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Li L, Zheng Z, Lan W, Tang N, Zhang D, Ling J, Wu Y, Yang P, Fu L, Liu J, Zhang J, Yu P, Huang T. Role of Exosomes in Cardiovascular Disease: A Key Regulator of Intercellular Communication in Cardiomyocytes. ACS OMEGA 2025; 10:18145-18169. [PMID: 40385188 PMCID: PMC12079207 DOI: 10.1021/acsomega.4c11423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/27/2025] [Accepted: 04/22/2025] [Indexed: 05/20/2025]
Abstract
In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.
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Affiliation(s)
- Liuxin Li
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Zhidong Zheng
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Wenyu Lan
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Nan Tang
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Deju Zhang
- Food
and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 0000, Hong Kong
| | - Jitao Ling
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Yuting Wu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Pingping Yang
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Linhua Fu
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jianping Liu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jing Zhang
- Department
of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical
College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Peng Yu
- Department
of Metabolism and Endocrinology, The Second
Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Tieqiu Huang
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
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2
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Gill SK, Gomer RH. Translational Regulators in Pulmonary Fibrosis: MicroRNAs, Long Non-Coding RNAs, and Transcript Modifications. Cells 2025; 14:536. [PMID: 40214489 PMCID: PMC11988943 DOI: 10.3390/cells14070536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Fibrosing disorders including idiopathic pulmonary fibrosis (IPF) are progressive irreversible diseases, often with poor prognoses, characterized by the accumulation of excessive scar tissue and extracellular matrix. Translational regulation has emerged as a critical aspect of gene expression control, and the dysregulation of key effectors is associated with disease pathogenesis. This review examines the current literature on translational regulators in IPF, focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and RNA transcript modifications including alternative polyadenylation and chemical modification. Some of these translational regulators potentiate fibrosis, and some of the regulators inhibit fibrosis. In IPF, some of the profibrotic regulators are upregulated, and some of the antifibrotic regulators are downregulated. Correcting these defects in IPF-associated translational regulators could be an intriguing avenue for therapeutics.
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Affiliation(s)
| | - Richard H. Gomer
- Department of Biology, Texas A&M University, College Station, TX 77843, USA;
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3
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Zhou ZY, Song K, Liu ZY, Ke YF, Shi Y, Cai K, Zhao R, Sun X, Tao H, Zhao JY. Branched-chain amino acids deficiency promotes diabetic cardiomyopathy by activating autophagy of cardiac fibroblasts. Theranostics 2024; 14:7333-7348. [PMID: 39659577 PMCID: PMC11626946 DOI: 10.7150/thno.102708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/20/2024] [Indexed: 12/12/2024] Open
Abstract
Rationale: More than half of the patients with type II diabetes mellitus (T2D) develop diabetic cardiomyopathy (DCM). Glycemic control alone cannot effectively prevent or alleviate DCM. Methods: Herein, we concentrated on the variations in levels of metabolites between DCM and T2D patients without cardiomyopathy phenotype. In high-fat diet/low-dose streptozotocin-induced T2D and leptin receptor-deficient diabetic mouse models, we investigated the effect of altering branched-chain amino acids (BCAAs) levels on DCM. Results: We discovered that the levels of plasma BCAAs are notably lower in 15 DCM patients compared to 19 T2D patients who do not exhibit cardiomyopathy phenotype, using nuclear magnetic resonance analysis. This finding was further validated in two additional batches of samples, 123 DCM patients and 129 T2D patients based on the BCAA assay kit, and 30 DCM patients and 30 T2D patients based on the LC-MS/MS method, respectively. Moreover, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated cardiomyopathy phenotypes in diabetic mice. Furthermore, BCAA deficiency promoted cardiac fibroblast activation by stimulating autophagy in DCM mice. Mechanistically, BCAA deficiency activated autophagy via the AMPK-ULK1 signaling pathway in cardiac fibroblasts. Using pharmacological approaches, we validated our findings that autophagy inhibition relieved, whereas autophagy activation aggravated, DCM phenotypes. Conclusions: Taken together, we describe a novel perspective wherein BCAA supplementation may serve as a potential therapeutic agent to mitigate DCM and fibrosis. Our findings provide insights for the development of preventive measures for DCM.
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Affiliation(s)
- Ze-Yu Zhou
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Kai Song
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Anesthesiology and Perioperative Medicine, Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Zhi-Yan Liu
- Department of Anesthesiology and Perioperative Medicine, Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Yu-Fan Ke
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yan Shi
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ke Cai
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xin Sun
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hui Tao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Anesthesiology and Perioperative Medicine, Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Jian-Yuan Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- International Human Phenome Institutes (Shanghai), Shanghai 200433, China
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4
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Wang N, Chen C, Ren J, Dai D. MicroRNA delivery based on nanoparticles of cardiovascular diseases. Mol Cell Biochem 2024; 479:1909-1923. [PMID: 37542599 DOI: 10.1007/s11010-023-04821-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 07/24/2023] [Indexed: 08/07/2023]
Abstract
Cardiovascular disease, especially myocardial infarction, is a serious threat to human health. Many drugs currently used cannot achieve the desired therapeutic effect due to the lack of selectivity. With the in-depth understanding of the role of microRNA (miRNA) in cardiovascular disease and the wide application of nanotechnology, loading drugs into nanoparticles with the help of nano-delivery system may have a better effect in the treatment of cardiomyopathy. In this review, we highlight the latest research on miRNAs in the treatment of cardiovascular disease in recent years and discuss the possibilities and challenges of using miRNA to treat cardiomyopathy. Secondly, we discuss the delivery of miRNA through different nano-carriers, especially inorganic, polymer and liposome nano-carriers. The preparation of miRNA nano-drugs by encapsulating miRNA in these nano-materials will provide a new treatment option. In addition, the research status of miRNA in the treatment of cardiomyopathy based on nano-carriers is summarized. The use of this delivery tool cannot only realize therapeutic potential, but also greatly improve drug targeting and reduce side effects.
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Affiliation(s)
- Nan Wang
- Department of Pharmacy, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, Zhejiang, China
| | - Chunyan Chen
- Department of Pharmacy, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, Zhejiang, China
| | - Jianmin Ren
- Department of Pharmacy, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, Zhejiang, China
| | - Dandan Dai
- Department of Pharmacy, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, Zhejiang, China.
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Casara A, Conti M, Bernardinello N, Tinè M, Baraldo S, Turato G, Semenzato U, Celi A, Spagnolo P, Saetta M, Cosio MG, Neri T, Biondini D, Bazzan E. Unveiling the Cutting-Edge Impact of Polarized Macrophage-Derived Extracellular Vesicles and MiRNA Signatures on TGF-β Regulation within Lung Fibroblasts. Int J Mol Sci 2024; 25:7490. [PMID: 39000595 PMCID: PMC11242851 DOI: 10.3390/ijms25137490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/16/2024] Open
Abstract
Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-β production in lung fibroblasts. EVs were isolated from supernatants of M0, M1, and M2 macrophages and quantified using nanoscale flow cytometry prior to fibroblast stimulation. The concentration of TGF-β in fibroblast supernatants was measured using ELISA assays. The expression levels of miRNA-19a-3p and miRNA-425-5p were assessed via TaqMan-qPCR. TGF-β production after stimulation with M0-derived EVs and with M1-derived EVs increased significantly compared to untreated fibroblasts. miRNA-425-5p, but not miRNA-19a-3p, was significantly upregulated in M2-derived EVs compared to M0- and M1-derived EVs. This study demonstrates that EVs derived from both M0 and M1 polarized macrophages induce the production of TGF-β in fibroblasts, with potential regulation by miRNA-425-5p.
