10:2075-2109. [PMID: 33304780 PMCID: PMC7714980 DOI: 10.1016/j.apsb.2020.10.005] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/24/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022] Open
Abstract
In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.
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Key Words
- 1,3-propanediol, PEG-b-PDMAEMA-b-Ppy
- 2-propylacrylicacid, PAH-b-PDMAPMA-b-PAH
- APOB, apolipoprotein B
- AQP-5, aquaporin-5
- AZEMA, azidoethyl methacrylate
- Atufect01, β-l-arginyl-2,3-l-diaminopropionicacid-N-palmityl-N-oleyl-amide trihydrochloride
- AuNPs, gold nanoparticles
- B-PEI, branched polyethlenimine
- BMA, butyl methacrylate
- CFTR, cystic fibrosis transmembrane conductance regulator gene
- CHEMS, cholesteryl hemisuccinate
- CHOL, cholesterol
- CMC, critical micelles concentration
- Cancer
- DC-Chol, 3β-[N-(N′,N′-dimethylaminoethane)carbamoyl]cholesterol
- DMAEMA, 2-dimethylaminoethyl methacrylate
- DNA, deoxyribonucleic acid
- DOPC, dioleylphosphatidyl choline
- DOPE, dioleylphosphatidyl ethanolamine
- DOTAP, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate
- DOTMA, N-[1-(2,3-dioleyloxy)propy]-N,N,N-trimethylammoniumchloride
- DOX, doxorubicin
- DSGLA, N,N-dis-tearyl-N-methyl-N-2[N′-(N2-guanidino-l-lysinyl)] aminoethylammonium chloride
- DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine
- DSPE, 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine
- DSPE-MPEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt)
- DSPE-PEG-Mal: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (mmmonium salt), EPR
- Liposomes
- Micelles
- N-acetylgalactosamine, HIF-1α
- Nanomedicine
- PE-PCL-b-PNVCL, pentaerythritol polycaprolactone-block-poly(N-vinylcaprolactam)
- PLA, poly-l-arginine
- PLGA, poly lactic-co-glycolic acid
- PLK-1, polo-like kinase 1
- PLL, poly-l-lysine
- PPES-b-PEO-b-PPES, poly(4-(phenylethynyl)styrene)-block-PEO-block-poly(4-(phenylethynyl)styrene)
- PTX, paclitaxel
- PiRNA, piwi-interacting RNA
- Polymer
- RES, reticuloendothelial system
- RGD, Arg-Gly-Asp peptide
- RISC, RNA-induced silencing complex
- RNA, ribonucleic acid
- RNAi, RNA interference
- RNAse III, ribonuclease III enzyme
- SEM, scanning electron microscope
- SNALP, stable nucleic acid-lipid particles
- SiRNA, short interfering rNA
- Small interfering RNA (siRNA)
- S–Au, thio‒gold
- TCC, transitional cell carcinoma
- TEM, transmission electron microscopy
- Tf, transferrin
- Trka, tropomyosin receptor kinase A
- USPIO, ultra-small superparamagnetic iron oxide nanoparticles
- UV, ultraviolet
- VEGF, vascular endothelial growth factor
- ZEBOV, Zaire ebola virus
- enhanced permeability and retention, Galnac
- hypoxia-inducible factor-1α, KSP
- kinesin spindle protein, LDI
- lipid-protamine-DNA/hyaluronic acid, MDR
- lysine ethyl ester diisocyanate, LPD/LPH
- messenger RNA, MTX
- methotrexate, NIR
- methoxy polyethylene glycol-polycaprolactone, mRNA
- methoxypoly(ethylene glycol), MPEG-PCL
- micro RNA, MPEG
- multiple drug resistance, MiRNA
- nanoparticle, NRP-1
- near-infrared, NP
- neuropilin-1, PAA
- poly(N,N-dimethylacrylamide), PDO
- poly(N-isopropyl acrylamide), pentaerythritol polycaprolactone-block-poly(N-isopropylacrylamide)
- poly(acrylhydrazine)-block-poly(3-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine), PCL
- poly(ethylene glycol)-block-poly(2-dimethylaminoethyl methacrylate)-block poly(pyrenylmethyl methacrylate), PEG-b-PLL
- poly(ethylene glycol)-block-poly(l-lysine), PEI
- poly(ethylene oxide)-block-poly(2-(diethylamino)ethyl methacrylate)-stat-poly(methoxyethyl methacrylate), PEO-b-PCL
- poly(ethylene oxide)-block-poly(Ε-caprolactone), PE-PCL-b-PNIPAM
- poly(Ε-caprolactone), PCL-PEG
- poly(Ε-caprolactone)-polyethyleneglycol-poly(l-histidine), PCL-PEI
- polycaprolactone-polyethyleneglycol, PCL-PEG-PHIS
- polycaprolactone-polyethylenimine, PDMA
- polyethylenimine, PEO-b-P(DEA-Stat-MEMA
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Affiliation(s)
