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Varghese LN, Sheard PW, Schwenke DO, Katare R. Sex-specific dysregulation of cardiac-enriched microRNAs with age in Drosophila melanogaster. Am J Physiol Cell Physiol 2025; 328:C1743-C1751. [PMID: 40250483 DOI: 10.1152/ajpcell.00134.2025] [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: 02/12/2025] [Revised: 02/28/2025] [Accepted: 04/10/2025] [Indexed: 04/20/2025]
Abstract
Dysregulation of cardiac-enriched microRNA (miRNA) expression is linked to age-associated cardiovascular diseases (CVDs). However, the sex-specificity and age at which dysregulation occurs remain unclear. Given the conserved nature of miRNAs and short lifespan of Drosophila melanogaster (fruit flies), we investigated age-related changes in the expression of cardiac enriched miRNAs (miR-1, -9, -34a, and -133, target miRNAs) and their impact on the cardiac tube in male and female flies. Cardiac tube tissues were collected from male and female flies (n = 5/group) at 7-day intervals from day 7 to day 70. miRNAs and predicted target mRNA gene (KCNQ, MRTF, and CCN) expression were quantified by RT-qPCR (n = 4-6/group). Myofibril diameter was assessed by Masson's trichrome staining (n = 4-6) to determine the structural effects of hypertrophic miR-9. In females, miR-1 was downregulated with age (P ≤ 0.0001), whereas in males, miR-9 (P ≤ 0.0001) and miR-34a (P = 0.0017) were downregulated. Interestingly, miR-133 was downregulated in both sexes (P ≤ 0.0001). In males, MRTF (miR-9 target) and CCN (miR-133 target) expression increased with age (P = 0.016 and P = 0.013, respectively), whereas in females, KCNQ (miR-1 target) and CCN expression decreased (P = 0.03 and P = 0.002, respectively). Myofibril thickness significantly increased with age in both sexes (P < 0.0001). miR-9 downregulation may contribute to this effect in males, whereas the mechanism in females remains unclear. This study provides novel insights into sex-specific miRNA dysregulation in cardiac aging, emphasizing the need to consider sex differences in miRNA-mediated cardiovascular aging and the potential of miRNAs as diagnostic tools in age-related CVDs.NEW & NOTEWORTHY Advancements in healthcare and diet have increased life expectancy, doubling the population aged 60 and above by 2050. However, this longevity raises the risk of chronic diseases, especially cardiovascular diseases. We examined age-related changes in cardiovascular-enriched microRNAs in the Drosophila melanogaster heart. This first-of-its-kind observational study tracks microRNA changes across life stages. It highlights sex-specific expression of miRNAs, providing crucial insights into cardiac aging. It lays a strong foundation for future research on microRNA in heart health.
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Affiliation(s)
- Lijo N Varghese
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Philip W Sheard
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Daryl O Schwenke
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Yu C, Lu Z, Du Y, Lv Y, Fang J, Zhao Y, Peng Z, Lu S. Inhibition of SFRP1 by microRNA‑206‑3p may be the underlying cause of osteosarcopenia. Biomed Rep 2025; 22:103. [PMID: 40322551 PMCID: PMC12046285 DOI: 10.3892/br.2025.1981] [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: 08/18/2024] [Accepted: 11/27/2024] [Indexed: 05/08/2025] Open
Abstract
Osteosarcopenia is characterized by a simultaneous decrease in bone mass and muscle quality. Thus, determining the common pathogenesis between osteoporosis and sarcopenia may aid in identifying a solution. Secreted frizzled-related protein 1 (SFRP1), a Wnt/β-catenin pathway inhibitor, reportedly decreases during the osteogenesis process and is increased in osteoporosis and sarcopenia mice models. As microRNAs (miRNAs/miRs) can regulate the expression of multiple proteins, the present study aimed to determine if miR-206-3p can promote the nuclear translocation of β-catenin by inhibiting SFRP1 during both osteogenesis and myogenesis. Transcriptome sequencing revealed that SFRP1 was markedly upregulated in the BMSCs derived from ovariectomized mice. In vitro induction of osteogenesis confirmed that SFRP1 negatively regulated osteogenesis. A luciferase reporter assay confirmed that miR-206-3p downregulated SFRP1 by directly binding to the 3' untranslated region. Subsequently, the BMSC and L6 cells were transfected with an miR-206-3p inhibitor or a corresponding negative control. Immunoblotting was performed to assess the relative expression levels of SFRP1 and Wnt/β-catenin signaling. The mRNA levels of SFRP1, osteogenesis-related molecules and myogenesis-related molecules were also detected by quantitative real-time PCR. The miR-206-3p inhibitor reduced the expression of osteogenesis- and myogenesis-related molecules and inactivated the Wnt/β-catenin signaling by releasing SFRP1. In conclusion, miR-206-3p downregulated SFRP1 and activated Wnt/β-catenin signaling to promote osteogenesis and myogenesis. Thus, miR-206-3p may be an important therapeutic target in osteosarcopenia. The present study aimed to uncover the genes and mechanisms that co-regulate muscle and bone. SFRP1, a known regulator of osteoporosis, was examined by analyzing its upstream regulatory microRNA and validating its molecular role. The diagnostic and therapeutic potential of miR-206-3p for osteomyopenia was evaluated by first focusing on osteoporosis and then validating findings with myofibroblasts. These data suggested that miR-206-3p can serve as a therapeutic target for osteomyopenia by inhibiting SFRP1, thereby activating the Wnt/β-catenin signaling pathway and promoting both osteogenesis and myogenesis.
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Affiliation(s)
- Chen Yu
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
- Graduate School, Kunming Medical University, Kunming, Yunnan 650000, P.R. China
| | - Zehui Lu
- Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia
| | - Yongjun Du
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
- Graduate School, Kunming Medical University, Kunming, Yunnan 650000, P.R. China
| | - Yan Lv
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
| | - Junhua Fang
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
- Graduate School, Kunming Medical University, Kunming, Yunnan 650000, P.R. China
| | - Yu Zhao
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100006, P.R. China
| | - Zhi Peng
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
| | - Sheng Lu
- Department of Orthopedics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, The Key Laboratory of Digital Orthopedics of Yunnan Provincial, Yunnan Provincial Center for Clinical Medicine in Spinal and Spinal Cord Disorders, Kunming, Yunnan 650000, P.R. China
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Yang L, Luo HJ, Gong ZA, Zhang WT, Cui JX, Fu XP, Zhang WW. miR-2400 promotes proliferation of bovine skeletal muscle-derived satellite cells by regulating MAGED1 genes expression. J Muscle Res Cell Motil 2025:10.1007/s10974-025-09695-x. [PMID: 40338441 DOI: 10.1007/s10974-025-09695-x] [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: 03/16/2025] [Accepted: 04/22/2025] [Indexed: 05/09/2025]
Abstract
microRNAs play a crucial role in the intricate process of muscle satellite cells proliferation and differentiation. Previous studies have demonstrated that miR-2400 can regulate bovine skeletal muscle satellite cell (MuSCs) proliferation, yet the underlying mechanism remains incompletely elucidated. In this study, we employed bioinformatics prediction and dual luciferase reporter assays to establish that miR-2400 directly targets the 3' untranslated regions (UTRs) of melanoma antigen family D1 (MAGED1) mRNA, thereby suppressing its expression. To ascertain whether miR-2400 affects the proliferation of MuSCs through MAGED1, we constructed the MAGED1 interference vector using RNA interference technology (RNAi) and assessed changes in MuSCs proliferation subsequent to MAGED1 interference. The experimental data indicate that the cell viability and the rate of EdU-positive cells of MuSCs were increased after interference with MAGED1. The proportion of S-phase cells and the expression level of cell cycle-associated proteins CCND2 and CCNB1 increased. These findings align with miR-2400's role in promoting cell proliferation and suggest that miR-2400 exerts its effects by directly targeting MAGED1.
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Affiliation(s)
- Li Yang
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Hai-Jing Luo
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Zhi-An Gong
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Wen-Tian Zhang
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Jing-Xuan Cui
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Xue-Peng Fu
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China
| | - Wei-Wei Zhang
- Department of Life Science and Agroforestry, Qiqihar University, No. 42 Wenhua Street, Jianhua District, Qiqihar, 161000, PR China.
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Shi B, Wang X, Xue T, Liu J, Wu W, Luo Y, Zhu H, Pan D. Expression level of miR-146a is associated with the coronary lesion severity and clinical prognosis in patients with unstable angina pectoris. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2025; 24:200367. [PMID: 39872631 PMCID: PMC11770491 DOI: 10.1016/j.ijcrp.2025.200367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 12/24/2024] [Accepted: 01/07/2025] [Indexed: 01/30/2025]
Abstract
Objective To investigate the association between plasma miR-146a expression levels, severity of coronary lesions, and clinical prognosis in patients with unstable angina pectoris (UAP). Methods A total of 100 patients with UAP and 100 controls were selected for assessment of plasma miRNA-146a expression levels. We assessed the severity of coronary lesions in patients with UAP using the Gensini score. Additionally, we analyzed the correlation between miR-146a expression and the degree of coronary artery stenosis in patients with UAP. The incidence of major adverse cardiovascular events (MACEs) was followed-up for 48 months after hospitalization and discharge. The median grouping method was employed to categorize patients into high- and low-expression groups based on their miR-146a levels. Thereafter, the incidence of MACEs in these groups was analyzed using the Kaplan-Meier method. Results The plasma expression level of miR-146a in the UAP group was 1.8-fold greater than that in the control group (Z = 6.970, P < 0.001) and correlated with the severity of coronary lesions; a high expression level was associated with a higher Gensini score (P < 0.05). Patients with high miR-146a expression levels showed a significantly higher incidence of MACEs than those with low miR-146a expression levels (log-rank test: P = 0.004). Conclusion Plasma miR-146a expression levels in patients with UAP correlated with the severity of coronary lesions, and patients with high miR-146a expression levels had poorer clinical prognoses than those with lower expression levels.
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Affiliation(s)
- Binbing Shi
- Department of General Practice, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Xiaotong Wang
- Department of Cardiology, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Tongneng Xue
- Department of Cardiology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Jie Liu
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Wanling Wu
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Yuanyuan Luo
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Hong Zhu
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Defeng Pan
- Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
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Qiu J, Ma Z, Hong Z, Yin X, Chen Y, Ahmed HQ, Zan L, Li A. Comparative analysis of the whole transcriptome landscapes of muscle and adipose tissue in Qinchuan beef cattle. BMC Genomics 2025; 26:32. [PMID: 39810084 PMCID: PMC11731550 DOI: 10.1186/s12864-025-11223-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Muscle and adipose tissue are the most critical indicators of beef quality, and their development and function are regulated by noncoding RNAs (ncRNAs). However, the differential regulatory mechanisms of ncRNAs in muscle and adipose tissue remain unclear. RESULTS In this study, 2,343 differentially expressed mRNAs (DEMs), 235 differentially expressed lncRNAs (DELs), 95 differentially expressed circRNAs (DECs) and 54 differentially expressed miRNAs (DEmiRs) were identified in longissimus dorsi muscle (LD), subcutaneous fat (SF) and perirenal fat (VF) in Qinchuan beef cattle. The results of functional enrichment analysis showed that DEMs, DELs, DECs and DEmiRs were enriched in biological processes related to development and function of muscle and fat deposition, including skeletal muscle contraction, muscle organ development, PPAR signaling pathway, fatty acid metabolism and MAPK signaling pathway. Based on the competing endogenous RNA (ceRNA) regulatory mechanism, we constructed a lncRNA/circRNA-miRNA-mRNA network consisting of 6 circRNAs, 5 lncRNAs, 6 miRNAs and 27 mRNAs. Among them, 55 ceRNA axes were involved, including circRNA12990 - bta-miR-133a_L-1R + 1 - MYO6/ZEB2, circRNA2893/MSTRG.28538.1/MSTRG.11613.4 - pma-miR-145-5p_R + 2 - EYA4 and MSTRG.26982.1 - bta-let-7e_R + 1 - RBM40. CONCLUSIONS This study identified a group of differentially expressed mRNAs, lncRNAs, circRNAs and miRNAs between muscle and adipose tissue and constructed a potential ceRNA regulatory network, which may serve as a foundation for studying the differential regulatory roles of ncRNAs in the development and function of muscle and adipose tissue.
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Affiliation(s)
- Ju Qiu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Zheng Ma
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Zhipeng Hong
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Xu Yin
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Yun Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Hafiz Qadeer Ahmed
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
- National Beef Cattle Improvement Center, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China
| | - Anning Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China.
- Shaanxi Modern Cattle Industry Engineering Research Center, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China.