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Affiliation(s)
- Alvise Casara
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Maria Conti
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
- Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
| | - Nicol Bernardinello
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Mariaenrica Tinè
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Simonetta Baraldo
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Graziella Turato
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Umberto Semenzato
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Alessandro Celi
- Centro Dipartimentale di Biologia Cellulare Cardiorespiratoria, Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università degli Studi di Pisa, 56124 Pisa, Italy;
| | - Paolo Spagnolo
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Marina Saetta
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
| | - Manuel G. Cosio
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
- Meakins-Christie Laboratories, Respiratory Division, McGill University, Montreal, QC H3A 0G4, Canada
| | - Tommaso Neri
- Centro Dipartimentale di Biologia Cellulare Cardiorespiratoria, Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università degli Studi di Pisa, 56124 Pisa, Italy;
| | - Davide Biondini
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
- Department of Medicine, University of Padova, 35128 Padova, Italy
| | - Erica Bazzan
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova and Padova City Hospital, 35128 Padova, Italy; (A.C.); (M.C.); (N.B.); (M.T.); (S.B.); (G.T.); (U.S.); (P.S.); (M.S.); (M.G.C.); (D.B.); (E.B.)
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Shi P, Tan A, Ma Y, Que L, Li C, Shao Y, Sun H, Li Y, Li J. MicroRNA-19a-3p augments TGF-β1-induced cardiac fibroblast activation via targeting BAMBI. J Biomed Res 2024; 39:1-14. [PMID: 38807415 PMCID: PMC11982684 DOI: 10.7555/jbr.37.20230313] [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: 12/18/2023] [Revised: 04/23/2024] [Accepted: 04/30/2024] [Indexed: 05/30/2024] Open
Abstract
The main pathogenic factor leading to cardiac remodeling and heart failure is myocardial fibrosis. Recent research indicates that microRNAs are essential for the progress of cardiac fibrosis. Myocardial fibrosis is considered to be alleviated through the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), which does this by blocking the transforming growth factor β1 (TGF-β1) signaling pathway. Here, this study sought to elucidate the post-transcriptional regulation of miR-19a-3p on BAMBI and its role in TGF-β1-induced cardiac fibroblast activation. Transverse aortic constriction (TAC) caused both myocardial interstitial and perivascular collagen deposition. RT-PCR showed that miR-19a-3p was upregulated in the myocardial tissue of cardiac fibrosis, and TGF-β1 induced an increase of miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter test and qRT-PCR confirmed that miR-19a-3p directly combined with BAMBI mRNA 3'UTR, thus reduced BAMBI expression, which diminished the capability of BAMBI to inhibit TGF-β1. Furthermore, miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling, which supported cardiac fibroblast activation, which blocked by overexpression of BAMBI. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts, and may thus offer a novel strategy to tackling myocardial fibrosis.
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Affiliation(s)
- Pengxi Shi
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Ao Tan
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yuanyuan Ma
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Lingli Que
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Chuanfu Li
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614-0575, USA
| | - Yongfeng Shao
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Haoliang Sun
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yuehua Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jiantao Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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7
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Lin LC, Liu ZY, Tu B, Song K, Sun H, Zhou Y, Sha JM, Zhang Y, Yang JJ, Zhao JY, Tao H. Epigenetic signatures in cardiac fibrosis: Focusing on noncoding RNA regulators as the gatekeepers of cardiac fibroblast identity. Int J Biol Macromol 2024; 254:127593. [PMID: 37898244 DOI: 10.1016/j.ijbiomac.2023.127593] [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: 04/02/2023] [Revised: 09/13/2023] [Accepted: 10/19/2023] [Indexed: 10/30/2023]
Abstract
Cardiac fibroblasts play a pivotal role in cardiac fibrosis by transformation of fibroblasts into myofibroblasts, which synthesis and secrete a large number of extracellular matrix proteins. Ultimately, this will lead to cardiac wall stiffness and impaired cardiac performance. The epigenetic regulation and fate reprogramming of cardiac fibroblasts has been advanced considerably in recent decades. Non coding RNAs (microRNAs, lncRNAs, circRNAs) regulate the functions and behaviors of cardiac fibroblasts, including proliferation, migration, phenotypic transformation, inflammation, pyroptosis, apoptosis, autophagy, which can provide the basis for novel targeted therapeutic treatments that abrogate activation and inflammation of cardiac fibroblasts, induce different death pathways in cardiac fibroblasts, or make it sensitive to established pathogenic cells targeted cytotoxic agents and biotherapy. This review summarizes our current knowledge in this field of ncRNAs function in epigenetic regulation and fate determination of cardiac fibroblasts as well as the details of signaling pathways contribute to cardiac fibrosis. Moreover, we will comment on the emerging landscape of lncRNAs and circRNAs function in regulating signal transduction pathways, gene translation processes and post-translational regulation of gene expression in cardiac fibroblast. In the end, the prospect of cardiac fibroblasts targeted therapy for cardiac fibrosis based on ncRNAs is discussed.
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Affiliation(s)
- Li-Chan Lin
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Zhi-Yan Liu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Bin Tu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Kai Song
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - He Sun
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Yang Zhou
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Ji-Ming Sha
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Ye Zhang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China.
| | - Jing-Jing Yang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China.
| | - Jian-Yuan Zhao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
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8
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Ren H, Huang M, Ou L, Deng X, Wu X, Gong Q, Liu B. Autophagy inhibitor 3-methyladenine attenuates renal injury in streptozotocin-induced diabetic mice. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:793-800. [PMID: 38800022 PMCID: PMC11127078 DOI: 10.22038/ijbms.2024.71378.15518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 11/13/2023] [Indexed: 05/29/2024]
Abstract
Objectives To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism. Materials and Methods STZ was used to induce diabetes in C57BL/6J mice. The mice were divided into normal control group (NC), diabetes group (DM), and diabetes+3-MA intervention group (DM+3-MA). Blood glucose, water consumption, and body weight were recorded weekly. At the end of the 6th week of drug treatment, 24-hour urine was collected. Blood and kidneys were collected for PAS staining to evaluate the degree of renal injury. Sirius red staining was used to assess collagen deposition. Blood urea nitrogen (BUN), serum creatinine, and 24-hour urine albumin were used to evaluate renal function. Western blot was used to detect fibrosis-related protein, inflammatory mediators, high mobility group box 1 (HMGB1)/NF-κB signal pathway molecule, vascular endothelial growth factor (VEGF), and podocin, and immunohistochemistry (IHC) was used to detect the expression and localization of autophagy-related protein and fibronectin. Results Compared with the kidney of normal control mice, the kidney of diabetes control mice was more pale and hypertrophic. Hyperglycemia induces renal autophagy and activates the HMGB1/NF-κB signal pathway, leading to the increase of inflammatory mediators, extracellular matrix (ECM) deposition, and proteinuria in the kidney. In diabetic mice treated with 3-MA, blood glucose decreased, autophagy and HMGB1/NF-κB signaling pathways in the kidneys were inhibited, and proteinuria, renal hypertrophy, inflammation, and fibrosis were improved. Conclusion 3-MA can attenuate renal injury in STZ-induced diabetic mice through inhibition of autophagy and HMGB1/NF-κB signaling pathway.