- Nitin Bharat Charbe
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
- Sri Adichunchunagiri College of Pharmacy, Sri Adichunchunagiri University, BG Nagar, Karnataka 571418, India
| | - Nikhil D. Amnerkar
- Adv V. R. Manohar Institute of Diploma in Pharmacy, Nagpur, Maharashtra 441110, India
| | - B. Ramesh
- Sri Adichunchunagiri College of Pharmacy, Sri Adichunchunagiri University, BG Nagar, Karnataka 571418, India
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Hamid A. Bakshi
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Alaa A.A. Aljabali
- Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan
| | - Saurabh C. Khadse
- Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Dist. Dhule, Maharashtra 425 405, India
| | - Rajendran Satheeshkumar
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Saurabh Satija
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411 Punjab, India
| | - Meenu Metha
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411 Punjab, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Garima Shrivastava
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi 110016, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur 302017, India
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, NSW 2308, Australia
| | - Flavia C. Zacconi
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 4860, Chile
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Gebert M, Jaśkiewicz M, Moszyńska A, Collawn JF, Bartoszewski R. The Effects of Single Nucleotide Polymorphisms in Cancer RNAi Therapies. Cancers (Basel) 2020; 12:E3119. [PMID: 33113880 PMCID: PMC7694039 DOI: 10.3390/cancers12113119] [Citation(s) in RCA: 5] [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: 09/21/2020] [Revised: 10/14/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022] Open
Abstract
Tremendous progress in RNAi delivery methods and design has allowed for the effective development of siRNA-based therapeutics that are currently under clinical investigation for various cancer treatments. This approach has the potential to revolutionize cancer therapy by providing the ability to specifically downregulate or upregulate the mRNA of any protein of interest. This exquisite specificity, unfortunately, also has a downside. Genetic variations in the human population are common because of the presence of single nucleotide polymorphisms (SNPs). SNPs lead to synonymous and non-synonymous changes and they occur once in every 300 base pairs in both coding and non-coding regions in the human genome. Much less common are the somatic mosaicism variations associated with genetically distinct populations of cells within an individual that is derived from postzygotic mutations. These heterogeneities in the population can affect the RNAi's efficacy or more problematically, which can lead to unpredictable and sometimes adverse side effects. From a more positive viewpoint, both SNPs and somatic mosaicisms have also been implicated in human diseases, including cancer, and these specific changes could offer the ability to effectively and, more importantly, selectively target the cancer cells. In this review, we discuss how SNPs in the human population can influence the development and success of novel anticancer RNAi therapies and the importance of why SNPs should be carefully considered.
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Affiliation(s)
- Magdalena Gebert
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, 80-416 Gdańsk, Poland; (M.G.); (M.J.); (A.M.)
| | - Maciej Jaśkiewicz
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, 80-416 Gdańsk, Poland; (M.G.); (M.J.); (A.M.)
| | - Adrianna Moszyńska
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, 80-416 Gdańsk, Poland; (M.G.); (M.J.); (A.M.)
| | - James F. Collawn
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Rafał Bartoszewski
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, 80-416 Gdańsk, Poland; (M.G.); (M.J.); (A.M.)