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Puurand M, Llorente A, Linē A, Kaambre T. Exercise-induced extracellular vesicles in reprogramming energy metabolism in cancer. Front Oncol 2025; 14:1480074. [PMID: 39834935 PMCID: PMC11743358 DOI: 10.3389/fonc.2024.1480074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 12/06/2024] [Indexed: 01/22/2025] Open
Abstract
Cancer is caused by complex interactions between genetic, environmental, and lifestyle factors, making prevention strategies, including exercise, a promising avenue for intervention. Physical activity is associated with reduced cancer incidence and progression and systemic anti-cancer effects, including improved tumor suppression and prolonged survival in preclinical models. Exercise impacts the body's nutrient balance and stimulates the release of several exercise-induced factors into circulation. The mechanisms of how exercise modulates cancer energy metabolism and the tumor microenvironment through systemic effects mediated, in part, by extracellular vesicles (EVs) are still unknown. By transferring bioactive cargo such as miRNAs, proteins and metabolites, exercise-induced EVs may influence cancer cells by altering glycolysis and oxidative phosphorylation, potentially shifting metabolic plasticity - a hallmark of cancer. This short review explores the roles of EVs in cancer as mediators to reprogram cellular energy metabolism through exchanging information inside the tumor microenvironment, influencing immune cells, fibroblast and distant cells. Considering this knowledge, further functional studies into exercise-induced EVs and cellular energy production pathways could inform more specific exercise interventions to enhance cancer therapy and improve patient outcomes.
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Affiliation(s)
- Marju Puurand
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department for Mechanical, Electronics and Chemical Engineering, Oslo Metropolitan University, Oslo, Norway
| | - Aija Linē
- Cancer Biomarker group, Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Tuuli Kaambre
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
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Kuang W, Huang J, Yang Y, Liao Y, Zhou Z, Liu Q, Wu H. Identification of markers correlating with mitochondrial function in myocardial infarction by bioinformatics. PLoS One 2024; 19:e0316463. [PMID: 39775580 PMCID: PMC11684664 DOI: 10.1371/journal.pone.0316463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Myocardial infarction (MI), one of the most serious cardiovascular diseases, is also affected by altered mitochondrial metabolism and immune status, but their crosstalk is poorly understood. In this paper, we use bioinformatics to explore key targets associated with mitochondrial metabolic function in MI. METHODS The datasets (GSE775, GSE183272 and GSE236374) were from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) in conjunction with mitochondrial gene data that were downloaded from the MitoCarta 3.0 database. Differentially expressed genes (DEGs) in the dataset were screened by ClusterGVis, Weighted Gene Co-Expression Network Analysis (WGCNA) and GEO2R, and functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genomes (KEGG). Then mitochondria-associated DEGs (MitoDEGs) were obtained. Protein-protein interaction (PPI) networks were constructed to identify central MitoDEGs that are strongly associated with MI. The Cytoscape and miRWalk databases were then used to predict the transcription factors and target miRNAs of the central MitoDEG, respectively. Finally, the mouse model has been established to demonstrate the expression of MitoDEGs and their association with cardiac function. RESULTS MitoDEGs in MI were mainly involved in mitochondrial function and adenosine triphosphate (ATP) synthesis pathways. The 10 MI-related hub MitoDEGs were then obtained by eight different algorithms. Immunoassays showed a significant increase in monocyte macrophage and T cell infiltration. According to animal experiments, the expression trends of the four hub MitoDEGs (Aco2, Atp5a1, Ndufs3, and Ndufv1) were verified to be consistent with the bioinformatics results. CONCLUSION Our study identified key genes (Aco2, Atp5a1, Ndufs3, and Ndufv1) associated with mitochondrial function in myocardial infarction.
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Affiliation(s)
- Wenlong Kuang
- Department of Cardiology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Wuhan No.1 Hospital, Wuhan, Hubei, China
| | - Jianwu Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yulu Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihua Zhou
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Liu
- Center for Reproductive Medicine, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailang Wu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Miśkowiec D, Szymczyk E, Wejner-Mik P, Michalski B, Lipiec P, Simiera M, Kupczyńska K, Kasprzak JD. Elevated miRNA-499 Levels in Early Phase of Non-ST Elevation Acute Coronary Syndromes Predict Increased Long-Term Risk of Major Adverse Cardiac Events. J Clin Med 2024; 13:7803. [PMID: 39768724 PMCID: PMC11727993 DOI: 10.3390/jcm13247803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 11/30/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Available data suggest the diagnostic potential of testing microRNAs (miRs) in myocardial infarction, but their prognostic value remains unclear. To evaluate the prognostic value of circulating miRs (miR-1, miR-21, miR-133a, miR-208 and miR-499) for predicting major adverse cardiac events (MACEs), including death, non-fatal myocardial infarction (MI) or cardiovascular rehospitalization, in patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS). Methods: Our prospective, single-center, observational study included patients (pts) with NSTE-ACS admitted <24 h after symptoms onset and pts with confirmed stable coronary artery disease (SCAD) as controls. Relative expression of miRs was calculated, and subjects were categorized according to miRs expression on hospital admission into two groups (≤median and >median). Results: Overall, 103 NSTE-ACS (52 NSTEMI/51 UA) and 47 SCAD pts (median age 66 years, 67% male) were included. During the median 895 (581-1134) days of the follow-up, MACE occurred in 75 (50%) patients: 20 (13%) died, 28 (19%) presented with MI, and 65 (43%) were readmitted due to cardiovascular reasons. Incidence of MI, rehospitalization and MACE was significantly higher in pts with elevated (>median) miR-499 [MI: 34.3% vs. 7.3%; HR = 6.0 (2.8-12.7) for rehospitalization; 53.7% vs. 36.2%, HR = 2.3 (1.4-3.8) for MACE; 62.7% vs. 42%, HR = 2.4 (1.5-3.8)] for hospital readmission. In the Cox proportional hazards regression model, miR-499 expression above the median level [HR = 1.8 (1.1-3.1)], high-sensitivity cardiac troponin T [HR = 1.2 (1.02-1.5)], diabetes [HR = 1.7 (1.1-2.8)] and percutaneous intervention during hospital stay [HR = 2.1 (1.1-3.8)] were identified as independent predictors of MACE in long-term observation, even after adjustment for covariates. Conclusions: Elevated miR-499 level on hospital admission in NSTE-ACS is related to an increased rate of MACE in the 2.5-year follow-up.
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Affiliation(s)
- Dawid Miśkowiec
- Department of Cardiology, Medical University of Lodz, Kniaziewicza Street 1/5, 91-347 Lodz, Poland
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Barden J, Kosloski O, Jadidian A, Akaaboune M. Regulation of miR-206 in denervated and dystrophic muscles, and its effect on acetylcholine receptor clustering. J Cell Sci 2024; 137:jcs262303. [PMID: 39575567 PMCID: PMC11795291 DOI: 10.1242/jcs.262303] [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: 05/27/2024] [Accepted: 11/05/2024] [Indexed: 12/17/2024] Open
Abstract
The muscle-specific microRNA miR-206 has recently emerged as a potential regulator of genes involved in the formation and regeneration of the neuromuscular junction (NMJ). This study investigated miR-206-3p (miR-206) expression in synaptic and non-synaptic regions of denervated mice and α-dystrobrevin (Dtna)-knockout mice, as well as its impact on the formation and/or maintenance of agrin-induced acetylcholine receptor (AChR) clusters. In denervated, Dtna-deficient and crushed muscles, miR-206 expression significantly increased compared to what was seen for innervated muscles. Although miR-206 expression was slightly elevated in the synaptic regions of innervated muscles, it was dramatically increased in non-synaptic areas of denervated muscles. miR-206 targets transcripts of essential NMJ proteins, such as Dtna, α-syntrophin (Snta1) and rapsyn, but not the AChRα subunit (encoded by Chrna1) or Lrp4 in innervated muscles. However, in denervated muscles, AChRα transcripts, which increased significantly, become a target of miR-206. Co-expression of miR-206 with rapsyn, Dtna and Snta1 in C2C12 myoblasts significantly reduced their protein levels, and overexpression of miR-206 in myotubes disrupted agrin-induced AChR clustering. These results indicate that miR-206 fine-tunes NMJ signaling proteins by regulating transcripts of various proteins with different localizations under normal and pathological conditions.
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Affiliation(s)
- Joseph Barden
- Department of Molecular, Cellular and Developmental Biology, 1105 N. University Avenue, Ann Arbor, MI 48109, USA
| | - Olivia Kosloski
- Department of Molecular, Cellular and Developmental Biology, 1105 N. University Avenue, Ann Arbor, MI 48109, USA
| | - Amir Jadidian
- Department of Molecular, Cellular and Developmental Biology, 1105 N. University Avenue, Ann Arbor, MI 48109, USA
| | - Mohammed Akaaboune
- Department of Molecular, Cellular and Developmental Biology, 1105 N. University Avenue, Ann Arbor, MI 48109, USA
- Michigan Neuroscience Institute and Program in Neuroscience, 205 Zina Pitcher Pl, Ann Arbor, MI 48109-5720, USA
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10
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Stavros S, Potiris A, Christopoulos P, Zacharopoulou N, Kyrli V, Mavrogianni D, Zikopoulos A, Drakaki E, Karampitsakos T, Topis S, Machairiotis N, Gerede A, Skentou C, Drakakis P, Domali E. Association of the miR-143 Gene rs353292 Polymorphism with Recurrent Pregnancy Loss in Caucasian Women: A Novel Finding in a Multifactorial Devastating Problem. Int J Mol Sci 2024; 25:11952. [PMID: 39596022 PMCID: PMC11593960 DOI: 10.3390/ijms252211952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024] Open
Abstract
The purpose of this prospective case-control study is to investigate the correlation of the miR-143 gene rs353292 polymorphism in Caucasian women with recurrent pregnancy loss (RPL) compared to a matched control group with at least one live birth and without pregnancy losses. In total, 110 women with recurrent pregnancy losses and 95 control women were recruited. Peripheral blood was collected from all women, and the isolation of DNA was performed with Monarch Genomic DNA Purification. Polymerase chain reaction was applied to amplify the DNA sequence of the miR-143 gene promoter, carrying the polymorphism rs353292. The incidence of genotype CC in the RPL group was statistically significantly higher than in control group (p < 0.0001). Allele C (CT + CC) in the control group was found in 47.36%, and in the RPL group was found in 68.17% (p = 0.006). SNP rs353292 T>C was associated with increased risk of recurrent pregnancy loss. The calculated odds ratio for CT + CC vs. TT and for CC vs. TT were significant higher (p = 0.0028 and p < 0.0001, respectively). The study results suggest that the rs353292 polymorphism is associated with a statistically significant increase in RPL prevalence. The present study provides additional evidence in favor of a shared pathophysiological mechanism that contributes to both RPLs, potentially through inflammatory processes and epithelial-mesenchymal transition dysregulation.
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Affiliation(s)
- Sofoklis Stavros
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Anastasios Potiris
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Panagiotis Christopoulos
- Second Department of Obstetrics and Gynecology, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Natalia Zacharopoulou
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.Z.); (V.K.); (D.M.); (E.D.); (E.D.)
| | - Vasiliki Kyrli
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.Z.); (V.K.); (D.M.); (E.D.); (E.D.)
| | - Despoina Mavrogianni
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.Z.); (V.K.); (D.M.); (E.D.); (E.D.)
| | - Athanasios Zikopoulos
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Eirini Drakaki
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.Z.); (V.K.); (D.M.); (E.D.); (E.D.)
| | - Theodoros Karampitsakos
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Spyridon Topis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Nikolaos Machairiotis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Angeliki Gerede
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 69100 Campus, Greece;
| | - Chara Skentou
- Department of Obstetrics and Gynecology, Medical School, University of Ioannina, 45110 Ioannina, Greece;
| | - Peter Drakakis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (A.Z.); (T.K.); (S.T.); (N.M.); (P.D.)
| | - Ekaterini Domali
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece; (N.Z.); (V.K.); (D.M.); (E.D.); (E.D.)
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11
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Schoettler FI, Fatehi Hassanabad A, Jadli AS, Patel VB, Fedak PWM. Exploring the role of pericardial miRNAs and exosomes in modulating cardiac fibrosis. Cardiovasc Pathol 2024; 73:107671. [PMID: 38906439 DOI: 10.1016/j.carpath.2024.107671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/26/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
The potential of the pericardial space as a therapeutic delivery tool for cardiac fibrosis and heart failure (HF) treatment has yet to be elucidated. Recently, miRNAs and exosomes have been discovered to be present in human pericardial fluid (PF). Novel studies have shown characteristic human PF miRNA compositions associated with cardiac diseases and higher miRNA expressions in PF compared to peripheral blood. Five key studies found differentially expressed miRNAs in HF, angina pectoris, aortic stenosis, ventricular tachycardia, and congenital heart diseases with either atrial fibrillation or sinus rhythm. As miRNA-based therapeutics for cardiac fibrosis and HF showed promising results in several in vivo studies for multiple miRNAs, we hypothesize a potential role of miRNA-based therapeutics delivered through the pericardial cavity. This is underlined by the favorable results of the first phase 1b clinical trial in this emerging field. Presenting the first human miRNA antisense drug trial, inhibition of miR-132 by intravenous administration of a novel antisense oligonucleotide, CDR132L, established efficacy in reducing miR-132 in plasma samples in a dose-dependent manner. We screened the literature, provided an overview of the miRNAs and exosomes present in PF, and drew a connection to those miRNAs previously elucidated in cardiac fibrosis and HF. Further, we speculate about clinical implications and potential delivery methods.