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Affiliation(s)
- Haiwen Ren
- Department of Clinical Laboratory, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China
- Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Mengxin Huang
- Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Liwen Ou
- Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Xuan Deng
- Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Xin Wu
- Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Quan Gong
- Department of Immunology, Medical School of Yangtze University, Jingzhou 434023, China
- Clinical Molecular Immunology Center, Medical School of Yangtze University, Jingzhou 434023, China
| | - Benju Liu
- Department of Human Anatomy, Medical School of Yangtze University, Jingzhou 434023, China
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9
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Zhang S, Yang Y, Lv X, Liu W, Zhu S, Wang Y, Xu H. Unraveling the Intricate Roles of Exosomes in Cardiovascular Diseases: A Comprehensive Review of Physiological Significance and Pathological Implications. Int J Mol Sci 2023; 24:15677. [PMID: 37958661 PMCID: PMC10650316 DOI: 10.3390/ijms242115677] [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] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/21/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Exosomes, as potent intercellular communication tools, have garnered significant attention due to their unique cargo-carrying capabilities, which enable them to influence diverse physiological and pathological functions. Extensive research has illuminated the biogenesis, secretion, and functions of exosomes. These vesicles are secreted by cells in different states, exerting either protective or harmful biological functions. Emerging evidence highlights their role in cardiovascular disease (CVD) by mediating comprehensive interactions among diverse cell types. This review delves into the significant impacts of exosomes on CVD under stress and disease conditions, including coronary artery disease (CAD), myocardial infarction, heart failure, and other cardiomyopathies. Focusing on the cellular signaling and mechanisms, we explore how exosomes mediate multifaceted interactions, particularly contributing to endothelial dysfunction, oxidative stress, and apoptosis in CVD pathogenesis. Additionally, exosomes show great promise as biomarkers, reflecting differential expressions of NcRNAs (miRNAs, lncRNAs, and circRNAs), and as therapeutic carriers for targeted CVD treatment. However, the specific regulatory mechanisms governing exosomes in CVD remain incomplete, necessitating further exploration of their characteristics and roles in various CVD-related contexts. This comprehensive review aims to provide novel insights into the biological implications of exosomes in CVD and offer innovative perspectives on the diagnosis and treatment of CVD.
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Affiliation(s)
| | | | | | | | | | - Ying Wang
- Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China; (S.Z.); (Y.Y.); (X.L.); (W.L.); (S.Z.)
| | - Hongfei Xu
- Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China; (S.Z.); (Y.Y.); (X.L.); (W.L.); (S.Z.)
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10
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Botor M, Auguściak-Duma A, Lesiak M, Sieroń Ł, Dziedzic-Kowalska A, Witecka J, Asman M, Madetko-Talowska A, Bik-Multanowski M, Galicka A, Sieroń AL, Gawron K. Analysis of miRNAs in Osteogenesis imperfecta Caused by Mutations in COL1A1 and COL1A2: Insights into Molecular Mechanisms and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2023; 16:1414. [PMID: 37895885 PMCID: PMC10609877 DOI: 10.3390/ph16101414] [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: 09/11/2023] [Revised: 09/29/2023] [Accepted: 10/01/2023] [Indexed: 10/29/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a group of connective tissue disorders leading to abnormal bone formation, mainly due to mutations in genes encoding collagen type I (Col I). Osteogenesis is regulated by a number of molecules, including microRNAs (miRNAs), indicating their potential as targets for OI therapy. The goal of this study was to identify and analyze the expression profiles of miRNAs involved in bone extracellular matrix (ECM) regulation in patients diagnosed with OI type I caused by mutations in COL1A1 or COL1A2. Primary skin fibroblast cultures were used for DNA purification and sequence analysis, followed by analysis of miRNA expression. Sequencing analysis revealed mutations of the COL1A1 or COL1A2 genes in all OI patients, including four previously unreported. Amongst the 40 miRNAs analyzed, 9 were identified exclusively in OI cells and 26 in both OI patients and the controls. In the latter case, the expression of six miRNAs (hsa-miR-10b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, has-miR-204-5p, has-miR-216a-5p, and hsa-miR-449a) increased, while four (hsa-miR-129-5p, hsa-miR-199b-5p, hsa-miR-664a-5p, and hsa-miR-30a-5p) decreased significantly in OI cells in comparison to their expression in the control cells. The identified mutations and miRNA expression profiles shed light on the intricate processes governing bone formation and ECM regulation, paving the way for further research and potential therapeutic advancements in OI and other genetic diseases related to bone abnormality management.
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Affiliation(s)
- Malwina Botor
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Aleksandra Auguściak-Duma
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Marta Lesiak
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Łukasz Sieroń
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Agata Dziedzic-Kowalska
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Joanna Witecka
- Department of Parasitology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
| | - Marek Asman
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-808 Zabrze, Poland;
| | - Anna Madetko-Talowska
- Department of Medical Genetics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (A.M.-T.); (M.B.-M.)
| | - Mirosław Bik-Multanowski
- Department of Medical Genetics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (A.M.-T.); (M.B.-M.)
| | - Anna Galicka
- Department of Medical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Aleksander L. Sieroń
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
| | - Katarzyna Gawron
- Department of Molecular Biology and Genetics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-055 Katowice, Poland; (A.A.-D.); (M.L.); (Ł.S.); (A.L.S.)
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11
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Coban N, Erkan AF, Ozuynuk-Ertugrul AS, Ekici B. Investigation of miR-26a-5p and miR-19a-3p expression levels in angiographically confirmed coronary artery disease. Acta Cardiol 2023; 78:945-956. [PMID: 37376990 DOI: 10.1080/00015385.2023.2227484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 05/31/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023]
Abstract
BACKGROUND MicroRNAs have been found to have an essential role in cardiovascular diseases. In previous experiments, the changed expressions of miR-26a-5p and miR-19a-3p were confirmed in patients with severe coronary atherosclerosis by miRNA microarrays. However, the role of two miRNAs in coronary artery diseases (CAD) still needs to be investigated further. Our current study aimed to analyse two miRNAs in angiographically confirmed CAD and non-CAD with insignificant coronary stenosis. This study aimed to identify the potential diagnostic value of circulating miRNA with CAD. METHODS The CAD patients (n = 50) and non-CAD controls (n = 43) were studied. miRNAs (miR-26a-5p and miR-19a-3p) were quantified by TaqMan miRNA assays using real-time PCR. We subsequently assessed the diagnostic value of the miRNAs and correlations of miRNA with clinical parameters. Target prediction tools were utilised to identify miRNA target genes. RESULTS The expression of miR-26a-5p was significantly increased in CAD compared to non-CAD controls (p < 0.05). Tertile groups were formed according to the expression levels of miRNAs, and high expression tertile (T3) was compared with low expression tertile (T1). It was found that CAD presence was more prevalent in T3 of miR-26a-5p, and the frequency of diabetes was higher in T3 of miR-19a-3p. There were significant correlations between miRNAs and diabetes risk factors such as HbA1c, glucose levels, and BMI (p < 0.05). CONCLUSIONS Our findings show that miR-26a-5p expression is altered in CAD presence while miR-19a-3p expression is different in diabetes. Both miRNAs are closely related to risk factors of CAD, therefore, could be therapeutic targets for CAD treatment.
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Affiliation(s)
- Neslihan Coban
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Aycan F Erkan
- Department of Cardiology, Faculty of Medicine, Ufuk University, Ankara, Turkey
| | - Aybike Sena Ozuynuk-Ertugrul
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Berkay Ekici
- Department of Cardiology, Faculty of Medicine, Ufuk University, Ankara, Turkey
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12
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Li J, Liu Y, Liu J. A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis. Front Physiol 2023; 14:1220450. [PMID: 37817984 PMCID: PMC10560738 DOI: 10.3389/fphys.2023.1220450] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/13/2023] [Indexed: 10/12/2023] Open
Abstract
Peritoneal dialysis (PD) is an effective alternative treatment for patients with end-stage renal disease (ESRD) and is increasingly being adopted and promoted worldwide. However, as the duration of peritoneal dialysis extends, it can expose problems with dialysis inadequacy and ultrafiltration failure. The exact mechanism and aetiology of ultrafiltration failure have been of great concern, with triggers such as biological incompatibility of peritoneal dialysis solutions, uraemia toxins, and recurrent intraperitoneal inflammation initiating multiple pathways that regulate the release of various cytokines, promote the transcription of fibrosis-related genes, and deposit extracellular matrix. As a result, peritoneal fibrosis occurs. Exploring the pathogenic factors and molecular mechanisms can help us prevent peritoneal fibrosis and prolong the duration of Peritoneal dialysis.