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Kim HK, Yeom JH, Kay MA. Transfer RNA-Derived Small RNAs: Another Layer of Gene Regulation and Novel Targets for Disease Therapeutics. Mol Ther 2020; 28:2340-2357. [PMID: 32956625 DOI: 10.1016/j.ymthe.2020.09.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/23/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Decades after identification as essential for protein synthesis, transfer RNAs (tRNAs) have been implicated in various cellular processes beyond translation. tRNA-derived small RNAs (tsRNAs), referred to as tRNA-derived fragments (tRFs) or tRNA-derived, stress-induced RNAs (tiRNAs), are produced by cleavage at different sites from mature or pre-tRNAs. They are classified into six major types representing potentially thousands of unique sequences and have been implicated to play a wide variety of regulatory roles in maintaining normal homeostasis, cancer cell viability, tumorigenesis, ribosome biogenesis, chromatin remodeling, translational regulation, intergenerational inheritance, retrotransposon regulation, and viral replication. However, the detailed mechanisms governing these processes remain unknown. Aberrant expression of tsRNAs is found in various human disease conditions, suggesting that a further understanding of the regulatory role of tsRNAs will assist in identifying novel biomarkers, potential therapeutic targets, and gene-regulatory tools. Here, we highlight the classification, biogenesis, and biological role of tsRNAs in regulatory mechanisms of normal and disease states.
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Affiliation(s)
- Hak Kyun Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
| | - Ji-Hyun Yeom
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Mark A Kay
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA.
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Ozbaki-Yagan N, Liu X, Bodnar A, Ho J, Butterworth M. Aldosterone-induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia. FASEB J 2020; 34:11714-11728. [PMID: 32652691 PMCID: PMC7725848 DOI: 10.1096/fj.201902254rr] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 06/17/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022]
Abstract
The final steps in the Renin-Angiotensin-Aldosterone signaling System (RAAS) involve binding of the corticosteroid hormone, aldosterone to its mineralocorticoid receptor (MR). The bound MR interacts with response elements to induce or repress the transcription of aldosterone-regulated genes. A well characterized aldosterone-induced gene is the serum and glucocorticoid-induced kinase (SGK1), which acts downstream to increase sodium transport in distal kidney nephron epithelial cells. The role of microRNAs (miRs) induced by extended aldosterone stimulation in regulating MR and SGK1 has not been reported. In these studies, miRs predicted to bind to the 3'-UTR of mouse MR were profiled by qRT-PCR after aldosterone stimulation. The miR-466a/b/c/e family was upregulated in mouse kidney cortical collecting duct epithelial cells. A luciferase reporter assay confirmed miR-466 binding to both MR and SGK1 3'-UTRs. Inhibition of miR-466 increased MR and SGK1 mRNA and protein levels. Inhibiting miR-466b and preventing its upregulation after aldosterone stimulation increased amiloride-sensitive sodium transport and sensitivity to aldosterone stimulation. In vivo upregulation of miR-466 was confirmed in distal nephrons of mice on low Na+ diets. Repression of MR and SGK1 by aldosterone-induced miRs may represent a negative feedback loop that contributes to a form of aldosterone escape in vivo.