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Affiliation(s)
- Friederike I Schoettler
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ali Fatehi Hassanabad
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Sciences, Section of Cardiac Surgery, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Anshul S Jadli
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Vaibhav B Patel
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Paul W M Fedak
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Sciences, Section of Cardiac Surgery, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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12
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Lattanzi GR, Dias MAD, Hashimoto DT, Costa AC, Neto SD, Pazo FD, Diaz J, Villanova GV, Reis Neto RV. Characterization of the myostatin gene in the neotropical species Piaractus mesopotamicus and the possibility of its use in genetic improvement programs. Mol Biol Rep 2024; 51:1048. [PMID: 39388010 DOI: 10.1007/s11033-024-09960-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND The myostatin gene has played an important role in the genetic improvement of the main species of economic importance; however, it has not yet been described for some Neotropical fish essential for aquaculture. This study aimed to characterize the myostatin gene of pacu, Piaractus mesopotamicus, and investigate the association of a microsatellite marker in this gene with the weight of fish. METHODS AND RESULTS The myostatin gene sequence was obtained after following a RACE-PCR strategy based on a partial mRNA sequence available in the GenBank database and the alignment of myostatin sequences from other fish species. The obtained sequence for the P. mesopotamicus gene was analyzed for short tandem repeats, and one dinucleotide was observed at the 3´untranslated region. A short tandem repeat polymorphism was verified in a wild population. Subsequently, the STR was evaluated in a test population of 232 animals in two 220 m² concrete tanks at the Aquaculture Center of Unesp. Eight alleles and 22 genotype combinations were identified. A significant association was observed between microsatellite marker polymorphisms and the weight traits (WEIGHT1 and WEIGHT2). Alleles 210, 222, 226, and 230 were found to favor weight gain. CONCLUSIONS In summary, this study contributes to the characterization of the myostatin gene in pacu fish and identifies an association between a STR and weight traits. Thus, this gene could be used as a target for genetic breeding using molecular strategies such as CRISPR and quantitative strategies such as marker-assisted selection, which would contribute to improving the production of the species.
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Affiliation(s)
| | | | | | | | | | - Felipe Del Pazo
- Laboratorio de Biotecnología Acuática-UNR, Rosario, Argentina
| | - Juan Diaz
- Laboratorio de Biotecnología Acuática-UNR, Rosario, Argentina
| | - Gabriela Vanina Villanova
- Laboratorio de Biotecnología Acuática-UNR, Rosario, Argentina
- National Scientific and Technical Research Council - Argentina (CONICET), Buenos Aires, Argentina
| | - Rafael Vilhena Reis Neto
- UNESP Aquaculture Center (CAUNESP), Jaboticabal, Brasil.
- Agricultural Sciences School of the Vale do Ribeira of UNESP (FCAVR), Registro, Brazil.
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13
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Llorente A, Brokāne A, Mlynska A, Puurand M, Sagini K, Folkmane S, Hjorth M, Martin‐Gracia B, Romero S, Skorinkina D, Čampa M, Cešeiko R, Romanchikova N, Kļaviņa A, Käämbre T, Linē A. From sweat to hope: The role of exercise-induced extracellular vesicles in cancer prevention and treatment. J Extracell Vesicles 2024; 13:e12500. [PMID: 39183543 PMCID: PMC11345496 DOI: 10.1002/jev2.12500] [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: 04/29/2024] [Revised: 07/03/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024] Open
Abstract
The benefits of regular physical exercise on cancer prevention, as well as reducing fatigue, treatment side effects and recurrence, and improving quality of life and overall survival of cancer patients, are increasingly recognised. Initial studies showed that the concentration of extracellular vesicles (EVs) increases during physical activity and that EVs carry biologically active cargo. These EVs are released by blood cells, skeletal muscle and other organs involved in exercise, thus suggesting that EVs may mediate tissue crosstalk during exercise. This possibility triggered a great interest in the study of the roles of EVs in systemic adaptation to exercise and in their potential applications in the prevention and treatment of various diseases, including cancer. This review presents studies exploring the concentration and molecular cargo of EVs released during exercise. Furthermore, we discuss putative stimuli that may trigger EV release from various cell types, the biological functions and the impact of exercise-induced EVs on cancer development and progression. Understanding the interplay between exercise, EVs, and cancer biology may offer insights into novel therapeutic strategies and preventive measures for cancer.
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Affiliation(s)
- Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer ResearchOslo University HospitalOsloNorway
- Centre for Cancer Cell Reprogramming, Faculty of MedicineUniversity of OsloOsloNorway
- Department for Mechanical, Electronics and Chemical EngineeringOslo Metropolitan UniversityOsloNorway
| | - Agnese Brokāne
- Cancer Biomarker groupLatvian Biomedical Research and Study CentreRigaLatvia
| | - Agata Mlynska
- Laboratory of ImmunologyNational Cancer InstituteVilniusLithuania
- Department of Chemistry and BioengineeringVilnius Gediminas Technical UniversityVilniusLithuania
| | - Marju Puurand
- Laboratory of Chemical BiologyNational Institute of Chemical Physics and BiophysicsTallinnEstonia
| | - Krizia Sagini
- Department of Molecular Cell Biology, Institute for Cancer ResearchOslo University HospitalOsloNorway
- Centre for Cancer Cell Reprogramming, Faculty of MedicineUniversity of OsloOsloNorway
| | - Signe Folkmane
- Cancer Biomarker groupLatvian Biomedical Research and Study CentreRigaLatvia
| | - Marit Hjorth
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Beatriz Martin‐Gracia
- Department of Molecular Cell Biology, Institute for Cancer ResearchOslo University HospitalOsloNorway
- Centre for Cancer Cell Reprogramming, Faculty of MedicineUniversity of OsloOsloNorway
| | - Silvana Romero
- Department of Molecular Cell Biology, Institute for Cancer ResearchOslo University HospitalOsloNorway
- Centre for Cancer Cell Reprogramming, Faculty of MedicineUniversity of OsloOsloNorway
| | - Diana Skorinkina
- Cancer Biomarker groupLatvian Biomedical Research and Study CentreRigaLatvia
| | - Mārtiņš Čampa
- Latvian Academy of Sport Education, Riga Stradins UniversityRigaLatvia
| | - Rūdolfs Cešeiko
- Latvian Academy of Sport Education, Riga Stradins UniversityRigaLatvia
| | | | - Aija Kļaviņa
- Latvian Academy of Sport Education, Riga Stradins UniversityRigaLatvia
- Department of Health Promotion and RehabilitationLithuanian Sports UniversityKaunasLithuania
| | - Tuuli Käämbre
- Laboratory of Chemical BiologyNational Institute of Chemical Physics and BiophysicsTallinnEstonia
| | - Aija Linē
- Cancer Biomarker groupLatvian Biomedical Research and Study CentreRigaLatvia
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14
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Canale P, Borghini A. Mitochondrial microRNAs: New Emerging Players in Vascular Senescence and Atherosclerotic Cardiovascular Disease. Int J Mol Sci 2024; 25:6620. [PMID: 38928325 PMCID: PMC11204228 DOI: 10.3390/ijms25126620] [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: 05/07/2024] [Revised: 06/04/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play an important role by controlling gene expression in the cytoplasm in almost all biological pathways. Recently, scientists discovered that miRNAs are also found within mitochondria, the energy-producing organelles of cells. These mitochondrial miRNAs, known as mitomiRs, can originate from the nuclear or mitochondrial genome, and they are pivotal in controlling mitochondrial function and metabolism. New insights indicate that mitomiRs may influence key aspects of the onset and progression of cardiovascular disease, especially concerning mitochondrial function and metabolic regulation. While the importance of mitochondria in cardiovascular health and disease is well-established, our understanding of mitomiRs' specific functions in crucial biological pathways, including energy metabolism, oxidative stress, inflammation, and cell death, is still in its early stages. Through this review, we aimed to delve into the mechanisms of mitomiR generation and their impacts on mitochondrial metabolic pathways within the context of vascular cell aging and atherosclerotic cardiovascular disease. The relatively unexplored field of mitomiR biology holds promise for future research investigations, with the potential to yield novel diagnostic tools and therapeutic interventions.
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Affiliation(s)
- Paola Canale
- Health Science Interdisciplinary Center, Sant’Anna School of Advanced Studies, 56124 Pisa, Italy;
- CNR Institute of Clinical Physiology, 56124 Pisa, Italy
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15
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Stańczak M, Wyszomirski A, Słonimska P, Kołodziej B, Jabłoński B, Stanisławska-Sachadyn A, Karaszewski B. Circulating miRNA profiles and the risk of hemorrhagic transformation after thrombolytic treatment of acute ischemic stroke: a pilot study. Front Neurol 2024; 15:1399345. [PMID: 38938784 PMCID: PMC11210454 DOI: 10.3389/fneur.2024.1399345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Background Hemorrhagic transformation (HT) in acute ischemic stroke is likely to occur in patients treated with intravenous thrombolysis (IVT) and may lead to neurological deterioration and symptomatic intracranial hemorrhage (sICH). Despite the complex inclusion and exclusion criteria for IVT and some useful tools to stratify HT risk, sICH still occurs in approximately 6% of patients because some of the risk factors for this complication remain unknown. Objective This study aimed to explore whether there are any differences in circulating microRNA (miRNA) profiles between patients who develop HT after thrombolysis and those who do not. Methods Using qPCR, we quantified the expression of 84 miRNAs in plasma samples collected prior to thrombolytic treatment from 10 individuals who eventually developed HT and 10 patients who did not. For miRNAs that were downregulated (fold change (FC) <0.67) or upregulated (FC >1.5) with p < 0.10, we investigated the tissue specificity and performed KEGG pathway annotation using bioinformatics tools. Owing to the small patient sample size, instead of multivariate analysis with all major known HT risk factors, we matched the results with the admission NIHSS scores only. Results We observed trends towards downregulation of miR-1-3p, miR-133a-3p, miR-133b and miR-376c-3p, and upregulation of miR-7-5p, miR-17-3p, and miR-296-5p. Previously, the upregulated miR-7-5p was found to be highly expressed in the brain, whereas miR-1, miR-133a-3p and miR-133b appeared to be specific to the muscles and myocardium. Conclusion miRNA profiles tend to differ between patients who develop HT and those who do not, suggesting that miRNA profiling, likely in association with other omics approaches, may increase the current power of tools predicting thrombolysis-associated sICH in acute ischemic stroke patients. This study represents a free hypothesis-approach pilot study as a continuation from our previous work. Herein, we showed that applying mathematical analyses to extract information from raw big data may result in the identification of new pathophysiological pathways and may complete standard design works.
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Affiliation(s)
- Marcin Stańczak
- Department of Adult Neurology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Department of Adult Neurology, University Clinical Center, Gdańsk, Poland
| | - Adam Wyszomirski
- Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland
| | - Paulina Słonimska
- Laboratory for Regenerative Biotechnology, Department of Biotechnology and Microbiology, Gdańsk University of Technology, Gdańsk, Poland
| | | | - Bartosz Jabłoński
- Department of Adult Neurology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Department of Adult Neurology, University Clinical Center, Gdańsk, Poland
| | - Anna Stanisławska-Sachadyn
- Department of Biotechnology and Microbiology, Gdańsk University of Technology, Gdańsk, Poland
- BioTechMed Center, Gdańsk University of Technology, Gdańsk, Poland
| | - Bartosz Karaszewski
- Department of Adult Neurology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Department of Adult Neurology, University Clinical Center, Gdańsk, Poland
- Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland
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16
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Mably JD, Wang DZ. Long non-coding RNAs in cardiac hypertrophy and heart failure: functions, mechanisms and clinical prospects. Nat Rev Cardiol 2024; 21:326-345. [PMID: 37985696 PMCID: PMC11031336 DOI: 10.1038/s41569-023-00952-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2023] [Indexed: 11/22/2023]
Abstract
The surge in reports describing non-coding RNAs (ncRNAs) has focused attention on their possible biological roles and effects on development and disease. ncRNAs have been touted as previously uncharacterized regulators of gene expression and cellular processes, possibly working to fine-tune these functions. The sheer number of ncRNAs identified has outpaced the capacity to characterize each molecule thoroughly and to reliably establish its clinical relevance; it has, nonetheless, created excitement about their potential as molecular targets for novel therapeutic approaches to treat human disease. In this Review, we focus on one category of ncRNAs - long non-coding RNAs - and their expression, functions and molecular mechanisms in cardiac hypertrophy and heart failure. We further discuss the prospects for this specific class of ncRNAs as novel targets for the diagnosis and treatment of these conditions.
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Affiliation(s)
- John D Mably
- Center for Regenerative Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Da-Zhi Wang
- Center for Regenerative Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
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17
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Pivonello C, Patalano R, Simeoli C, Montò T, Negri M, Amatrudo F, Di Paola N, Larocca A, Crescenzo EM, Pirchio R, Solari D, de Angelis C, Auriemma RS, Cavallo LM, Colao A, Pivonello R. Circulating myomiRNAs as biomarkers in patients with Cushing's syndrome. J Endocrinol Invest 2024; 47:655-669. [PMID: 37682493 PMCID: PMC10904409 DOI: 10.1007/s40618-023-02184-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/22/2023] [Indexed: 09/09/2023]
Abstract
PURPOSE Impairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle. METHODS C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation. RESULTS HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients. CONCLUSIONS HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.