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Affiliation(s)
- Jin’e Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinghong Liu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianping Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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13
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Khamis T, Alsemeh AE, Alanazi A, Eltaweel AM, Abdel-Ghany HM, Hendawy DM, Abdelkhalek A, Said MA, Awad HH, Ibrahim BH, Mekawy DM, Pascu C, Florin C, Arisha AH. Breast Milk Mesenchymal Stem Cells and/or Derived Exosomes Mitigated Adenine-Induced Nephropathy via Modulating Renal Autophagy and Fibrotic Signaling Pathways and Their Epigenetic Regulations. Pharmaceutics 2023; 15:2149. [PMID: 37631363 PMCID: PMC10458733 DOI: 10.3390/pharmaceutics15082149] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/01/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in CKD. Eighty adult male Sprague Dawley rats were randomly assigned to one of six groups, including control, nephropathy, nephropathy + conditioned media (CM), nephropathy + Br-MSCs, nephropathy + Br-MSCs derived exosomes (Br-MSCs-EXOs), and nephropathy + Br-MSCs + Br-MSCs-EXOs. Before administration, Br-MSCs and Br-MSCs-EXOs were isolated, identified, and labeled with PKH-26. SOX2, Nanog, and OCT3/4 expression levels in Br-MSCs and miR-29b, miR-181, and Let-7b in both Br-MSCs and Br-MSCs-EXOs were assayed. Twelve weeks after transplantation, renal function tests, oxidative stress, expression of the long non-coding RNA SNHG-7, autophagy, fibrosis, and expression of profibrotic miR-34a and antifibrotic miR-29b, miR-181, and Let-7b were measured in renal tissues. Immunohistochemical analysis for renal Beclin-1, LC3-II, and P62, Masson trichome staining, and histopathological examination of kidney tissues were also performed. The results showed that Br-MSCs expressed SOX2, Nanog, and OCT3/4, while both Br-MSCs and Br-MSCs-EXOs expressed antifibrotic miR-181, miR-29b, and Let-7b, with higher expression levels in exosomes than in Br-MSCs. Interestingly, the administration of Br-MSCs + EXOs, EXOs, and Br-MSCs improved renal function tests, reduced renal oxidative stress, upregulated the renal expression of SNHG-7, AMPK, ULK-1, Beclin-1, LC3, miR-29b, miR-181, Let-7b, and Smad-7, downregulated the renal expression of miR-34a, AKT, mTOR, P62, TGF-β, Smad-3, and Coli-1, and ameliorated renal pathology. Thus, Br-MSCs and/or their derived exosomes appear to reduce adenine-induced renal damage by secreting antifibrotic microRNAs and potentiate renal autophagy by modulating SNHG-7 expression.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Amira Ebrahim Alsemeh
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Asma Alanazi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh 11481, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia
| | - Asmaa Monir Eltaweel
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh 11481, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia
| | - Heba M. Abdel-Ghany
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Doaa M. Hendawy
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Adel Abdelkhalek
- Department of Food Hygiene, Safety and Technology, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
| | - Mahmoud A. Said
- Zagazig University Hospital, Zagazig University, Zagazig 44511, Egypt
| | - Heba H. Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 12451, Egypt
| | - Basma Hamed Ibrahim
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Dina Mohamed Mekawy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt;
| | - Corina Pascu
- Faculty of Veterinary Medicine, University of Life Sciences, King Mihai I from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania;
| | - Crista Florin
- Department of Soil Science, Faculty of Agriculture, University of Life Sciences, King Mihai I from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
- Department of Physiology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
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14
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Guardado-Estrada M, Cárdenas-Monroy CA, Martínez-Rivera V, Cortez F, Pedraza-Lara C, Millan-Catalan O, Pérez-Plasencia C. A miRNome analysis at the early postmortem interval. PeerJ 2023; 11:e15409. [PMID: 37304870 PMCID: PMC10257396 DOI: 10.7717/peerj.15409] [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: 01/24/2023] [Accepted: 04/23/2023] [Indexed: 06/13/2023] Open
Abstract
The postmortem interval (PMI) is the time elapsing since the death of an individual until the body is examined. Different molecules have been analyzed to better estimate the PMI with variable results. The miRNAs draw attention in the forensic field to estimate the PMI as they can better support degradation. In the present work, we analyzed the miRNome at early PMI in rats' skeletal muscle using the Affymetrix GeneChip™ miRNA 4.0 microarrays. We found 156 dysregulated miRNAs in rats' skeletal muscle at 24 h of PMI, out of which 84 were downregulated, and 72 upregulated. The miRNA most significantly downregulated was miR-139-5p (FC = -160, p = 9.97 × 10-11), while the most upregulated was rno-miR-92b-5p (FC = 241.18, p = 2.39 × 10-6). Regarding the targets of these dysregulated miRNAs, the rno-miR-125b-5p and rno-miR-138-5p were the miRNAs with more mRNA targets. The mRNA targets that we found in the present study participate in several biological processes such as interleukin secretion regulation, translation regulation, cell growth, or low oxygen response. In addition, we found a downregulation of SIRT1 mRNA and an upregulation of TGFBR2 mRNA at 24 h of PMI. These results suggest there is an active participation of miRNAs at early PMI which could be further explored to identify potential biomarkers for PMI estimation.
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Affiliation(s)
- Mariano Guardado-Estrada
- Laboratorio de Genética, Ciencia Forense, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Christian A. Cárdenas-Monroy
- Laboratorio de Genética, Ciencia Forense, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Vanessa Martínez-Rivera
- Laboratorio de Genética, Ciencia Forense, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Fernanda Cortez
- Computational Genomics Division, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Carlos Pedraza-Lara
- Laboratorio de Entomología, Ciencia Forense, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Oliver Millan-Catalan
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Carlos Pérez-Plasencia
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
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15
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Identification of Potential microRNA Panels for Male Non-Small Cell Lung Cancer Identification Using Microarray Datasets and Bioinformatics Methods. J Pers Med 2022; 12:jpm12122056. [PMID: 36556276 PMCID: PMC9780989 DOI: 10.3390/jpm12122056] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Non-small cell lung cancer (NSCLC) is still one of the types of cancer with the highest death rates. MicroRNAs (miRNAs) play essential roles in NSCLC development. This study evaluates miRNA expression patterns and specific mechanisms in male patients with NSCLC. Methods: We report an integrated microarray analysis of miRNAs for eight matched samples of males with NSCLC compared to the study of public datasets of males with NSCLC from TCGA, followed by qRT-PCR validation. Results: For the TCGA dataset, we identified 385 overexpressed and 75 underexpressed miRNAs. Our cohort identified 54 overexpressed and 77 underexpressed miRNAs, considering a fold-change (FC) of ±1.5 and p < 0.05 as the cutoff value. The common miRNA signature consisted of eight overexpressed and nine underexpressed miRNAs. Validation was performed using qRT-PCR on the tissue samples for miR-183-3p and miR-34c-5p and on plasma samples for miR-34c-5p. We also created mRNA-miRNA regulatory networks to identify critical molecules, revealing NSCLC signaling pathways related to underexpressed and overexpressed transcripts. The genes targeted by these transcripts were correlated with overall survival. Conclusions: miRNAs and some of their target genes could play essential roles in investigating the mechanisms involved in NSCLC evolution and provide opportunities to identify potential therapeutic targets.