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Affiliation(s)
- N. Ozbaki-Yagan
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - X. Liu
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - A.J. Bodnar
- Division of Nephrology in the Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - J. Ho
- Division of Nephrology in the Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - M.B. Butterworth
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
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Zhou M, Jia X, Wan H, Wang S, Zhang X, Zhang Z, Wang Y. miR-9 and miR-263 Regulate the Key Genes of the ERK Pathway in the Ovary of Mud Crab Scylla paramamosain. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2020; 22:594-606. [PMID: 32651722 DOI: 10.1007/s10126-020-09981-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 05/25/2020] [Indexed: 06/11/2023]
Abstract
Mud crab Scylla paramamosain is one of the most important economic crabs in China. The molecular regulatory mechanism of ovarian development has received considerable attention in recent years. Some studies found that ERK (extracellular signal-regulated protein kinase) signaling pathway plays an important role in ovarian development and is negatively regulated by microRNAs (miRNAs). However, the study about the regulation of miRNA on the ERK pathway in crustacean's ovary remains unknown. In this study, the target genes of the ERK signaling pathway regulated by selected miRNAs identified from the ovary of mud crab in our previous research were predicted by using bioinformatics tools. The results showed that the ERK2 might be a target gene of miR-9c, miR-263a, and miR-263b; MEK2 may be a target gene of miR-263a; and Rap-1b may be a target gene of miR-9, miR-9c, and miR-263a. Results of in vitro dual-luciferase reporter assay showed that the relative luciferase activities were significantly lower in HEK293T cells co-transfected with the combination of miRNA mimics and pmir-RB-REPORTTM-target gene-3'UTR than those with the combination of mimics NC and pmir-RB-REPORTTM-target gene-3'UTR. In contrast, the relative luciferase activities were significantly higher in HEK293T cells co-transfected with miRNA inhibitor than those with inhibitor NC. To further validate in vitro results, the miRNA reagents were injected into the living female mud crabs, and the expression levels of miRNAs and target genes after the injection were analyzed by quantitative real-time PCR. The in vivo experimental results showed that miRNAs (miR-9c/miR-263a) agomir (enhancers)/antagomir (inhibitors) can enhance/decrease the expression of two miRNAs, respectively, and the expression of target genes in the ovary was declined/increased after injection of agomir/antagomir reagent. In conclusion, miR-9/miR-263 can negatively regulate the expression of the ERK pathway genes (ERK2, MEK2, and Rap-1b) in the ovary of mud crab.
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Affiliation(s)
- Mingcan Zhou
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen, 361021, China
- College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Xiwei Jia
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen, 361021, China
| | - Haifu Wan
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen, 361021, China
| | - Shuhong Wang
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen, 361021, China
| | - Xin Zhang
- College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Ziping Zhang
- College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
| | - Yilei Wang
- Fujian Engineering Research Center of Aquatic Breeding and Healthy Aquaculture, Fisheries College, Jimei University, Xiamen, 361021, China.
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Zhu X, He S, Fang D, Guo L, Zhou X, Guo Y, Gao L, Qiao Y. High-Throughput Sequencing-Based Identification of Arabidopsis miRNAs Induced by Phytophthora capsici Infection. Front Microbiol 2020; 11:1094. [PMID: 32655510 PMCID: PMC7324540 DOI: 10.3389/fmicb.2020.01094] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/01/2020] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding endogenous RNAs. In plants, miRNAs play vital functions in regulating growth, development, and stress response. However, the role of miRNAs in Arabidopsis-Phytophthora capsici (P. capsici) model pathosystem is poorly understood. Here, we used a high-throughput sequencing approach to identify pathogen-responsive miRNAs using 15 small RNA (sRNA) libraries prepared from Arabidopsis thaliana leaves collected at 0, 3, 6, 12, and 24 h post-inoculation with P. capsici. A total of 293 known miRNAs and 6 potential novel sRNAs (miRNAs or siRNAs) were identified, of which 33 miRNAs were differentially expressed at four different infection stages. To verify the reliability of the sRNA-seq results, we investigated the expression of five sRNAs upregulated throughout the four infection stages and their potential target genes using northern blot analysis and/or stem-loop quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the potential target genes of the differentially expressed miRNAs, both conserved and novel, were enriched in pathways such as starch and sugar metabolism, spliceosome, and plant-pathogen interaction, indicating that the splicing machinery and pathogenesis-related (PR) proteins play important roles in the response to P. capsici infection. Taken together, these results provide novel insights into the molecular mechanisms of pathogenesis by P. capsici. Additionally, these results will serve as a strong foundation for further in-depth analysis of miRNAs involved in the resistance to Phytophthora species in other crops.