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Affiliation(s)
- C Pivonello
- Department of Public Health, Federico II University, Naples, Italy
| | - R Patalano
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - C Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - T Montò
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - M Negri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - F Amatrudo
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - N Di Paola
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - A Larocca
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - E M Crescenzo
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - R Pirchio
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - D Solari
- Department of Neuroscience, Division of Neurosurgery, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
| | - C de Angelis
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - R S Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
| | - L M Cavallo
- Department of Neuroscience, Division of Neurosurgery, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
| | - A Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy
- UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy
| | - R Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università Federico II di Napoli, Naples, Italy.
- UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy.
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18
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Qi W, Guan W. A Comprehensive Review on the Importance of MiRNA-206 in the Animal Model and Human Diseases. Curr Neuropharmacol 2024; 22:1064-1079. [PMID: 37032500 PMCID: PMC10964108 DOI: 10.2174/1570159x21666230407124146] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/08/2023] [Accepted: 02/15/2023] [Indexed: 04/11/2023] Open
Abstract
MicroRNA-206 (miR-206) is a microRNA that is involved in many human diseases, such as myasthenia gravis, osteoarthritis, depression, cancers, etc. Both inhibition effects and progression roles of miR-206 have been reported for the past few years. High expression of miR-206 was observed in patients with osteoarthritis, gastric cancer and epithelial ovarian cancer compared to normal people. The study also showed that miR-206 promotes cancer progression in breast cancer patients and avascular necrosis of the femoral head. Meanwhile, several studies have shown that expression levels of miR-206 were down-regulated in laryngeal carcinoma cell multiplication, as well as in hepatocellular carcinoma, non-small lung cancer and infantile hemangioma. Moreover, miR-206 was up-regulated in the mild stage of amyotrophic lateral sclerosis patients and then down-regulated in the moderate and severe stages, indicating that miR-206 has the double effects of starting and aggravating the disease. In neuropsychiatric disorders, such as depression, miR-206 also plays an important role in the progression of the disease; the level of miR-206 is most highly expressed in the brains of patients with depression. In the current review, we summarize the role of miR-206 in various diseases, and miR-206 may be developed as a new biomarker for diagnosing diseases in the near future.
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Affiliation(s)
- Wang Qi
- Department of Pharmacology, The First People's Hospital of Yancheng, Yancheng, 224000, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, Pharmacy College, Nantong University, Nantong, 226001, Jiangsu, China
- School of Medicine, Nantong University, Nantong, China
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19
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Verleih M, Visnovska T, Nguinkal JA, Rebl A, Goldammer T, Andreassen R. The Discovery and Characterization of Conserved and Novel miRNAs in the Different Developmental Stages and Organs of Pikeperch ( Sander lucioperca). Int J Mol Sci 2023; 25:189. [PMID: 38203361 PMCID: PMC10778745 DOI: 10.3390/ijms25010189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Micro RNAs (miRNAs) are short non-coding RNAs that act as post-transcriptional gene expression regulators. Genes regulated in vertebrates include those affecting growth and development or stress and immune response. Pikeperch (Sander lucioperca) is a species that is increasingly being considered for farming in recirculation aquaculture systems. We characterized the pikeperch miRNA repertoire to increase the knowledge of the genomic mechanisms affecting performance and health traits by applying small RNA sequencing to different developmental stages and organs. There were 234 conserved and 8 novel miRNA genes belonging to 104 families. A total of 375 unique mature miRNAs were processed from these genes. Many mature miRNAs showed high relative abundances or were significantly more expressed at early developmental stages, like the miR-10 and miR-430 family, let-7, the miRNA clusters 106-25-93, and 17-19-92. Several miRNAs associated with immune responses (e.g., slu-mir-731-5p, slu-mir-2188-5p, and slu-mir-8159-5p) were enriched in the spleen. The mature miRNAs slu-mir-203a-3p and slu-mir-205-5p were enriched in gills. These miRNAs are similarly abundant in many vertebrates, indicating that they have shared regulatory functions. There was also a significantly increased expression of the disease-associated miR-462/miR-731 cluster in response to hypoxia stress. This first pikeperch miRNAome reference resource paves the way for future functional studies to identify miRNA-associated variations that can be utilized in marker-assisted breeding programs.
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Affiliation(s)
- Marieke Verleih
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany; (M.V.); (A.R.)
| | - Tina Visnovska
- Bioinformatics Core Facility, Oslo University Hospital, 0424 Oslo, Norway
| | - Julien A. Nguinkal
- Department of Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany;
| | - Alexander Rebl
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany; (M.V.); (A.R.)
| | - Tom Goldammer
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany; (M.V.); (A.R.)
- Faculty of Agriculture and Environmental Sciences, University of Rostock, 18059 Rostock, Germany
| | - Rune Andreassen
- Department of Life Sciences and Health, OsloMet—Oslo Metropolitan University, 0167 Oslo, Norway;
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20
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Haybar H, Sadati NS, Purrahman D, Mahmoudian-Sani MR, Saki N. lncRNA TUG1 as potential novel biomarker for prognosis of cardiovascular diseases. Epigenomics 2023; 15:1273-1290. [PMID: 38088089 DOI: 10.2217/epi-2023-0242] [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: 01/05/2024] Open
Abstract
Globally, cardiovascular diseases (CVDs) are among the leading causes of death. In light of the high prevalence and mortality of CVDs, it is imperative to understand the molecules involved in CVD pathogenesis and the signaling pathways that they initiate. This may facilitate the development of more precise and expedient diagnostic techniques, the identification of more effective prognostic molecules and the identification of potential therapeutic targets. Numerous studies have examined the role of lncRNAs, such as TUG1, in CVD pathogenesis in recent years. According to this review article, TUG1 can be considered a biomarker for predicting the prognosis of CVD.
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Affiliation(s)
- Habib Haybar
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Narjes Sadat Sadati
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Daryush Purrahman
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Dai S, Li F, Xu S, Hu J, Gao L. The important role of miR-1-3p in cancers. J Transl Med 2023; 21:769. [PMID: 37907984 PMCID: PMC10617136 DOI: 10.1186/s12967-023-04649-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/22/2023] [Indexed: 11/02/2023] Open
Abstract
Cancer is a malignant tumor that seriously threatens human life and health. At present, the main treatment methods include surgical resection, chemotherapy, radiotherapy, and immunotherapy. However, the mechanism of tumor occurrence and development is complex, and it produces resistance to some traditional treatment methods, leading to treatment failure and a high mortality rate for patients. Therefore, exploring the molecular mechanisms of tumor occurrence, development, and drug resistance is a very important task. MiRNAs are a type of non-coding small RNA that regulate a series of biological effects by binding to the 3'-UTR of the target mRNA, degrading the mRNA, or inhibiting its translation. MiR-1-3p is an important member of them, which is abnormally expressed in various tumors and closely related to the occurrence and development of tumors. This article introduces miR-1-3p from multiple aspects, including its production and regulation, role in tumor occurrence and development, clinical significance, role in drug resistance, and approaches for targeting miR-1-3p. Intended to provide readers with a comprehensive understanding of the important role of miR-1-3p in tumors.
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Affiliation(s)
- Shangming Dai
- Department of Pharmacy, School of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Fengjiao Li
- Department of Pharmacy, School of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Shuoguo Xu
- Department of Pharmacy, School of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Jinda Hu
- Department of Pharmacy, School of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Lichen Gao
- Department of Pharmacy, School of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China.
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22
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Lin H, Chu J, Yuan D, Wang K, Chen F, Liu X. MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1. BMC Cardiovasc Disord 2023; 23:470. [PMID: 37730550 PMCID: PMC10512505 DOI: 10.1186/s12872-023-03481-8] [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: 04/23/2023] [Accepted: 08/29/2023] [Indexed: 09/22/2023] Open
Abstract
Myocardial infarction (MI) is a leading cause of mortality. To better understand its molecular and cellular mechanisms, we used bioinformatic tools and molecular experiments to explore the pathogenesis and prognostic markers. Differential gene expression analysis was conducted using GSE60993 and GSE66360 datasets. Hub genes were identified through pathway enrichment analysis and PPI network construction, and four hub genes (AQP9, MMP9, FPR1, and TREM1) were evaluated for their predictive performance using AUC and qRT-PCR. miR-206 was identified as a potential regulator of TREM1. Finally, miR-206 was found to induce EC senescence and ER stress through upregulating mitochondrial ROS levels via TREM1. These findings may contribute to understanding the pathogenesis of MI and identifying potential prognostic markers.
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Affiliation(s)
- Hao Lin
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China
| | - Jiapeng Chu
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China
| | - Deqiang Yuan
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China
| | - Kangwei Wang
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China
| | - Fei Chen
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China.
| | - Xuebo Liu
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, No.389, Xincun Road, Shanghai, 200092, Putuo District, China.
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23
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Dong J, Wang L, Xing Y, Qian J, He X, Wu J, Zhou J, Hai L, Wang J, Yang H, Huang J, Gou X, Ju Y, Wang X, He Y, Su D, Kong L, Liang B, Wang X. Dynamic peripheral blood microRNA expression landscape during the peri-implantation stage in women with successful pregnancy achieved by single frozen-thawed blastocyst transfer. Hum Reprod Open 2023; 2023:hoad034. [PMID: 37700872 PMCID: PMC10493182 DOI: 10.1093/hropen/hoad034] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 08/07/2023] [Indexed: 09/14/2023] Open
Abstract
STUDY QUESTION What are the dynamic expression features of plasma microRNAs (miRNAs) during the peri-implantation period in women with successful pregnancy via single frozen-thawed blastocyst transfer? SUMMARY ANSWER There is a significant change in the plasma miRNA expression profile before and after blastocyst transfer, during the window of implantation. WHAT IS KNOWN ALREADY The expression of miRNAs in peripheral blood has indicative functions during the peri-implantation period. Nevertheless, the dynamic expression profile of circulating miRNAs during the peri-implantation stage in women with a successful pregnancy has not been studied. STUDY DESIGN SIZE DURATION Seventy-six women treated for infertility with a single frozen-thawed blastocyst transfer in a natural cycle were included in this study. Among them, 57 women had implantation success and a live birth, while 19 patients experienced implantation failure. Peripheral blood samples were collected at five different time points throughout the peri-implantation period, including D0 (ovulation day), D3, D5, D7, and D9 in this cycle of embryo transfer. The plasma miRNAs in women with blastocyst transfer were isolated, sequenced, and analyzed. PARTICIPANTS/MATERIALS SETTING METHODS Peripheral blood samples were collected in EDTA tubes and stored at -80°C until further use. miRNAs were isolated from blood, cDNA libraries were constructed, and the resulting sequences were mapped to the human genome. The plasma miRNAs were initially analyzed in a screening cohort (n = 34) with successful pregnancy. Trajectory analysis, including a global test and pairwise comparisons, was performed to detect dynamic differentially expressed (DE) miRNAs. Fuzzy c-means clustering was conducted for all dynamic DE miRNAs. The correlation between DE miRNAs and clinical characteristics of patients was investigated using a linear mixed model. Target genes of the miRNAs were predicted, and functional annotation analysis was performed. The expression of DE miRNAs was also identified in a validation set consisting of women with successful (n = 23) and unsuccessful (n = 19) pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE Following small RNA sequencing, a total of 2656 miRNAs were determined as valid read values. After trajectory analysis, 26 DE miRNAs (false discovery rate < 0.05) were identified by the global test, while pairwise comparisons in addition identified 20 DE miRNAs. A total of seven distinct clusters representing different temporal patterns of miRNA expression were discovered. Nineteen DE miRNAs were further identified to be associated with at least one clinical trait. Endometrium thickness and progesterone level showed a correlation with multiple DE miRNAs (including two of the same miRNAs, hsa-miR-1-3p and hsa-miR-6741-3p). Moreover, the 19 DE miRNAs were predicted to have 403 gene targets, and there were 51 (12.7%) predicted genes likely involved in both decidualization and embryo implantation. Functional annotation for predicted targets of those clinically related DE miRNAs suggested the involvement of vascular endothelial growth factor and Wnt signaling pathways, as well as responses to hormones, immune responses, and cell adhesion-related signaling pathways during the peri-implantation stage. LARGE SCALE DATA The raw miRNA sequence data reported in this article have been deposited in the Genome Sequence Archive (GSA-Human: HRA005227) and are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA005227. LIMITATIONS REASONS FOR CAUTION Although the RNA sequencing results revealed the global dynamic changes of miRNA expression, further experiments examining the clinical significance of the identified DE miRNAs in embryo implantation outcome and the relevant regulatory mechanisms involved are warranted. WIDER IMPLICATIONS OF THE FINDINGS Understanding the dynamic landscape of the miRNA transcriptome could shed light on the physiological mechanisms involved from ovulation to the post-implantation stage, as well as identifying biomarkers that characterize stage-related biological process. STUDY FUNDING/COMPETING INTERESTS The study was funded by the Major clinical research project of Tangdu Hospital (2021LCYJ004) and the Discipline Platform Improvement Plan of Tangdu Hospital (2020XKPT003). The funders had no influence on the study design, data collection, and analysis, decision to publish, or preparation of the article. There are no conflicts of interest to declare.