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16
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Differential expression of aqueous humor microRNAs in central retinal vein occlusion and its association with matrix metalloproteinases: a pilot study. Sci Rep 2022; 12:16429. [PMID: 36180575 PMCID: PMC9525721 DOI: 10.1038/s41598-022-20834-z] [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: 03/07/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
The aim of this study is to investigate the differential expression of microRNAs (miRNAs) in the aqueous humor (AH) of patients with central retinal vein occlusion (CRVO), and their association with AH matrix metalloproteinase (MMP) activity. Eighteen subjects, including 10 treatment naïve patients with CRVO and 8 control subjects, scheduled for intravitreal injection and cataract surgery, respectively, were included. AH samples were collected at the beginning of the procedure. A microarray composed of 84 miRNAs was performed to identify differentially expressed miRNAs in CRVO AH, which were further analyzed using bioinformatic tools to identify directly related cytokines/proteins. Eight miRNAs (hsa-mir-16-5p, hsa-mir-142-3p, hsa-mir-19a-3p, hsa-mir-144-3p, hsa-mir-195-5p, hsa-mir-17-5p, hsa-mir-93-5p, and hsa-mir-20a-5p) were significantly downregulated in the CRVO group. Bioinformatic analysis revealed a direct relationship among downregulated miRNAs, CRVO, and the following proteins: MMP-2, MMP-9, tumor necrosis factor, transforming growth factor beta-1, caspase-3, interleukin-6, interferon gamma, and interleukin-1-beta. Activities of MMP-2 and -9 in AH were detected using gelatin zymography, showing significant increase in the CRVO group compared to the control group (p < 0.01). This pilot study first revealed that MMP-2 and -9 were directly related to downregulated miRNAs and showed significant increase in activity in AH of patients with CRVO. Therefore, the relevant miRNAs and MMPs in AH could serve as potential biomarkers or therapeutic targets for CRVO.
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17
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Zhang R, Li W, Jiang X, Cui X, You H, Tang Z, Liu W. Ferulic Acid Combined With Bone Marrow Mesenchymal Stem Cells Attenuates the Activation of Hepatic Stellate Cells and Alleviates Liver Fibrosis. Front Pharmacol 2022; 13:863797. [PMID: 35721175 PMCID: PMC9205407 DOI: 10.3389/fphar.2022.863797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 04/13/2022] [Indexed: 01/28/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) can effectively alleviate liver fibrosis, but the efficacy of cell therapy alone is insufficient. In recent years, a combination of traditional Chinese medicine (TCM) and cell therapy has been increasingly used to treat diseases in clinical trials. Ferulic acid (FA) is highly effective in treating liver fibrosis, and a combination of cells and drugs is being tested in clinical trials. Therefore, we combined BMSCs and Ferulic acid to treat CCl4-induced fibrosis and determine whether this combination was more effective than single treatment. We used BMSCs and FA to treat CCl4-induced fibrosis in rat models, observed their therapeutic effects, and investigated the specific mechanism of this combination therapy in liver fibrosis. We created a BMSC/hepatic stellate cell (HSC) coculture system and used FA to treat activated HSCs to verify the specific mechanism. Then, we used cytochalasin D and angiotensin II to investigate whether BMSCs and FA inactivate HSCs through cytoskeletal rearrangement. MiR-19b-3p was enriched in BMSCs and targeted TGF-β receptor II (TGF-βR2). We separately transfected miR-19b-3p into HSCs and BMSCs and detected hepatic stellate cell activation. We found that the expression of the profibrotic markers α-SMA and COL1-A1 was significantly decreased in the combination group of rats. α-SMA and COL1-A1 levels were also significantly decreased in the HSCs with the combination treatment. Cytoskeletal rearrangement of HSCs was inhibited in the combination group, and RhoA/ROCK pathway gene expression was decreased. Following angiotensin II treatment, COL1-A1 and α-SMA expression increased, while with cytochalasin D treatment, profibrotic gene expression decreased in HSCs. The expression of COL1-A1, α-SMA and RhoA/ROCK pathway genes was decreased in the activated HSCs treated with a miR-19b-3p mimic, indicating that miR-19b-3p inactivated HSCs by suppressing RhoA/ROCK signalling. In contrast, profibrotic gene expression was significantly decreased in the BMSCs treated with the miR-19b-3p mimic and FA or a miR-19b-3p inhibitor and FA compared with the BMSCs treated with the miR-19b-3p mimic alone. In conclusion, the combination therapy had better effects than FA or BMSCs alone. BMSC and FA treatment attenuated HSC activation and liver fibrosis by inhibiting cytoskeletal rearrangement and delivering miR-19b-3p to activated HSCs, inactivating RhoA/ROCK signalling. FA-based combination therapy showed better inhibitory effects on HSC activation.
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Affiliation(s)
- Rui Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenhang Li
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xiaodan Jiang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xinyi Cui
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hongjie You
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zuoqing Tang
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Wenlan Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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18
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Zdanowicz A, Urban S, Ponikowska B, Iwanek G, Zymliński R, Ponikowski P, Biegus J. Novel Biomarkers of Renal Dysfunction and Congestion in Heart Failure. J Pers Med 2022; 12:jpm12060898. [PMID: 35743683 PMCID: PMC9224642 DOI: 10.3390/jpm12060898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/15/2022] [Accepted: 05/26/2022] [Indexed: 02/04/2023] Open
Abstract
Heart failure is a major public health problem and, despite the constantly emerging, new, effective treatments, it remains a leading cause of morbidity and mortality. Reliable tools for early diagnosis and risk stratification are crucial in the management of HF. This explains a growing interest in the development of new biomarkers related to various pathophysiological mechanisms of HF. In the course of this review, we focused on the markers of congestion and renal dysfunction in terms of their interference with cardiovascular homeostasis. Congestion is a hallmark feature of heart failure, contributing to symptoms, morbidity, and hospitalizations of patients with HF and has, therefore, become a therapeutic target in AHF. On the other hand, impaired renal function by altering the volume status contributes to the development and progression of HF and serves as a marker of an adverse clinical outcome. Early detection of congestion and an adequate assessment of renal status are essential for the prompt administration of patient-tailored therapy. This review provides an insight into recent advances in the field of HF biomarkers that could be potentially implemented in diagnosis and risk stratification of patients with HF.
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Affiliation(s)
- Agata Zdanowicz
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Szymon Urban
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
- Correspondence: ; Tel.: +48-71-733-11-12
| | - Barbara Ponikowska
- Student Scientific Organization, Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland;
| | - Gracjan Iwanek
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Robert Zymliński
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Piotr Ponikowski
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
| | - Jan Biegus
- Institute of Heart Diseases, Medical University, 50-556 Wroclaw, Poland; (A.Z.); (G.I.); (R.Z.); (P.P.); (J.B.)