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Affiliation(s)
- Xiaoguo Zhu
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Shidan He
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Di Fang
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Liang Guo
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Xiaoyi Zhou
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
- College of Agriculture, Yangtze University, Jingzhou, China
| | - Yushuang Guo
- Laboratory of Molecular Genetics, China National Tobacco Corporation, Guizhou Institute of Tobacco Science, Guiyang, China
| | - Lei Gao
- Guangdong Provincial Key Laboratory for Plant Epigenetics, Longhua Bioindustry and Innovation Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Yongli Qiao
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
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Xiao H, Liang S, Wang L. Competing endogenous RNA regulation in hematologic malignancies. Clin Chim Acta 2020; 509:108-116. [PMID: 32479763 DOI: 10.1016/j.cca.2020.05.045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 12/18/2022]
Abstract
The clinical application of cytogenetic analysis and molecular-targeted drugs has dramatically improved the prognosis for many patients with hematologic malignancy, especially for those with chronic myeloid leukemia (CML) and acute promyelocytic leukemia (APL). Nevertheless, the treatment of hematologic malignancies is still faced with problems, such as disease recurrence and drug resistance, so further exploring the underlying molecular mechanism is urgent. With the discovery of different RNA species, the mechanism of RNA-RNA interaction has caught more and more attention. "Competing endogenous RNA (ceRNA) hypothesis" is one of the fascinating products of recent researches. CeRNAs are endogenous RNA transcripts that share mutual microRNA response elements (MREs) and regulate expression of each other by competing for the same microRNAs pools. The hypothesis links different RNA species together and enriches our understanding of the human genome. Here, we introduce the hypothesis critically, summary the research progress in the field of hematologic malignancies and the current investigation methods, and address its promising clinical value in offering new predictive, prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Han Xiao
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Simin Liang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
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Gong Y, Kong T, Ren X, Chen J, Lin S, Zhang Y, Li S. Exosome-mediated apoptosis pathway during WSSV infection in crustacean mud crab. PLoS Pathog 2020; 16:e1008366. [PMID: 32433716 PMCID: PMC7266354 DOI: 10.1371/journal.ppat.1008366] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/02/2020] [Accepted: 04/29/2020] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs are regulatory molecules that can be packaged into exosomes to modulate cellular response of recipients. While the role of exosomes during viral infection is beginning to be appreciated, the involvement of exosomal miRNAs in immunoregulation in invertebrates has not been addressed. Here, we observed that exosomes released from WSSV-injected mud crabs could suppress viral replication by inducing apoptosis of hemocytes. Besides, miR-137 and miR-7847 were found to be less packaged in mud crab exosomes during viral infection, with both miR-137 and miR-7847 shown to negatively regulate apoptosis by targeting the apoptosis-inducing factor (AIF). Our data also revealed that AIF translocated to the nucleus to induce DNA fragmentation, and could competitively bind to HSP70 to disintegrate the HSP70-Bax (Bcl-2-associated X protein) complex, thereby activating the mitochondria apoptosis pathway by freeing Bax. The present finding therefore provides a novel mechanism that underlies the crosstalk between exosomal miRNAs and apoptosis pathway in innate immune response in invertebrates. As a form of intercellular vesicular transport, exosomes are widely involved in the regulation of a variety of pathological processes in mammals, yet, the role of exosomes during virus infection in crustaceans remains unknown. In the present study, we identified the miRNAs packaged by exosomes that were possibly involved in WSSV infection by mediating hemocytes apoptosis in crustacean mud crab Scylla paramamosain. The results revealed that exosomes released from WSSV-injected mud crabs could suppress viral replication by inducing hemocytes apoptosis. Moreover, it was found that miR-137 and miR-7847 were less packaged in exosomes after WSSV challenge, resulting in the activation of AIF, while AIF could translocate to nucleus to induce DNA fragmentation or disintegrate the HSP70-Bax complex and freeing Bax to mitochondria, which eventually caused apoptosis and suppressed viral infection of the recipient hemocytes. Our finding is the first to reveal the involvement of exosomal miRNAs in antiviral immune response in mud crabs, which shows a novel molecular mechanism of invertebrate resistance to pathogenic microbial infection.