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Affiliation(s)
- Jie Dong
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Lu Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Yanru Xing
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Jun Qian
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Xiao He
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jing Wu
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Juan Zhou
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Li Hai
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jun Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Hongya Yang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jianlei Huang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xingqing Gou
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Ying Ju
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xiyi Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Yunan He
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Danjie Su
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Lingyin Kong
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Bo Liang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaohong Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
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Pérez-Cremades D, Chen J, Assa C, Feinberg MW. MicroRNA-mediated control of myocardial infarction in diabetes. Trends Cardiovasc Med 2023; 33:195-201. [PMID: 35051592 PMCID: PMC9288556 DOI: 10.1016/j.tcm.2022.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus is a global public health problem whose cases will continue to rise along with the progressive increase in obesity and the aging of the population. People with diabetes exhibit higher risk of cardiovascular complications, especially myocardial infarction (MI). microRNAs (miRNAs) are evolutionary conserved small non-coding RNAs involved in the regulation of biological processes by interfering in gene expression at the post-transcriptional level. Accumulating studies in the last two decades have uncovered the role of stage-specific miRNAs associated with key pathobiological events observed in the hearts of people with diabetes and MI, including cardiomyocyte death, angiogenesis, inflammatory response, myocardial remodeling, and myocardial lipotoxicity. A better understanding of the importance of these miRNAs and their targets may provide novel opportunities for RNA-based therapeutic interventions to address the increased risk of MI in diabetes.
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Affiliation(s)
- Daniel Pérez-Cremades
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 02115; Department of Physiology, University of Valencia and INCLIVA Biomedical Research Institute, Valencia, Spain 46010
| | - Jingshu Chen
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 02115
| | - Carmel Assa
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 02115
| | - Mark W Feinberg
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 02115.
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25
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Integrative Analysis of miRNAs Involved in Fat Deposition in Different Pig Breeds. Genes (Basel) 2022; 14:genes14010094. [PMID: 36672834 PMCID: PMC9859024 DOI: 10.3390/genes14010094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND miRNAs are a set of small, noncoding RNAs that bind to partially complementary sequences on target mRNAs. This leads to the post-transcriptional regulation of gene expression. Many studies have shown that microRNAs play critical roles in adipose cell differentiation and fat metabolism. The aim of this study was to explore the regulatory functions of miRNAs in fat deposition for the prevention and therapy of lipid metabolism-related diseases. METHODS The significant differences in the fat deposition of Laiwu (LW) pigs and Large White (LY) pigs were studied. To investigate the genetic relationships of miRNAs that regulate fat deposition, we performed a genome-wide analysis of miRNAs derived from subcutaneous adipose tissue of LW and LY pigs using RNA-seq. RESULTS There were 39 known miRNAs and 56 novel miRNAs significantly differential expressed between the two breeds of pigs. In the analysis of the Gene Ontology and KEGG pathways, predicted targets of these differentially expressed miRNAs were involved in several fat-associated pathways, such as the peroxisome proliferator-activated receptor (PPAR), mitogen-activated protein kinases (MAPK) and Wnt signaling pathways. In addition, ssc-miR-133a-3p, ssc-miR-486 and ssc-miR-1 each had a great impact on the development of porcine subcutaneous fat through the PPAR signaling pathway. CONCLUSIONS We explored the role of differentially expressed miRNAs and studied the mechanisms of adipogenesis and fat deposition between two different pig breeds. In addition, these results also contribute to research relevant to human obesity.
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Sumaiya K, Ponnusamy T, Natarajaseenivasan K, Shanmughapriya S. Cardiac Metabolism and MiRNA Interference. Int J Mol Sci 2022; 24:50. [PMID: 36613495 PMCID: PMC9820363 DOI: 10.3390/ijms24010050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
The aberrant increase in cardio-metabolic diseases over the past couple of decades has drawn researchers' attention to explore and unveil the novel mechanisms implicated in cardiometabolic diseases. Recent evidence disclosed that the derangement of cardiac energy substrate metabolism plays a predominant role in the development and progression of chronic cardiometabolic diseases. Hence, in-depth comprehension of the novel molecular mechanisms behind impaired cardiac metabolism-mediated diseases is crucial to expand treatment strategies. The complex and dynamic pathways of cardiac metabolism are systematically controlled by the novel executor, microRNAs (miRNAs). miRNAs regulate target gene expression by either mRNA degradation or translational repression through base pairing between miRNA and the target transcript, precisely at the 3' seed sequence and conserved heptametrical sequence in the 5' end, respectively. Multiple miRNAs are involved throughout every cardiac energy substrate metabolism and play a differential role based on the variety of target transcripts. Novel theoretical strategies have even entered the clinical phase for treating cardiometabolic diseases, but experimental evidence remains inadequate. In this review, we identify the potent miRNAs, their direct target transcripts, and discuss the remodeling of cardiac metabolism to cast light on further clinical studies and further the expansion of novel therapeutic strategies. This review is categorized into four sections which encompass (i) a review of the fundamental mechanism of cardiac metabolism, (ii) a divulgence of the regulatory role of specific miRNAs on cardiac metabolic pathways, (iii) an understanding of the association between miRNA and impaired cardiac metabolism, and (iv) summary of available miRNA targeting therapeutic approaches.
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Affiliation(s)
- Krishnamoorthi Sumaiya
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India
| | - Thiruvelselvan Ponnusamy
- Department of Medicine, Department of Cellular and Molecular Physiology, Heart and Vascular Institute, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Department of Medicine, Department of Cellular and Molecular Physiology, Heart and Vascular Institute, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
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Luo J, Zhao S, Ren Q, Wang Q, Chen Z, Cui J, Jing Y, Liu P, Yan R, Song X, Liu G, Li X. Dynamic Analysis of microRNAs from Different Life Stages of Rhipicephalus microplus (Acari: Ixodidae) by High-Throughput Sequencing. Pathogens 2022; 11:pathogens11101148. [PMID: 36297205 PMCID: PMC9611014 DOI: 10.3390/pathogens11101148] [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: 09/20/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/07/2022] Open
Abstract
MicroRNAs (miRNAs), which are small, noncoding RNA molecules, play an important regulatory role in gene expression at the posttranscriptional level. Relatively limited knowledge exists on miRNAs in Rhipicephalus microplus ticks in China; however, understanding the physiology of miRNA functions and expression at different developmental stages is important. In this study, three small RNA libraries were constructed for R. microplus eggs, larvae, and female adults; miRNAs were detected during these developmental stages by high-throughput sequencing, with 18,162,337, 8,090,736, and 11,807,326 clean reads, respectively. A total of 5132 known miRNAs and 31 novel miRNAs were identified. A total of 1736 differentially expressed miRNAs were significantly different at a p-value of <0.01; in female adults, 467 microRNAs were upregulated and 376 miRNAs downregulated compared to larval tick controls. Using larvae as controls, 218 upregulated and 203 downregulated miRNAs were detected in eggs; in eggs, 108 miRNAs were upregulated and 364 downregulated compared to female adults controls. To verify the reliability of the sequencing data, RT−qPCR was applied to compare expression levels of novel miRNAs. Some differentially expressed miRNAs are involved in developmental physiology, signal transduction, and cell-extracellular communications based on GO annotation and KEGG pathway analyses. Here, we provide a dynamic analysis of miRNAs in R. microplus and their potential targets, which has significance for understanding the biology of ticks and lays the foundation for improved understanding of miRNA functioning in the regulation of R. microplus development. These results can assist future miRNA studies in other tick species that have great significance for human and animal health.
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Affiliation(s)
- Jin Luo
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Shuaiyang Zhao
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Qiaoyun Ren
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Qilin Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Zeyu Chen
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Jingjing Cui
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Yujiao Jing
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Peiwen Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
| | - Ruofeng Yan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiaokai Song
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Guangyuan Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Science, Xujiaping 1, Lanzhou 730046, China
- Correspondence: (G.L.); (X.L.)
| | - Xiangrui Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- Correspondence: (G.L.); (X.L.)
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Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases. Int J Mol Sci 2022; 23:ijms231710174. [PMID: 36077591 PMCID: PMC9456330 DOI: 10.3390/ijms231710174] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.
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Xiao Z, He F, Feng M, Liu Z, Liu Z, Li S, Wang W, Yao H, Wu J. Engineered coxsackievirus B3 containing multiple organ-specific miRNA targets showed attenuated viral tropism and protective immunity. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 103:105316. [PMID: 35718333 DOI: 10.1016/j.meegid.2022.105316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/07/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023]
Abstract
Coxsackievirus B3 (CVB3) can cause viral myocarditis, pancreatitis, and aseptic meningitis. This study aimed to construct an engineered CVB3 harboring three different tissue-specific miRNA targets (CVB3-miR3*T) to decrease the virulence of CVB3 in muscles, pancreas, and brain. CVB3-miR3*T and CVB3-miR-CON (containing three sequences not found in the human genome) were engineered and replicated in HELA cells. A viral plaque assay was used to determine the titers in HELA cells and TE671 cells (high miRNA-206 expression), MIN-6 cells (high miRNA-29a-3p expression), and mouse astrocytes (high miRNA-124-3p expression). We found that engineered CVB3 showed attenuated replication and reduced cytotoxicity, the variability of each type of cell was also increased in the CVB3-miR3*T group. Male BALB/c mice were infected to determine the LD50 and examine heart, pancreas, and brain titers and injury. Viral replication of the engineered viruses was restricted in infected mouse heart, pancreas, and brain, and viral plaques were about 100 fold lower compared with the control group. Mice immunized using CVB3-miR3*T, UV-inactivated CVB3-WT, and CVB3-miR-CON were infected with 100 × LD50 of CVB3-WT to determine neutralization. CVB3-miRT*3-preimmunized mice exhibited complete protection and remained alive after lethal virus infection, while only 5/15 were alive in the UV-inactivated mice, and all 15 mice were dead in the PBS-immunized group. The results demonstrate that miR-206-, miRNA-29a-3p-, and miRNA-124-3p-mediated CVB3 detargeting from the pancreas, heart, and brain might be a highly effective strategy for viral vaccine development.
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Affiliation(s)
- Zonghui Xiao
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Feng He
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Miao Feng
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Zhuo Liu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Zhewei Liu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Sen Li
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Wei Wang
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Hailan Yao
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China.
| | - Jianxin Wu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China; Beijing Municipal Key Laboratory of Child Development and Nutriomics, Beijing, China; Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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Yang Y, Yang H, Lian X, Yang S, Shen H, Wu S, Wang X, Lyu G. Circulating microRNA: Myocardium-derived prenatal biomarker of ventricular septal defects. Front Genet 2022; 13:899034. [PMID: 36035156 PMCID: PMC9403759 DOI: 10.3389/fgene.2022.899034] [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: 03/18/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Recently, circulating microRNAs (miRNAs) from maternal blood and amniotic fluid have been used as biomarkers for ventricular septal defect (VSD) diagnosis. However, whether circulating miRNAs are associated with fetal myocardium remains unknown.Methods: Dimethadione (DMO) induced a VSD rat model. The miRNA expression profiles of the myocardium, amniotic fluid and maternal serum were analyzed. Differentially expressed microRNAs (DE-microRNAs) were verified by qRT–PCR. The target gene of miR-1-3p was confirmed by dual luciferase reporter assays. Expression of amniotic fluid-derived DE-microRNAs was verified in clinical samples.Results: MiRNAs were differentially expressed in VSD fetal rats and might be involved in cardiomyocyte differentiation and apoptosis. MiR-1-3p, miR-1b and miR-293-5p were downregulated in the myocardium and upregulated in amniotic fluid/maternal serum. The expression of amniotic fluid-derived DE-microRNAs (miR-1-3p, miR-206 and miR-184) was verified in clinical samples. Dual luciferase reporter assays confirmed that miR-1-3p directly targeted SLC8A1/NCX1.Conclusion: MiR-1-3p, miR-1b and miR-293-5p are downregulated in VSD myocardium and upregulated in circulation and may be released into circulation by cardiomyocytes. MiR-1-3p targets SLC8A1/NCX1 and participates in myocardial apoptosis. MiR-1-3p upregulation in circulation is a direct and powerful indicator of fetal VSD and is expected to serve as a prenatal VSD diagnostic marker.
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Affiliation(s)
- Yiru Yang
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Hainan Yang
- Department of Ultrasound, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Xihua Lian
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Shuping Yang
- Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China
| | - Haolin Shen
- Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China
| | - Shufen Wu
- Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China
| | - Xiali Wang
- Collaborative Innovation Center for Maternal and Infant Health Service Application Technology, Quanzhou Medical College, Quanzhou, Fujian, China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Collaborative Innovation Center for Maternal and Infant Health Service Application Technology, Quanzhou Medical College, Quanzhou, Fujian, China
- *Correspondence: Guorong Lyu,
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Huang Y, Chen H, Gao X, Ren H, Gao S. Identification and functional analysis of miRNAs in skeletal muscle of juvenile and adult largemouth bass, Micropterus salmoides. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2022; 42:100985. [PMID: 35381488 DOI: 10.1016/j.cbd.2022.100985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/20/2022] [Accepted: 03/25/2022] [Indexed: 11/28/2022]
Abstract
MicroRNAs (miRNAs) are considered key regulators to post-transcriptionally regulate gene expression affecting multiple biological activities. However, the developmental process of fish skeletal muscles is regulated by complicated molecular mechanism that has not been completely well-described. In this study, two small RNAs libraries from skeletal muscle of juvenile as well as adult largemouth bass (LMB) were obtained and sequenced using deep sequencing to investigate the development-related miRNAs. We identified an overall number of 486 already recognized miRNAs in addition to 43 novel miRNAs. Comparison of two different skeletal muscle development stages led to the identification of 220 differently expressed miRNAs between juvenile and adult LMB containing 116 up-regulated as well as 104 down-regulated miRNAs. Of them, confirmation of some differently expressed miRNAs was performed via a stem-loop qRT-PCR, which exhibited differently expressed level in juvenile and adult LMB. Furthermore, GO and KEGG enrichment analyses of targets of differently-expressed miRNAs were carried out. Additionally, the analysis of miRNAs-targets interaction network showed that miR-181b-5p_R-1, miR-725 and miR-103 as the nodal miRNAs has over 20 target genes. Moreover, miR-103 could bind the 3'-UTR of actr8, which was validated via dual-luciferase reporter assay. It has been reasonably hypothesized that miR-103 may play a crucial role, which regulate skeletal muscle development of LMB. The present study provides the first identification of miRNA expression profiles at two different skeletal muscle development stages in LMB. Results may be valuable in interpreting the regulatory role miRNAs plays in the growth and developmental process of skeletal muscle and its possible use in LMB breeding.