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19
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Zhang L, Zhang J, Qin Z, Liu N, Zhang Z, Lu Y, Xu Y, Zhang J, Tang J. Diagnostic and Predictive Values of Circulating Extracellular Vesicle-Carried microRNAs in Ischemic Heart Disease Patients With Type 2 Diabetes Mellitus. Front Cardiovasc Med 2022; 9:813310. [PMID: 35295267 PMCID: PMC8918773 DOI: 10.3389/fcvm.2022.813310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/05/2022] [Indexed: 12/14/2022] Open
Abstract
Ischemic heart disease patients with diabetes mellitus (IHD-DM) have a higher risk of cardiovascular events than those without DM. Rapid identification of IHD-DM can enable early access to medical treatment and reduce the occurrence of cardiovascular adverse events. In the present study, we identified and examined extracellular vesicle (EV)-carried microRNAs (miRNAs) as the possible diagnostic biomarkers of IHD-DM. Small RNA sequencing was performed to analyze the EV-carried miRNAs spectrum, and differentially expressed miRNAs were further confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Through small RNA sequencing, we identified 138 differentially expressed EV-carried miRNAs between IHD-DM patients and healthy controls. Furthermore, we identified that five EV-carried miRNAs (miR-15a-3p, miR-18a-5p, miR-133a-3p, miR-155-5p, and miR-210-3p) were significantly down-regulated and one (miR-19a-3p) was significantly up-regulated in the IHD-DM patients compared to healthy controls. The receiver–operating characteristic curve analysis showed that the above six EV-carried miRNAs have excellent diagnostic efficacy of IHD-DM. Our findings indicated that the circulating EV-miRNAs might be promising biomarkers for the convenient and rapid diagnosis of IHD-DM.
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Affiliation(s)
- Li Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Jianchao Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Zhen Qin
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Na Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zenglei Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Yongzheng Lu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Yanyan Xu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
| | - Jinying Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
- Jinying Zhang
| | - Junnan Tang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, China
- *Correspondence: Junnan Tang
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20
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li X, Dong Z, chang H, zhou H, Wang J, Yang Z, Min Q, Bai W, Shi S. Screening and identification of key microRNAs and regulatory pathways associated with renal fibrosis process. Mol Omics 2022; 18:520-533. [DOI: 10.1039/d1mo00498k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To reveal the pathogenesis of renal fibrosis. Renal fibrosis was induced with unilateral ureteral obstruction (UUO). Related biochemical indices in rat serum were determined, and histopathological morphology observed. Tissue transcriptome...
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21
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Su Y, Sun Y, Tang Y, Li H, Wang X, Pan X, Liu W, Zhang X, Zhang F, Xu Y, Yan C, Ong SB, Xu D. Circulating miR-19b-3p as a Novel Prognostic Biomarker for Acute Heart Failure. J Am Heart Assoc 2021; 10:e022304. [PMID: 34612058 PMCID: PMC8751856 DOI: 10.1161/jaha.121.022304] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Circulating microRNAs are emerging biomarkers for heart failure (HF). Our study aimed to assess the prognostic value of microRNA signature that is differentially expressed in patients with acute HF. Methods and Results Our study comprised a screening cohort of 15 patients with AHF and 5 controls, a PCR-discovery cohort of 50 patients with AHF and 26 controls and a validation cohort of 564 patients with AHF from registered study DRAGON-HF (Diagnostic, Risk Stratification and Prognostic Value of Novel Biomarkers in Patients With Heart Failure). Through screening by RNA-sequencing and verification by reverse-transcription quantitative polymerase chain reaction, 9 differentially expressed microRNAs were verified (miR-939-5p, miR-1908-5p, miR-7706, miR-101-3p, miR-144-3p, miR-4732-3p, miR-3615, miR-484 and miR-19b-3p). Among them, miR-19b-3p was identified as the microRNA signature with the highest fold-change of 8.4 and the strongest prognostic potential (area under curve with 95% CI, 0.791, 0.654-0.927). To further validate its prognostic value, in the validation cohort, the baseline level of miR-19b-3p was measured. During a follow-up period of 19.1 (17.7, 20.7) months, primary end point comprising of all-cause mortality or readmission due to HF occurred in 48.9% patients, while patients in the highest quartile of miR-19b-3p level presented the worst survival (Log-rank P<0.001). Multivariate Cox model showed that the level of miR-19b-3p could independently predict the occurrence of primary end point (adjusted hazard ratio,1.39; 95% CI, 1.18-1.64). In addition, miR-19b-3p positively correlated with soluble suppression of tumorigenicity 2 and echocardiographic indexes of left ventricular hypertrophy. Conclusions Circulating miR-19b-3p could be a valuable prognostic biomarker for AHF. In addition, a high level of circulating miR-19b-3p might indicate ventricular hypertrophy in AHF subjects. Registration URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03727828.
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Affiliation(s)
- Yang Su
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China.,Department of Cardiology Qidong People's Hospital Qidong Jiangsu China
| | - Yuxi Sun
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Yansong Tang
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Hao Li
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Xiaoyu Wang
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Xin Pan
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Weijing Liu
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Xianling Zhang
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Fenglei Zhang
- Department of Cardiology Qidong People's Hospital Qidong Jiangsu China
| | - Yawei Xu
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China
| | - Chunxi Yan
- Department of Cardiology Qidong People's Hospital Qidong Jiangsu China
| | - Sang-Bing Ong
- Centre for Cardiovascular Genomics and Medicine (CCGM) Lui Che Woo Institute of Innovative MedicineChinese University of Hong Kong (CUHK) Hong Kong SAR.,Department of Medicine and Therapeutics Faculty of Medicine CUHK Hong Kong SAR.,Hong Kong Hub of Paediatric Excellence (HK HOPE)Hong Kong Children's Hospital (HKCH) Kowloon Bay Hong Kong SAR.,Institute for Translational MedicineXiamen Cardiovascular HospitalXiamen University Xiamen Fujian China.,Kunming Institute of Zoology - The Chinese University of Hong Kong (KIZ-CUHK)Joint Laboratory of Bioresources and Molecular Research of Common DiseasesKunming Institute of ZoologyChinese Academy of Sciences Kunming Yunnan China
| | - Dachun Xu
- Department of Cardiology Shanghai Tenth People's HospitalTongji University School of Medicine Shanghai China.,Department of Cardiology Qidong People's Hospital Qidong Jiangsu China
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22
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Ruan Y, Li H, Cao X, Meng S, Jia R, Pu L, Fu H, Jin Z. Inhibition of the lncRNA DANCR attenuates cardiomyocyte injury induced by oxygen-glucose deprivation via the miR-19a-3p/MAPK1 axis. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1377-1386. [PMID: 34515297 DOI: 10.1093/abbs/gmab110] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 08/03/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been considered as crucial regulators of acute myocardial infarction (AMI). In this study, to analyze the effect of differentiation antagonizing nonprotein coding RNA (DANCR) of lncRNA on cardiomyocyte damage in AMI, cardiomyocyte injury was induced by oxygen-glucose deprivation (OGD). Cell counting kit-8 (CCK-8) assay and flow cytometry were used to assess cell viability and apoptosis, respectively. Quantitative real-time PCR was used to measure the expression levels of DANCR and miR-19a-3p. Bioinformatics analysis and luciferase gene reporter assay were utilized to explore the relationship among DANCR, miR-19a-3p, and mitogen-activated protein kinase 1 (MAPK1). CCK-8 and TUNEL assays were used to explore the effects of DANCR alone or plus miR-19a-3p on the viability and apoptosis of OGD/R-exposed HL-1 cells. Western blot analysis was used to detect changes in the MAPK1/ERK1/2 pathway in HL-1 cells. We found that DANCR expression and miR-19a-3p level are negatively correlated as DANCR expression is increased, while miR-19a-3p level is decreased in AMI patients' serum and OGD/R-exposed HL-1 cells. DANCR knockdown increased miR-19a-3p level, and miR-19a-3p inhibition increased DANCR expression. Moreover, DANCR directly binds to miR-19a-3p. DANCR knockdown reduced viability but induced apoptosis in OGD/R-exposed HL-1 cells, while miR-19a-3p inhibition weakens these effects. Furthermore, MAPK1 is a target of miR-19a-3p. miR-19a-3p overexpression decreases MAPK1 and ERK1/2 in HL-1 cells, while miR-19a-3p inhibition increases MAPK1 and ERK1/2 in HL-1 cells. Moreover, DANCR knockdown reduces myocardium apoptosis in mice with the left anterior descending artery ligated. DANCR knockdown effectively restores myocardial cell apoptosis by regulating the miR-19a-3p/MAPK1/ERK1/2 axis.