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Affiliation(s)
- Yi Gong
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Tongtong Kong
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
| | - Xin Ren
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
| | - Jiao Chen
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
| | - Shanmeng Lin
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
| | - Yueling Zhang
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
| | - Shengkang Li
- Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China
- Institute of Marine Sciences, Shantou University, Shantou, China
- Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou, China
- STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, China
- * E-mail:
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Li X, Wang X, Cheng Z, Zhu Q. AGO2 and its partners: a silencing complex, a chromatin modulator, and new features. Crit Rev Biochem Mol Biol 2020; 55:33-53. [DOI: 10.1080/10409238.2020.1738331] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Xiaojing Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Xueying Wang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Zeneng Cheng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Qubo Zhu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
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Dong Y, Xiao Y, Shi Q, Jiang C. Dysregulated lncRNA-miRNA-mRNA Network Reveals Patient Survival-Associated Modules and RNA Binding Proteins in Invasive Breast Carcinoma. Front Genet 2020; 10:1284. [PMID: 32010179 PMCID: PMC6975227 DOI: 10.3389/fgene.2019.01284] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the most common cancer in women, but few biomarkers are effective in clinic. Previous studies have shown the important roles of non-coding RNAs in diagnosis, prognosis, and therapy selection for breast cancer and have suggested the significance of integrating molecules at different levels to interpret the mechanism of breast cancer. Here, we collected transcriptome data including long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA for ~1,200 samples, including 1079 invasive breast carcinoma samples and 104 normal samples, from The Cancer Genome Atlas (TCGA) project. We identified differentially expressed lncRNAs, miRNAs, and mRNAs that distinguished invasive carcinoma samples from normal samples. We further constructed an integrated dysregulated network consisting of differentially expressed lncRNAs, miRNAs, and mRNAs and found housekeeping and cancer-related functions. Moreover, 58 RNA binding proteins (RBPs) involved in biological processes that are essential to maintain cell survival were found in the dysregulated network, and 10 were correlated with overall survival. In addition, we identified two modules that stratify patients into high- and low-risk subgroups. The expression patterns of these two modules were significantly different in invasive carcinoma versus normal samples, and some molecules were high-confidence biomarkers of breast cancer. Together, these data demonstrated an important clinical application for improving outcome prediction for invasive breast cancers.
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Affiliation(s)
- Yu Dong
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Xiao
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Qihui Shi
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chunjie Jiang
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
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45
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Salim L, Islam G, Desaulniers JP. Targeted delivery and enhanced gene-silencing activity of centrally modified folic acid-siRNA conjugates. Nucleic Acids Res 2020; 48:75-85. [PMID: 31777918 PMCID: PMC6943128 DOI: 10.1093/nar/gkz1115] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/28/2019] [Accepted: 11/11/2019] [Indexed: 12/20/2022] Open
Abstract
One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne-azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid-siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.