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Affiliation(s)
- Yong Huang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China.
| | - Haigang Chen
- Guangdong Province Key Laboratory of Fish Ecology and Environment, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510300, China
| | - Xiaochan Gao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
| | - Hongtao Ren
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
| | - Shiyang Gao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
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Pan-cancer analysis of microRNA expression profiles highlights microRNAs enriched in normal body cells as effective suppressors of multiple tumor types: A study based on TCGA database. PLoS One 2022; 17:e0267291. [PMID: 35476804 PMCID: PMC9045663 DOI: 10.1371/journal.pone.0267291] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are frequently deregulated in various types of cancer. While antisense oligonucleotides are used to block oncomiRs, delivery of tumour-suppressive miRNAs holds great potential as a potent anti-cancer strategy. Here, we aim to determine, and functionally analyse, miRNAs that are lowly expressed in various types of tumour but abundantly expressed in multiple normal tissues. METHODS The miRNA sequencing data of 14 cancer types were downloaded from the TCGA dataset. Significant differences in miRNA expression between tumor and normal samples were calculated using limma package (R programming). An adjusted p value < 0.05 was used to compare normal versus tumor miRNA expression profiles. The predicted gene targets were obtained using TargetScan, miRanda, and miRDB and then subjected to gene ontology analysis using Enrichr. Only GO terms with an adjusted p < 0.05 were considered statistically significant. All data from wet-lab experiments (cell viability assays and flow cytometry) were expressed as means ± SEM, and their differences were analyzed using GraphPad Prism software (Student's t test, p < 0.05). RESULTS By compiling all publicly available miRNA profiling data from The Cancer Genome Atlas (TCGA) Pan-Cancer Project, we reveal a small set of tumour-suppressing miRNAs (which we designate as 'normomiRs') that are highly expressed in 14 types of normal tissues but poorly expressed in corresponding tumour tissues. Interestingly, muscle-enriched miRNAs (e.g. miR-133a/b and miR-206) and miRNAs from DLK1-DIO3 locus (e.g. miR-381 and miR-411) constitute a large fraction of the normomiRs. Moreover, we define that the CCCGU motif is absent in the oncomiRs' seed sequences but present in a fraction of tumour-suppressive miRNAs. Finally, the gain of function of candidate normomiRs across several cancer cell types indicates that miR-206 and miR-381 exert the most potent inhibition on multiple cancer types in vitro. CONCLUSION Our results reveal a pan-cancer set of tumour-suppressing miRNAs and highlight the potential of miRNA-replacement therapies for targeting multiple types of tumour.
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Abstract
PURPOSE OF REVIEW This review highlights the key studies investigating various types of biomarkers in Duchenne muscular dystrophy (DMD). RECENT FINDINGS Several proteomic and metabolomic studies have been undertaken in both human DMD patients and animal models of DMD that have identified potential biomarkers in DMD. Although there have been a number of proteomic and metabolomic studies that have identified various potential biomarkers in DMD, more definitive studies still need to be undertaken in DMD patients to firmly correlate these biomarkers with diagnosis, disease progression, and monitoring the effects of novel treatment strategies being developed.
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Affiliation(s)
- Theo Lee-Gannon
- Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Xuan Jiang
- Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Tara C Tassin
- Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Pradeep P A Mammen
- Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
- Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
- UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
- Heart Failure, Ventricular Assist Device & Heart Transplant Program, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
- Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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lncRNA ADAMTS9-AS1/circFN1 Competitively Binds to miR-206 to Elevate the Expression of ACTB, Thus Inducing Hypertrophic Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1450610. [PMID: 35401927 PMCID: PMC8989615 DOI: 10.1155/2022/1450610] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 11/17/2022]
Abstract
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease and can result in substantial disability. The current study explored the potentials of long noncoding RNA- (lncRNA-) circular RNA- (circRNA-) microRNA- (miRNA-) messenger RNA (mRNA) networks in HCM. Firstly, HCM-related microarray data were procured from the GEO database, with differentially expressed genes (DEGs) obtained. HCM-related target genes were retrieved in combination with GeneCards and CTD databases, and candidate target genes were subsequently obtained by intersection screening. Further, an interaction network diagram of candidate target genes was constructed using the STRING database, and the hub genes in the network were determined according to the core degree. The “ClusterProfiler” package of the R software was adopted for GO and KEGG analyses of candidate target genes, to analyze the potential molecular pathways in HCM. Next, upstream miRNA, lncRNA, and circRNA of ACTB were predicted with RNAInter, mirDIP, TargetScan, DIANA-LncBase, and StarBase databases, followed by construction of lncRNA/circRNA-miRNA-mRNA coexpression networks. ACTB, miR-206, circFN1, and ADAMTS9-AS1 expression in peripheral blood samples from HCM patients and normal healthy controls were detected using RT-qPCR. Moreover, rat cardiomyocyte cell lines H9c2 and HEK293 cells were selected for in vitro verification of competitive endogenous RNA (ceRNA) regulation mechanism. A total of 15 candidate target genes related to HCM were screened using the online databases. Further protein-protein interaction analysis identified ACTB as the hub gene for HCM. The targeted binding relationship between miR-206, miR-145-5p, miR-1-3p, and ACTB was found. Furthermore, ADAMTS9-AS1 and circFN1 were discovered as the upstream genes of miR-206. Moreover, ADAMTS9-AS1, circFN1, and ACTB were found to be poorly expressed, and miR-206 was highly expressed in HCM. In vitro experimentation further confirmed that ADAMTS9-AS1 and circFN1 could competitively bind to miR-206, thereby augmenting ACTB expression. Taken all, ADAMTS9-AS1/circFN1-miR-206-ACTB regulatory network may involve in HCM occurrence, providing a novel theoretical basis for in-depth understanding of mechanism of HCM.
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Ye J, Zhao X, Xue H, Zou X, Liu G, Deng M, Sun B, Guo Y, Liu D, Li Y. RNA-Seq Reveals miRNA and mRNA Co-regulate Muscle Differentiation in Fetal Leizhou Goats. Front Vet Sci 2022; 9:829769. [PMID: 35400087 PMCID: PMC8990838 DOI: 10.3389/fvets.2022.829769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Muscle differentiation is an essential link in animal growth and development, and microRNA and mRNA are indispensable in skeletal muscle differentiation. To improve the meat quality and production of the Leizhou goat, it is vital to understand the molecular mechanism by which its skeletal muscle differentiates. By RNA sequencing (RNA-SEQ), we established miRNA-mRNA profiles of Leizhou goats at three stages: fetal day 70, 90, and 120. There were 991 differently expressed mRNAs and 39 differentially expressed miRNAs found, with the differentially expressed mRNAs mainly enriched in calcium ion binding, ECM-receptor interaction, and Focal adhesion. CKM and MYH3, two muscle differentiation markers, were significantly differentially expressed during this period. In addition, we found that chi-miR-129-5p, chi-miR-433, and chi-miR-24-3p co-regulate muscle differentiation with their target genes. Finally, we can confirm that muscle differentiation occurred in Leizhou goat between 90 and 120 days of the fetus. This study is helpful to better explore the molecular mechanism of goat muscle differentiation.
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Affiliation(s)
- Junning Ye
- College of Animal Science, South China Agricultural University, Guangzhou, China
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Xiuhui Zhao
- College of Animal Science, South China Agricultural University, Guangzhou, China
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Huiwen Xue
- College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xian Zou
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Guangbin Liu
- College of Animal Science, South China Agricultural University, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Ming Deng
- College of Animal Science, South China Agricultural University, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Baoli Sun
- College of Animal Science, South China Agricultural University, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Yongqing Guo
- College of Animal Science, South China Agricultural University, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Dewu Liu
- College of Animal Science, South China Agricultural University, Guangzhou, China
- National Local Joint Engineering Research Center of Livestock and Poultry, South China Agricultural University, Guangzhou, China
| | - Yaokun Li
- College of Animal Science, South China Agricultural University, Guangzhou, China
- *Correspondence: Yaokun Li
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Impact of miR-1/ miR-133 Clustered miRNAs: PFN2 Facilitates Malignant Phenotypes in Head and Neck Squamous Cell Carcinoma. Biomedicines 2022; 10:biomedicines10030663. [PMID: 35327465 PMCID: PMC8944972 DOI: 10.3390/biomedicines10030663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/06/2022] [Accepted: 03/10/2022] [Indexed: 12/14/2022] Open
Abstract
Based on our original RNA sequence-based microRNA (miRNA) signatures of head and neck squamous cell carcinoma (HNSCC), it was revealed that the expression levels of miR-1-3p, miR-206, miR-133a-3p, and miR-133b were significantly suppressed in cancer specimens. Seed sequences of miR-1-3p/miR-206 and miR-133a-3p/miR-133b are identical. Interestingly, miR-1-3p/miR-133a-3p and miR-206/miR-133b are clustered in the human genome. We hypothesized that the genes coordinately controlled by these miRNAs are closely involved in the malignant transformation of HNSCC. Our in silico analysis identified a total of 28 genes that had putative miR-1-3p/miR-133a-3p and miR-206/miR-133b binding sites. Moreover, their expression levels were upregulated in HNSCC tissues. Multivariate Cox regression analyses showed that expression of PFN2 and PSEN1 were independent prognostic factors for patients with HNSCC (p < 0.05). Notably, four miRNAs (i.e., miR-1-3p, miR-206, miR-133a-3p, and miR-133b) directly bound the 3′untranslated region of PFN2 and controlled expression of the gene in HNSCC cells. Overexpression of PFN2 was confirmed in clinical specimens, and its aberrant expression facilitated cancer cell migration and invasion abilities. Our miRNA-based strategy continues to uncover novel genes closely involved in the oncogenesis of HNSCC.
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Matsuzaka Y, Hirai Y, Hashido K, Okada T. Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy. Int J Mol Sci 2022; 23:1551. [PMID: 35163475 PMCID: PMC8836108 DOI: 10.3390/ijms23031551] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 02/04/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is caused by loss-of-function mutations in the dystrophin gene on chromosome Xp21. Disruption of the dystrophin-glycoprotein complex (DGC) on the cell membrane causes cytosolic Ca2+ influx, resulting in protease activation, mitochondrial dysfunction, and progressive myofiber degeneration, leading to muscle wasting and fragility. In addition to the function of dystrophin in the structural integrity of myofibers, a novel function of asymmetric cell division in muscular stem cells (satellite cells) has been reported. Therefore, it has been suggested that myofiber instability may not be the only cause of dystrophic degeneration, but rather that the phenotype might be caused by multiple factors, including stem cell and myofiber functions. Furthermore, it has been focused functional regulation of satellite cells by intracellular communication of extracellular vesicles (EVs) in DMD pathology. Recently, a novel molecular mechanism of DMD pathogenesis-circulating RNA molecules-has been revealed through the study of target pathways modulated by the Neutral sphingomyelinase2/Neutral sphingomyelinase3 (nSMase2/Smpd3) protein. In addition, adeno-associated virus (AAV) has been clinically applied for DMD therapy owing to the safety and long-term expression of transduction genes. Furthermore, the EV-capsulated AAV vector (EV-AAV) has been shown to be a useful tool for the intervention of DMD, because of the high efficacy of the transgene and avoidance of neutralizing antibodies. Thus, we review application of AAV and EV-AAV vectors for DMD as novel therapeutic strategy.