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Affiliation(s)
- Yang Ruan
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Hong Li
- Ward Three, Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Xiaojing Cao
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Shuai Meng
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Ruofei Jia
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Lianmei Pu
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Hao Fu
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Zening Jin
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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23
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Ragusa R, Di Molfetta A, Del Turco S, Cabiati M, Del Ry S, Basta G, Mercatanti A, Pitto L, Amodeo A, Trivella MG, Rizzo M, Caselli C. Epigenetic Regulation of Cardiac Troponin Genes in Pediatric Patients with Heart Failure Supported by Ventricular Assist Device. Biomedicines 2021; 9:biomedicines9101409. [PMID: 34680526 PMCID: PMC8533380 DOI: 10.3390/biomedicines9101409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/30/2021] [Accepted: 10/03/2021] [Indexed: 11/16/2022] Open
Abstract
Ventricular Assist Device (VAD) therapy is considered as a part of standard care for end-stage Heart Failure (HF) children unresponsive to medical management, but the potential role of miRNAs in response to VAD therapy on molecular pathways underlying LV remodeling and cardiac function in HF is unknown. The aims of this study were to evaluate the effects of VAD on miRNA expression profile in cardiac tissue obtained from HF children, to determine the putative miRNA targets by an in-silico analysis as well as to verify the changes of predicated miRNA target in the same cardiac samples. The regulatory role of selected miRNAs on predicted targets was evaluated by a dedicated in vitro study. miRNA profile was determined in cardiac samples obtained from 13 HF children [median: 29 months; 19 LVEF%; 9 Kg] by NGS before VAD implant (pre-VAD) and at the moment of heart transplant (Post-VAD). Only hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-1246 were differentially expressed at post-VAD when compared to pre-VAD, and validated by real-time PCR. Putative targets of the selected miRNAs were involved in regulation of sarcomere genes, such as cardiac troponin (cTns) complex. The expression levels of fetal ad adult isoforms of cTns resulted significantly higher after VAD in cardiac tissue of HF pediatric patients when compared with HF adults. An in vitro study confirmed a down-regulatory effect of hsa-miR-19a-3p on cTnC expression. The effect of VAD on sarcomere organization through cTn isoform expression may be epigenetically regulated, suggesting for miRNAs a potential role as therapeutic targets to improve heart function in HF pediatric patients.
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Affiliation(s)
- Rosetta Ragusa
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
- Scuola Superiore Sant’Anna, 56127 Pisa, Italy
| | - Arianna Di Molfetta
- Departement of Cardiothoracic Surgery, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; (A.D.M.); (A.A.)
| | - Serena Del Turco
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Manuela Cabiati
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Silvia Del Ry
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Alberto Mercatanti
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Letizia Pitto
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Antonio Amodeo
- Departement of Cardiothoracic Surgery, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; (A.D.M.); (A.A.)
| | - Maria Giovanna Trivella
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Milena Rizzo
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Chiara Caselli
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
- Fondazione Toscana Gabriele Monasterio, 56124 Pisa, Italy
- Correspondence: ; Tel.: +39-050-3153551; Fax: +39-050-3152166
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24
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Algeciras L, Palanca A, Maestro D, RuizdelRio J, Villar AV. Epigenetic alterations of TGFβ and its main canonical signaling mediators in the context of cardiac fibrosis. J Mol Cell Cardiol 2021; 159:38-47. [PMID: 34119506 DOI: 10.1016/j.yjmcc.2021.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 05/26/2021] [Accepted: 06/07/2021] [Indexed: 12/13/2022]
Abstract
Cardiac fibrosis is a pathological process that presents a continuous overproduction of extracellular matrix (ECM) components in the myocardium, which negatively influences the progression of many cardiac diseases. Transforming growth factor β (TGFβ) is the main ligand that triggers the production of pro-fibrotic ECM proteins. In the cardiac fibrotic process, TGFβ and its canonical signaling mediators are tightly regulated at different levels as well as epigenetically. Cardiac fibroblasts are one of the most important TGFβ target cells activated after cardiac injury. TGFβ-driven fibroblast activation is subject to epigenetic modulation and contributes to the progression of cardiac fibrosis, mainly through the expression of pro-fibrotic molecules implicated in the disease. In this review, we describe epigenetic regulation related to canonical TGFβ signaling in cardiac fibroblasts.
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Affiliation(s)
- Luis Algeciras
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain; Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Ana Palanca
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain; Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain; Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - David Maestro
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain; Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Jorge RuizdelRio
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain; Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Ana V Villar
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain; Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain; Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
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25
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Logan SM, Gupta A, Wang A, Levy RJ, Storey KB. Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart. Cell Stress Chaperones 2021; 26:541-548. [PMID: 33661504 PMCID: PMC8065082 DOI: 10.1007/s12192-021-01199-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/08/2021] [Accepted: 02/12/2021] [Indexed: 11/30/2022] Open
Abstract
Anesthetics such as isoflurane are known to cause apoptosis in the developing mammalian brain. However, isoflurane may have protective effects on the heart via relieving ischemia and downregulating genes related to apoptosis. Ischemic preconditioning, e.g. through the use of low levels of carbon monoxide (CO), has promise in preventing ischemia-reperfusion injury and cell death. However, it is still unclear how it either triggers the stress response in neonatal hearts. For this reason, thirty-three microRNAs (miRNAs) known to be differentially expressed following anesthesia and/or ischemic or hypoxic heart damage were investigated in the hearts from neonatal mice exposed to isoflurane or low level of CO, using an air-exposed control group. Only miR-93-5p increased with isoflurane exposure, which may be associated with the suppression of cell death, autophagy, and inflammation. By contrast, twelve miRNAs were differentially expressed in the heart following CO treatment. Many miRNAs previously shown to be responsible for suppressing cell death, autophagy, and myocardial hypertrophy were upregulated (e.g., 125b-3p, 19-3p, and 21a-5p). Finally, some miRNAs (miR-103-3p, miR-1a-3p, miR-199a-1-5p) which have been implicated in regulating energy balance and cardiac contraction were also differentially expressed. Overall, this study demonstrated that CO-mediated miRNA regulation may promote ischemic preconditioning and cardioprotection based on the putative protective roles of the differentially expressed miRNAs explored herein and the consistency of these results with those that have shown positive effects of CO on heart viability following anesthesia and ischemia-reperfusion stress.
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Affiliation(s)
- Samantha M Logan
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Aakriti Gupta
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Aili Wang
- Department of Anesthesiology, Columbia University Medical Center, 622 West 168th Street, New York, NY, 10032, USA
| | - Richard J Levy
- Department of Anesthesiology, Columbia University Medical Center, 622 West 168th Street, New York, NY, 10032, USA
| | - Kenneth B Storey
- Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
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26
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The Impact of microRNAs in Renin-Angiotensin-System-Induced Cardiac Remodelling. Int J Mol Sci 2021; 22:ijms22094762. [PMID: 33946230 PMCID: PMC8124994 DOI: 10.3390/ijms22094762] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.