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Affiliation(s)
- Lidya Salim
- Faculty of Science, University of Ontario Institute of Technology, Oshawa, Ontario L1G 0C5, Canada
| | - Golam Islam
- Faculty of Science, University of Ontario Institute of Technology, Oshawa, Ontario L1G 0C5, Canada
| | - Jean-Paul Desaulniers
- Faculty of Science, University of Ontario Institute of Technology, Oshawa, Ontario L1G 0C5, Canada
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46
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Zhu X, He S, Fang D, Guo L, Zhou X, Guo Y, Gao L, Qiao Y. High-Throughput Sequencing-Based Identification of Arabidopsis miRNAs Induced by Phytophthora capsici Infection. Front Microbiol 2020. [PMID: 32655510 DOI: 10.3389/fmicb.2020.01094/bibtex] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding endogenous RNAs. In plants, miRNAs play vital functions in regulating growth, development, and stress response. However, the role of miRNAs in Arabidopsis-Phytophthora capsici (P. capsici) model pathosystem is poorly understood. Here, we used a high-throughput sequencing approach to identify pathogen-responsive miRNAs using 15 small RNA (sRNA) libraries prepared from Arabidopsis thaliana leaves collected at 0, 3, 6, 12, and 24 h post-inoculation with P. capsici. A total of 293 known miRNAs and 6 potential novel sRNAs (miRNAs or siRNAs) were identified, of which 33 miRNAs were differentially expressed at four different infection stages. To verify the reliability of the sRNA-seq results, we investigated the expression of five sRNAs upregulated throughout the four infection stages and their potential target genes using northern blot analysis and/or stem-loop quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed that the potential target genes of the differentially expressed miRNAs, both conserved and novel, were enriched in pathways such as starch and sugar metabolism, spliceosome, and plant-pathogen interaction, indicating that the splicing machinery and pathogenesis-related (PR) proteins play important roles in the response to P. capsici infection. Taken together, these results provide novel insights into the molecular mechanisms of pathogenesis by P. capsici. Additionally, these results will serve as a strong foundation for further in-depth analysis of miRNAs involved in the resistance to Phytophthora species in other crops.
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Affiliation(s)
- Xiaoguo Zhu
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Shidan He
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Di Fang
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Liang Guo
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Xiaoyi Zhou
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
- College of Agriculture, Yangtze University, Jingzhou, China
| | - Yushuang Guo
- Laboratory of Molecular Genetics, China National Tobacco Corporation, Guizhou Institute of Tobacco Science, Guiyang, China
| | - Lei Gao
- Guangdong Provincial Key Laboratory for Plant Epigenetics, Longhua Bioindustry and Innovation Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Yongli Qiao
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, China
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Bartoszewski R, Sikorski AF. Editorial focus: understanding off-target effects as the key to successful RNAi therapy. Cell Mol Biol Lett 2019; 24:69. [PMID: 31867046 PMCID: PMC6902517 DOI: 10.1186/s11658-019-0196-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022] Open
Abstract
With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.
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Affiliation(s)
- Rafal Bartoszewski
- Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland
| | - Aleksander F. Sikorski
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
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48
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Gougelet A, Desbois-Mouthon C. Non-coding RNAs open a new chapter in liver cancer treatment. Clin Res Hepatol Gastroenterol 2019; 43:630-637. [PMID: 31401041 DOI: 10.1016/j.clinre.2019.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 07/16/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023]
Abstract
Despite the intensive efforts to identify the molecular events responsible for the emergence of liver cancer, hepatocellular carcinoma (HCC) remains a major health problem in the world. Thus, the identification of new therapeutic opportunities is a short-term necessity. These last few decades, non-coding RNAs appeared as interesting therapeutic strategies with their pleiotropic inhibitory action in the cell itself but also in recipient cells via their secretion into extracellular vesicles. This short review recapitulates recent advancements concerning non-coding RNAs and their deregulations in liver cancer.
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Affiliation(s)
- Angélique Gougelet
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Team "Oncogenic functions of beta-catenin signaling in the liver", 75006 Paris, France.