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Affiliation(s)
- Yasunari Matsuzaka
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan;
| | - Yukihiko Hirai
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
| | - Kazuo Hashido
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan;
| | - Takashi Okada
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
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Mytidou C, Koutsoulidou A, Zachariou M, Prokopi M, Kapnisis K, Spyrou GM, Anayiotos A, Phylactou LA. Age-Related Exosomal and Endogenous Expression Patterns of miR-1, miR-133a, miR-133b, and miR-206 in Skeletal Muscles. Front Physiol 2021; 12:708278. [PMID: 34867435 PMCID: PMC8637414 DOI: 10.3389/fphys.2021.708278] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle growth and maintenance depend on two tightly regulated processes, myogenesis and muscle regeneration. Both processes involve a series of crucial regulatory molecules including muscle-specific microRNAs, known as myomiRs. We recently showed that four myomiRs, miR-1, miR-133a, miR-133b, and miR-206, are encapsulated within muscle-derived exosomes and participate in local skeletal muscle communication. Although these four myomiRs have been extensively studied for their function in muscles, no information exists regarding their endogenous and exosomal levels across age. Here we aimed to identify any age-related changes in the endogenous and muscle-derived exosomal myomiR levels during acute skeletal muscle growth. The four endogenous and muscle-derived myomiRs were investigated in five skeletal muscles (extensor digitorum longus, soleus, tibialis anterior, gastrocnemius, and quadriceps) of 2-week–1-year-old wild-type male mice. The expression of miR-1, miR-133a, and miR-133b was found to increase rapidly until adolescence in all skeletal muscles, whereas during adulthood it remained relatively stable. By contrast, endogenous miR-206 levels were observed to decrease with age in all muscles, except for soleus. Differential expression of the four myomiRs is also inversely reflected on the production of two protein targets; serum response factor and connexin 43. Muscle-derived exosomal miR-1, miR-133a, and miR-133b levels were found to increase until the early adolescence, before reaching a plateau phase. Soleus was found to be the only skeletal muscle to release exosomes enriched in miR-206. In this study, we showed for the first time an in-depth longitudinal analysis of the endogenous and exosomal levels of the four myomiRs during skeletal muscle development. We showed that the endogenous expression and extracellular secretion of the four myomiRs are associated to the function and size of skeletal muscles as the mice age. Overall, our findings provide new insights for the myomiRs’ significant role in the first year of life in mice.
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Affiliation(s)
- Chrystalla Mytidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Margarita Zachariou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marianna Prokopi
- Theramir Ltd., Limassol, Cyprus.,Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - George M Spyrou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Liu Q, Deng J, Qiu Y, Gao J, Li J, Guan L, Lee H, Zhou Q, Xiao J. Non-coding RNA basis of muscle atrophy. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1066-1078. [PMID: 34786211 PMCID: PMC8569427 DOI: 10.1016/j.omtn.2021.10.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Muscle atrophy is a common complication of many chronic diseases including heart failure, cancer cachexia, aging, etc. Unhealthy habits and usage of hormones such as dexamethasone can also lead to muscle atrophy. However, the underlying mechanisms of muscle atrophy are not completely understood. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in muscle atrophy. This review mainly discusses the regulation of ncRNAs in muscle atrophy induced by various factors such as heart failure, cancer cachexia, aging, chronic obstructive pulmonary disease (COPD), peripheral nerve injury (PNI), chronic kidney disease (CKD), unhealthy habits, and usage of hormones; highlights the findings of ncRNAs as common regulators in multiple types of muscle atrophy; and summarizes current therapies and underlying mechanisms for muscle atrophy. This review will deepen the understanding of skeletal muscle biology and provide new strategies and insights into gene therapy for muscle atrophy.
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Affiliation(s)
- Qi Liu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jiali Deng
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Yan Qiu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Juan Gao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jin Li
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Longfei Guan
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Qiulian Zhou
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Junjie Xiao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
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Cardona E, Guyomar C, Desvignes T, Montfort J, Guendouz S, Postlethwait JH, Skiba-Cassy S, Bobe J. Circulating miRNA repertoire as a biomarker of metabolic and reproductive states in rainbow trout. BMC Biol 2021; 19:235. [PMID: 34781956 PMCID: PMC8594080 DOI: 10.1186/s12915-021-01163-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 10/08/2021] [Indexed: 12/16/2022] Open
Abstract
Background Circulating miRNAs (c-miRNAs) are found in most, if not all, biological fluids and are becoming well-established non-invasive biomarkers of many human pathologies. However, their features in non-pathological contexts and whether their expression profiles reflect normal life history events have received little attention, especially in non-mammalian species. The aim of the present study was to investigate the potential of c-miRNAs to serve as biomarkers of reproductive and metabolic states in fish. Results The blood plasma was sampled throughout the reproductive cycle of female rainbow trout subjected to two different feeding regimes that triggered contrasting metabolic states. In addition, ovarian fluid was sampled at ovulation, and all samples were subjected to small RNA-seq analysis, leading to the establishment of a comprehensive miRNA repertoire (i.e., miRNAome) and enabling subsequent comparative analyses to a panel of RNA-seq libraries from a wide variety of tissues and organs. We showed that biological fluid miRNAomes are complex and encompass a high proportion of the overall rainbow trout miRNAome. While sharing a high proportion of common miRNAs, the blood plasma and ovarian fluid miRNAomes exhibited strong fluid-specific signatures. We further revealed that the blood plasma miRNAome significantly changed depending on metabolic and reproductive states. We subsequently identified three evolutionarily conserved muscle-specific miRNAs or myomiRs (miR-1-1/2-3p, miR-133a-1/2-3p, and miR-206-3p) that accumulated in the blood plasma in response to high feeding rates, making these myomiRs strong candidate biomarkers of active myogenesis. We also identified miR-202-5p as a candidate biomarker for reproductive success that could be used to predict ovulation and/or egg quality. Conclusions Together, these promising results reveal the high potential of c-miRNAs, including evolutionarily conserved myomiRs, as physiologically relevant biomarker candidates and pave the way for the use of c-miRNAs for non-invasive phenotyping in various fish species. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-021-01163-5.
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Affiliation(s)
- Emilie Cardona
- INRAE, LPGP, Fish Physiology and Genomics, F-35000, Rennes, France.,INRAE, Univ. Pau & Pays Adour, E2S UPPA, NUMEA, 64310, Saint-Pée-sur-Nivelle, France
| | - Cervin Guyomar
- INRAE, LPGP, Fish Physiology and Genomics, F-35000, Rennes, France.,GenPhySE, University of Toulouse, INRAE, ENVT, F-31326, Castanet-Tolosan, France
| | - Thomas Desvignes
- Institute of Neurosciences, University of Oregon, Eugene, OR, 97403, USA
| | - Jérôme Montfort
- INRAE, LPGP, Fish Physiology and Genomics, F-35000, Rennes, France
| | - Samia Guendouz
- Institute of Functional Genomics, MGX, UMR 5203 CNRS - U1191 INSERM, F-34094, Montpellier, France
| | | | - Sandrine Skiba-Cassy
- INRAE, Univ. Pau & Pays Adour, E2S UPPA, NUMEA, 64310, Saint-Pée-sur-Nivelle, France
| | - Julien Bobe
- INRAE, LPGP, Fish Physiology and Genomics, F-35000, Rennes, France.
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Srivastava S, Rathor R, Singh SN, Suryakumar G. Emerging role of MyomiRs as biomarkers and therapeutic targets in skeletal muscle diseases. Am J Physiol Cell Physiol 2021; 321:C859-C875. [PMID: 34586896 DOI: 10.1152/ajpcell.00057.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Several chronic diseases lead to skeletal muscle loss and a decline in physical performance. MicroRNAs (miRNAs) are small, noncoding RNAs, which have exhibited their role in the development and diseased state of the skeletal muscle. miRNA regulates gene expression by binding to the 3' untranslated region of its target mRNA. Due to the robust stability in biological fluids, miRNAs are ideal candidate as biomarker. These miRNAs provide a novel avenue in strengthening our awareness and knowledge about the factors governing skeletal muscle functions such as development, growth, metabolism, differentiation, and cell proliferation. It also helps in understanding the therapeutic strategies in improving or conserving skeletal muscle health. This review outlines the evidence regarding the present knowledge on the role miRNA as a potential biomarker in skeletal muscle diseases and their exploration might be a unique and potential therapeutic strategy for various skeletal muscle disorders.
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Affiliation(s)
| | - Richa Rathor
- Defence Institute of Physiology & Allied Sciences (DIPAS), Delhi, India
| | - Som Nath Singh
- Defence Institute of Physiology & Allied Sciences (DIPAS), Delhi, India
| | - Geetha Suryakumar
- Defence Institute of Physiology & Allied Sciences (DIPAS), Delhi, India
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42
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Greer JB, Magnuson JT, McGruer V, Qian L, Dasgupta S, Volz DC, Schlenk D. miR133b Microinjection during Early Development Targets Transcripts of Cardiomyocyte Ion Channels and Induces Oil-like Cardiotoxicity in Zebrafish ( Danio rerio) Embryos. Chem Res Toxicol 2021; 34:2209-2215. [PMID: 34558284 DOI: 10.1021/acs.chemrestox.1c00238] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Previous studies have shown that altered expression of a family of small noncoding RNAs (microRNAs, or miRs) regulates the expression of downstream mRNAs and is associated with diseases and developmental disorders. miR133b is highly expressed in mammalian cardiac and skeletal muscle, and aberrant expression is associated with cardiac disorders and electrophysiological changes in cardiomyocytes. Similarly, cardiac dysfunction has been observed in early life-stage mahi-mahi (Coryphaena hippurus) exposed to crude oil, a phenotype that has been associated with an upregulation of miR133b as well as subsequent downregulation of a delayed rectifier potassium channel (IKr) and calcium signaling genes that are important for proper heart development during embryogenesis. To examine the potential role of miR133b in oil-induced early life-stage cardiotoxicity in fish, cleavage-stage zebrafish (Danio rerio) embryos were either (1) microinjected with ∼3 nL of negative control miR (75 μM) or miR133b (75 μM) or (2) exposed to a treatment solution containing 5 μM benzo(a)pyrene (BaP), a model polycyclic aromatic hydrocarbon, as a positive control. At 72 h post fertilization (hpf), miR133b-injected fish exhibited BaP-like cardiovascular malformations, including a significantly increased pericardial area relative to negative control miR-injected embryos, as well as a significantly reduced eye area. qPCR revealed that miR133b microinjection decreased the abundance of cardiac-specific IKr kcnh6 at 5 hpf, which may contribute to action potential elongation in oil-exposed cardiomyocytes. Additionally, ryanodine receptor 2, a crucial calcium receptor in the sarcoplasmic reticulum, was also downregulated by miR133b. These results indicate that an oil-induced increase in miR133b may contribute to cardiac abnormalities in oil-exposed fish by targeting cardiac-specific genes essential for proper heart development.
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Affiliation(s)
- Justin B Greer
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States.,U.S. Geological Survey, Western Fisheries Research Center, Seattle, Washington 98115, United States
| | - Jason T Magnuson
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - Victoria McGruer
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - Le Qian
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States.,College of Sciences, China Agricultural University, Beijing 100083, China
| | - Subham Dasgupta
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - David C Volz
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - Daniel Schlenk
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States.,Institute of Environmental Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
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Huang JH, Jiao YH, Li L, Li DW, Li HY, Yang WD. Small RNA analysis of Perna viridis after exposure to Prorocentrum lima, a DSP toxins-producing dinoflagellate. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 239:105950. [PMID: 34474269 DOI: 10.1016/j.aquatox.2021.105950] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 06/13/2023]
Abstract
Diarrheic shellfish poisoning toxins (DSP toxins) are a set of the most important phycotoxins produced by some dinoflagellates. Studies have shown that DSP toxins have various toxicities such as genotoxicity, cytotoxicity, and immunotoxicity to bivalve mollusks. However, these toxicities appear decreasing with exposure time and concentration of DSP toxins. The underlying mechanism involved remains unclear. In this study, small RNA sequencing was performed in the digestive gland of the mussel Perna viridis after exposure to DSP toxins-producing dinoflagellate Prorocentrum lima for different time periods. The potential roles of miRNAs in response and detoxification to DSP toxins in the mussel were analyzed. Small RNA sequencing of 12 samples from 72 individuals was conducted by BGISEQ-500. A total of 123 mature miRNAs were identified, including 90 conserved miRNAs and 33 potential novel miRNAs. After exposure to P. lima, multiple important miRNAs displayed some alterations. Further miRNA target prediction revealed some important genes involved in cytoskeleton, apoptosis, complement system and immune stress. qPCR demonstrated that miR-71_5, miR-750_1 and novel_mir4 were significantly up-regulated at 6 h after exposure to P. lima, while miR-100_2 was significantly down-regulated after 96 h of exposure. Accordingly, putative target genes of these differentially expressed miRNAs experienced some changes. After 6 h of DSP toxins exposure, NHLRC2 and C1q-like were significantly down-regulated. After 96 h of DSP toxins exposure, NHLRC2 was significantly up-regulated. It is reasonable to speculate that the mussel P. viridis might respond to DSP toxins through miR-750_1, novel_mir4 and miR-71_5 regulating the expression of relevant target genes involved in apoptosis, cytoskeleton, and immune response, etc. This study might provide new clues to uncover the toxic response of bivalve to DSP toxins and lay a foundation for revealing the roles of miRNAs in the environmental adaptation in shellfish.
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Affiliation(s)
- Jia-Hui Huang
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China
| | - Yu-Hu Jiao
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China
| | - Li Li
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China
| | - Da-Wei Li
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China
| | - Hong-Ye Li
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China
| | - Wei-Dong Yang
- College of Life Science and Technology, Key Laboratory of Aquatic Eutrophication and Control of Harmful Algal Blooms of Guangdong Higher Education Institute, Jinan University, Guangzhou 510632, China.
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Kuter E, Ӧnol AG. Increased dietary methionine levels and supplemental L-carnitine do not prevent the development of white striping in broiler chickens. Anim Feed Sci Technol 2021. [DOI: 10.1016/j.anifeedsci.2021.115059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Wang Y, Zhen D, Fu D, Fu Y, Zhang X, Gong G, Wei C. 1, 8-cineole attenuates cardiac hypertrophy in heart failure by inhibiting the miR-206-3p/SERP1 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 91:153672. [PMID: 34385094 DOI: 10.1016/j.phymed.2021.153672] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/06/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND 1,8-Cineole (1,8-CIN) is a monoterpene found in diverse dietary and medicinal herbs that has been reported to be effective against cardiovascular diseases. PURPOSE The present research was designed to elucidate the treatment effects and the underlying mechanism of 1,8-CIN on heart failure (HF). METHOD An in vitro cardiac hypertrophy model and an in vivo heart failure (HF) model induced by isoprenaline (ISO) were established and treated with or without 1,8-CIN. In vitro miR-206-3p mimic or inhibitors were created. MiR-206-3p, SERP1 and related mRNAs or proteins were detected using qPCR or western blotting. Cell viability was tested by MTT assay, and apoptosis was measured using TUNEL assay, AO/EB assay and flow cytometry. Actin was stained with FITC-phalloidin. MiR-206-3p and related mRNAs or proteins in cardiac muscle tissues were measured using qPCR or western blotting, HE staining, Masson staining. RESULTS ISO subcutaneous injection increased cardiac hypertrophy, cytoplasmic vacuole formation, myofiber loss and fibrosis and decreased cardiomyocyte viability. 1,8-CIN treatment improved cardiomyocyte viability and reduced cardiac hypertrophy, cytoplasmic vacuole formation, myofibre loss and fibrosis. We found that 1,8-CIN attenuated apoptosis. We observed that expression of miR-206-3p was dramatically increased in ISO-exposed cardiomyocytes or ISO-treated rat hearts. MiR-206-3p was identified to target the 3'UTR of SERP1, resulting in the accumulation of un- or misfolded proteins, leading to endoplasmic reticulum (ER) stress. CONCLUSION These results suggest that 1,8-CIN reduces the apoptosis induced by ER stress through inhibiting miR-206-3p, which inhibits the expression of SERP1.
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Affiliation(s)
- Yu Wang
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China
| | - Dong Zhen
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China
| | - Danni Fu
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China
| | - Yao Fu
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China
| | - Xuan Zhang
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China
| | - Guohua Gong
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China; Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, PR China.
| | - Chengxi Wei
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China., Tongliao, Inner Mongolia, PR China.
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Chiti E, Di Paolo M, Turillazzi E, Rocchi A. MicroRNAs in Hypertrophic, Arrhythmogenic and Dilated Cardiomyopathy. Diagnostics (Basel) 2021; 11:diagnostics11091720. [PMID: 34574061 PMCID: PMC8469137 DOI: 10.3390/diagnostics11091720] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs of about 20 nucleotides in length, involved in the regulation of many biochemical pathways in the human body. The level of miRNAs in tissues and circulation can be deregulated because of altered pathophysiological mechanisms; thus, they can be employed as biomarkers for different pathological conditions, such as cardiac diseases. This review summarizes published findings of these molecular biomarkers in the three most common structural cardiomyopathies: human dilated, arrhythmogenic and hypertrophic cardiomyopathy.
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Affiliation(s)
- Enrica Chiti
- Institute of Life Science, Scuola Superiore Sant’Anna, 56124 Pisa, Italy;
| | - Marco Di Paolo
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Emanuela Turillazzi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Anna Rocchi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
- Correspondence:
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Caporali S, Calabrese C, Minieri M, Pieri M, Tarantino U, Marini M, D’Ottavio S, Angeletti S, Mauriello A, Cortese C, Bernardini S, Terrinoni A. The miR-133a, TPM4 and TAp63γ Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression. Int J Mol Sci 2021; 22:ijms22189818. [PMID: 34575979 PMCID: PMC8472330 DOI: 10.3390/ijms22189818] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/01/2021] [Accepted: 09/05/2021] [Indexed: 01/16/2023] Open
Abstract
MicroRNAs (miRNAs) play an essential role in the regulation of a number of physiological functions. miR-133a and other muscular miRs (myomiRs) play a key role in muscle cell growth and in some type of cancers. Here, we show that miR133a is upregulated in individuals that undertake physical exercise. We used a skeletal muscle differentiation model to dissect miR-133a's role and to identify new targets, identifying Tropomyosin-4 (TPM4). This protein is expressed during muscle differentiation, but importantly it is an essential component of microfilament cytoskeleton and stress fibres formation. The microfilament scaffold remodelling is an essential step in cell transformation and tumour progression. Using the muscle system, we obtained valuable information about the microfilament proteins, and the knowledge on these molecular players can be transferred to the cytoskeleton rearrangement observed in cancer cells. Further investigations showed a role of TPM4 in cancer physiology, specifically, we found that miR-133a downregulation leads to TPM4 upregulation in colon carcinoma (CRC), and this correlates with a lower patient survival. At molecular level, we demonstrated in myocyte differentiation that TPM4 is positively regulated by the TA isoform of the p63 transcription factor. In muscles, miR-133a generates a myogenic stimulus, reducing the differentiation by downregulating TPM4. In this system, miR-133a counteracts the differentiative TAp63 activity. Interestingly, in CRC cell lines and in patient biopsies, miR-133a is able to regulate TPM4 activity, while TAp63 is not active. The downregulation of the miR leads to TPM4 overexpression, this modifies the architecture of the cell cytoskeleton contributing to increase the invasiveness of the tumour and associating with a poor prognosis. These results add data to the interesting question about the link between physical activity, muscle physiology and protection against colorectal cancer. The two phenomena have in common the cytoskeleton remodelling, due to the TPM4 activity, that is involved in stress fibres formation.
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Affiliation(s)
- Sabrina Caporali
- Department of Industrial Engineering, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Cosimo Calabrese
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Umberto Tarantino
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (S.D.)
| | - Mario Marini
- Centre of Space Biomedicine and Department of Systems Medicine of the University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Stefano D’Ottavio
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (S.D.)
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 00128 Rome, Italy;
| | - Alessandro Mauriello
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Claudio Cortese
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
| | - Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.C.); (M.M.); (M.P.); (A.M.); (C.C.); (S.B.)
- Correspondence:
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48
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Telles GD, Libardi CA, Conceição MS, Vechin FC, Lixandrão ME, DE Andrade ALL, Guedes DN, Ugrinowitsch C, Camera DM. Time Course of Skeletal Muscle miRNA Expression after Resistance, High-Intensity Interval, and Concurrent Exercise. Med Sci Sports Exerc 2021; 53:1708-1718. [PMID: 33731656 DOI: 10.1249/mss.0000000000002632] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Exercise-induced microRNA (miRNA) expression has been implicated in the regulation of skeletal muscle plasticity. However, the specificity and acute time course in miRNA expression after divergent exercise modes are unknown. In a randomized crossover design, we compared the acute expression profile of eight skeletal muscle miRNAs previously reported to be involved in skeletal muscle development, growth, and maintenance after a bout of either resistance exercise (RE), high-intensity interval exercise (HIIE), and concurrent resistance and high-intensity interval exercises (CE). METHODS Nine untrained young men (23.9 ± 2.8 yr, 70.1 ± 14.9 kg, 177.2 ± 3.0 cm, 41.4 ± 5.2 mL·kg-1·min-1) underwent a counterbalanced crossover design in which they performed bouts of RE (2 × 10 repetitions maximum 45° leg press and leg extension exercises), HIEE (12 × 1-min sprints at V˙O2peak with 1-min rest intervals between sprints), and CE (RE followed by HIIE), separated by 1 wk. Vastus lateralis biopsies were harvested immediately before (Pre) and immediately (0 h), 4 h, and 8 h after each exercise bout. RESULTS There were similar increases (main effect of time; P < 0.05) in miR-1-3p, miR-133a-3p, miR-133b, miR-181a-3p, and miR-486 expression at 8 h from Pre with all exercise modes. Besides a main effect of time, miR-23a-3p and miR-206 presented a main effect of condition with lower expression after HIIE compared with RE and CE. CONCLUSIONS Select miRNAs (miR-1-3p, miR-133a-3p, miR-133b, miR-23a-3p, miR-181a-3p, miR-206, miR-486) do not exhibit an expression specificity in the acute recovery period after a single bout of RE, HIIE, or CE in skeletal muscle. Our data also indicate that RE has a higher effect on the expression of miR-23a-3p and miR-206 than HIIE. As upregulation of these miRNAs seems to be confined to the 8-h period after exercise, this may subsequently affect the expression patterns of target mRNAs forming the basis of exercise-induced adaptive responses.
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Affiliation(s)
- Guilherme Defante Telles
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Cleiton Augusto Libardi
- MUSCULAB-Laboratory of Neuromuscular Adaptations to Resistance Training, Department of Physical Education, Federal University of São Carlos-UFSCar, São Carlos, São Paulo, BRAZIL
| | - Miguel Soares Conceição
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Felipe Cassaro Vechin
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Manoel Emílio Lixandrão
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | | | | | - Carlos Ugrinowitsch
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Donny Michael Camera
- Department of Health and Medical Sciences, Swinburne University, Melbourne, Victoria, AUSTRALIA
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Mytidou C, Koutsoulidou A, Katsioloudi A, Prokopi M, Kapnisis K, Michailidou K, Anayiotos A, Phylactou LA. Muscle-derived exosomes encapsulate myomiRs and are involved in local skeletal muscle tissue communication. FASEB J 2021; 35:e21279. [PMID: 33484211 DOI: 10.1096/fj.201902468rr] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/02/2020] [Accepted: 12/01/2020] [Indexed: 12/23/2022]
Abstract
Exosomes are extracellular vesicles that are released from most cell types encapsulating specific molecular cargo. Exosomes serve as mediators of cell-to-cell and tissue-to-tissue communications under normal and pathological conditions. It has been shown that exosomes carrying muscle-specific miRNAs, myomiRs, are secreted from skeletal muscle cells in vitro and are elevated in the blood of muscle disease patients. The aim of this study was to investigate the secretion of exosomes encapsulating the four myomiRs from skeletal muscle tissues and to assess their role in inter-tissue communication between neighboring skeletal muscles in vivo. We demonstrate, for the first time, that isolated, intact skeletal muscle tissues secrete exosomes encapsulating the four myomiRs, miR-1, miR-133a, miR-133b, and miR-206. Notably, we show that the sorting of the four myomiRs within exosomes varies between skeletal muscles of different muscle fiber-type composition. miR-133a and miR-133b downregulation in TA muscles caused a reduction of their levels in neighboring skeletal muscles and in serum exosomes. In conclusion, our results reveal that skeletal muscle-derived exosomes encapsulate the four myomiRs, some of which enter the blood, while a portion is used for the local communication between proximal muscle tissues. These findings provide important evidence regarding novel pathways implicated in skeletal muscle function.
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Affiliation(s)
- Chrystalla Mytidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | | | - Marianna Prokopi
- Theramir Ltd, Limassol, Cyprus.,Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus.,Department of Research and Development, German Oncology Center, Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Kyriaki Michailidou
- The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,Biostatistics Unit, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
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50
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Diao LT, Xie SJ, Lei H, Qiu XS, Huang MC, Tao S, Hou YR, Hu YX, Sun YJ, Zhang Q, Xiao ZD. METTL3 regulates skeletal muscle specific miRNAs at both transcriptional and post-transcriptional levels. Biochem Biophys Res Commun 2021; 552:52-58. [PMID: 33740664 DOI: 10.1016/j.bbrc.2021.03.035] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/07/2021] [Indexed: 12/31/2022]
Abstract
METTL3 increasing the mature miRNA levels via N6-Methyladenosine (m6A) modification of primary miRNA (pri-miRNA) transcripts has emerged as an important post-transcriptional regulation of miRNA biogenesis. Our previous studies and others have showed that muscle specific miRNAs are essential for skeletal muscle differentiation. Whether these miRNAs are also regulated by METTL3 is still unclear. Here, we found that m6A motifs were present around most of these miRNAs, which were indeed m6A modified as confirmed by m6A-modified RNA immunoprecipitation (m6A RIP). However, we surprisingly found that these muscle specific miRNAs were repressed instead of increased by METTL3 in C2C12 in vitro differentiation and mouse skeletal muscle regeneration after injury in vivo model. To elucidate the underlined mechanism, we performed reporter assays in 293T cells and validated METTL3 increasing these miRNAs at post-transcriptional level as expected. Furthermore, in myogenic C2C12 cells, we found that METTL3 not only repressed the expression of myogenic transcription factors (TFs) which can enhance the muscle specific miRNAs, but also increased the expression of epigenetic regulators which can repress these miRNAs. Thus, METTL3 could repress the muscle specific miRNAs at transcriptional level indirectly. Taken together, our results demonstrated that skeletal muscle specific miRNAs were repressed by METTL3 and such repression is likely synthesized transcriptional and post-transcriptional regulations.
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Affiliation(s)
- Li-Ting Diao
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shu-Juan Xie
- Vaccine Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Hang Lei
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiu-Sheng Qiu
- Vaccine Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Meng-Chun Huang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shuang Tao
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Ya-Rui Hou
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yan-Xia Hu
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yu-Jia Sun
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China; Vaccine Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Zhen-Dong Xiao
- Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
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