| | - Christèle Desbois-Mouthon
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Team "Oncogenic functions of beta-catenin signaling in the liver", 75006 Paris, France
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49
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Kim YR, Ryu CS, Kim JO, An HJ, Cho SH, Ahn EH, Kim JH, Lee WS, Kim NK. Association study of AGO1 and AGO2 genes polymorphisms with recurrent pregnancy loss. Sci Rep 2019; 9:15591. [PMID: 31666609 PMCID: PMC6821863 DOI: 10.1038/s41598-019-52073-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 10/08/2019] [Indexed: 12/18/2022] Open
Abstract
An Argonaute (AGO) protein within the RNA-induced silencing complex binds a microRNA, permitting the target mRNA to be silenced. We hypothesized that variations in AGO genes had the possibility including affected the miRNA function and associated with recurrent pregnancy loss (RPL) susceptibility. Especially, we were chosen the AGO1 (rs595961, rs636832) and AGO2 (rs2292779, rs4961280) polymorphisms because of those polymorphisms have already reported in other diseases excluding the RPL. Here, we conducted a case-control study (385 RPL patients and 246 controls) to evaluate the association of four polymorphisms with RPL. We found that the AGO1 rs595961 AA genotype, recessive model (P = 0.039; P = 0.043, respectively), the AGO1 rs636832 GG genotype, and recessive model (P = 0.037; P = 0.016, respectively) were associated with RPL in women who had had four or more consecutive pregnancy losses. The patients with the AGO1 rs636832 GG genotypes had greater platelet counts (P = 0.023), while the patients with the AGO2 rs4961280 CA genotypes had less homocysteine (P = 0.027). Based on these results, we propose that genetic variations with respect to the AGO1 and AGO2 genotypes are associated with risk for RPL, and might serve as useful biomarkers for the prognosis of RPL.
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Affiliation(s)
- Young Ran Kim
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, 65th Street, Yatap Road, Bundang-gu, Seongnam, 13497, South Korea
| | - Chang Soo Ryu
- Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, 13488, South Korea
| | - Jung Oh Kim
- Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, 13488, South Korea
| | - Hui Jeong An
- Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, 13488, South Korea
| | - Sung Hwan Cho
- Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, 13488, South Korea
| | - Eun Hee Ahn
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, 65th Street, Yatap Road, Bundang-gu, Seongnam, 13497, South Korea
| | - Ji Hyang Kim
- Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, 65th Street, Yatap Road, Bundang-gu, Seongnam, 13497, South Korea
| | - Woo Sik Lee
- Fertility Center of CHA Gangnam Medical Center, CHA University, 566 Nonhyeon-ro, Gangnam-gu, Seoul, 06135, South Korea
| | - Nam Keun Kim
- Department of Biomedical Science, College of Life Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, 13488, South Korea.
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50
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Wang Z, Wang Y, Liu T, Wang Y, Zhang W. Effects of the PIWI/MID domain of Argonaute protein on the association of miRNAi's seed base with the target. RNA (NEW YORK, N.Y.) 2019; 25:620-629. [PMID: 30770397 PMCID: PMC6467011 DOI: 10.1261/rna.069328.118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/01/2019] [Indexed: 05/24/2023]
Abstract
The small interfering RNAs (siRNA) or microRNAs (miRNA) incorporated into the RNA-induced silencing complex with the Argonaute (Ago) protein associates with target mRNAs through base-pairing, which leads to the cleavage or knockdown of the target mRNA. The seed region of the s(m)iRNA is crucial for target recognition. In this work, a molecular dynamic simulation was utilized to study the thermodynamics and kinetic properties of the third seed base binding to the target in the presence of the PIWI/MID domain of Ago. The results showed that in the presence of the PIWI/MID domain, the entropy and enthalpy changes for the association of the seed base with the target were smaller than those in the absence of protein. The binding affinity was increased due to the reduced entropy penalty, which resulted from the preorganization of the seed base into the A-helix form. In the presence of the protein, the association barrier resulting from the unfavorable entropy loss and the dissociation barrier coming from the destruction of hydrogen bonding and base-stacking interactions were lower than those in the absence of the protein. These results indicate that the seed region is crucial for fast recognition and association with the correct target.
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Affiliation(s)
- Zhen Wang
- Department of Physics, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Yanli Wang
- Department of Physics, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Taigang Liu
- Department of Physics, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Yujie Wang
- Department of Physics, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Wenbing Zhang
- Department of Physics, Wuhan University, Wuhan, Hubei 430072, P.R. China
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