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27
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Huang JH, Han TT, Li LX, Qu T, Zhang XY, Liao X, Zhong Y. Host microRNAs regulate expression of hepatitis B virus genes during transmission from patients' sperm to embryo. Reprod Toxicol 2021; 100:1-6. [PMID: 33338580 DOI: 10.1016/j.reprotox.2020.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 09/21/2020] [Accepted: 11/06/2020] [Indexed: 02/05/2023]
Abstract
Human sperm nucleus contains diverse RNA populations. This study aimed to screen and identify host microRNAs (miRs) that regulate gene expression of hepatitis B virus (HBV) during transmission from patients' sperm to sperm-derived embryos. Using microarrays, 336 miRs were found to be differentially expressed. After validation using real-time quantitative RT-PCR (RT-qPCR), four miRs were selected as targets. Using RT-qPCR and enzyme-linked immunosorbent assays, when patients' sperm were treated with mimics (or inhibitors) specific for hsa-miR-19a-3p and hsa-miR-29c-3p, the S gene transcription in sperm and translation in sperm-derived embryos was downregulated (or upregulated). There were significant differences in transcriptional and translational levels of the S gene between the test and control groups. These findings suggest that hsa-miR-19a-3p and hsa-miR-29c-3p significantly suppressed expression of the S gene, offering potential therapeutic targets for treating patients with HBV infection, and further reducing the negative impact of HBV infection on sperm fertilizing capacity.
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Affiliation(s)
- Ji-Hua Huang
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ting-Ting Han
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China; Research Center for Reproductive Medicine, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, China.
| | - Ling-Xiao Li
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ting Qu
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Xin-Yue Zhang
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Xue Liao
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ying Zhong
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
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Guo Y, Yang JH, Cao SD, Gao CX, He Y, Wang Y, Wan HT, Jin B. Effect of main ingredients of Danhong Injection against oxidative stress induced autophagy injury via miR-19a/SIRT1 pathway in endothelial cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 83:153480. [PMID: 33548866 DOI: 10.1016/j.phymed.2021.153480] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 12/25/2020] [Accepted: 01/21/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Autophagy plays an important role in cellular homeostasis. Oxidative stress stimulated endothelial excessive autophagy has been proposed as a major risk factor for cardiovascular diseases (CVD). Danhong injection (DHI), the most prescribed traditional Chinese medicine for the treatment of CVD, has been shown to elicit vascular protective effects. However, its underlying mechanisms remain poorly defined. This study aimed to uncover the protective effects of DHI and its main bioactive components on autophagy injury of human umbilical vein endothelial cells (HUVECs) induced by H2O2 and reveal the possible mechanisms. METHODS HUVECs were treated with different concentrations of DHI or its components, after exposed to H2O2. The protective effects of DHI and its components in H2O2-induced HUVECs were examined via a cytotoxicity assay and western blot. Apoptosis was evaluated with flow cytometry. Autophagy flux was assessed by transmission electron microscopy and LC3 plasmid transfection. Besides, the role miR-19a and SIRT1 in DHI and components-mediated anti-autophagy responses were validated with inhibitors transfection. RESULTS Our results showed that DHI and its components do have different effects on different aspects. In terms of HUVECs survival rate, Salvianolic acid B (Sal B) and danshensu (DSS) performed better than DHI, Hydroxysafflor yellow A (HSYA) and Tanshinone IIA (DST-IIA). As for the proliferation effect on HUVECs, only Sal B has the most obvious performance as same as 3MA. Besides, DHI and its components are sensitive and superior in regulating and balancing ROS concentration. Among the GSH/GSSG indicators, DSS and HSYA performed better. In terms of SOD content and apoptotic rate, the SOD level showed the opposite trend compared with H2O2 group. For the expression of LC3, Beclin-1 and P62, DHI and its components all had significant effects. When miR-19a or SIRT1 was inhibited, Sal B (0.5 μg/ml) can not decrease autophagy-related protein effectively. CONCLUSION DHI and its components all had anti-autophagy effects. And Sal B (0.5 μg/ml) inhibited HUVECs autophagy via miR-19a/SIRT1 pathway.
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Affiliation(s)
- Yan Guo
- College of Basic Medicine &Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Jie-Hong Yang
- College of Basic Medicine &Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Shi-Dong Cao
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Cheng-Xian Gao
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Yu He
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Yu Wang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Hai-Tong Wan
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Bo Jin
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
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Saadat S, Noureddini M, Mahjoubin-Tehran M, Nazemi S, Shojaie L, Aschner M, Maleki B, Abbasi-Kolli M, Rajabi Moghadam H, Alani B, Mirzaei H. Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players. Front Cardiovasc Med 2021; 7:588347. [PMID: 33569393 PMCID: PMC7868343 DOI: 10.3389/fcvm.2020.588347] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/15/2020] [Indexed: 12/21/2022] Open
Abstract
Unintended cardiac fibroblast proliferation in many pathophysiological heart conditions, known as cardiac fibrosis, results in pooling of extracellular matrix (ECM) proteins in the heart muscle. Transforming growth factor β (TGF-β) as a pivotal cytokine/growth factor stimulates fibroblasts and hastens ECM production in injured tissues. The TGF-β receptor is a heterodimeric receptor complex on the plasma membrane, made up from TGF-β type I, as well as type II receptors, giving rise to Smad2 and Smad3 transcription factors phosphorylation upon canonical signaling. Phosphorylated Smad2, Smad3, and cytoplasmic Smad4 intercommunicate to transfer the signal to the nucleus, culminating in provoked gene transcription. Additionally, TGF-β receptor complex activation starts up non-canonical signaling that lead to the mitogen-stimulated protein kinase cascade activation, inducing p38, JNK1/2 (c-Jun NH2-terminal kinase 1/2), and ERK1/2 (extracellular signal–regulated kinase 1/2) signaling. TGF-β not only activates fibroblasts and stimulates them to differentiate into myofibroblasts, which produce ECM proteins, but also promotes fibroblast proliferation. Non-coding RNAs (ncRNAs) are important regulators of numerous pathways along with cellular procedures. MicroRNAs and circular long ncRNAs, combined with long ncRNAs, are capable of affecting TGF-β/Smad signaling, leading to cardiac fibrosis. More comprehensive knowledge based on these processes may bring about new diagnostic and therapeutic approaches for different cardiac disorders.
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Affiliation(s)
- Somayeh Saadat
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahdi Noureddini
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Nazemi
- Vascular and Thorax Surgery Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Layla Shojaie
- Department of Medicine, Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Behnaz Maleki
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hasan Rajabi Moghadam
- Department of Cardiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Peng T, Yang F, Sun Z, Yan J. miR-19a-3p Facilitates Lung Adenocarcinoma Cell Phenotypes by Inhibiting TEK. Cancer Biother Radiopharm 2021; 37:589-601. [PMID: 33493418 DOI: 10.1089/cbr.2020.4456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background: Both TEK and miR-19a-3p have been reported to regulate lung adenocarcinoma (LUAD) progression. However, the association between TEK and miR-19a-3p in LUAD remained unknown. This research aimed to investigate a novel miR-19a-3p/TEK interactome in LUAD cells. Methods: The mRNA expression and protein expression in the cell lines were determined using qPCR and Western blot assay, respectively. CCK-8 assay, EDU assay, flow cytometry cell apoptosis assay, scratch assay, and cell-to-extracellular matrix adhesion assay were performed to detect the proliferation, apoptosis, migration, and adhesion ability of A549 and H1975 cell lines. Results: Findings revealed that both mRNA and protein levels of TEK were downregulated in the LUAD tumor tissues and cell lines. It was also found that compared with the control group, the transfection of TEK overexpression plasmids into H1975 and A549 cell lines significantly inhibited cancerous phenotypes. However, experimental results indicated that by downregulating TEK, miR-19a-3p promoted LUAD cell phenotypes. Conclusion: This research demonstrated that an interactome existed between miR-19a-3p and TEK and that miR-19a-3p could suppress LUAD tumors by inhibiting TEK. This novel interactome could be used as a novel therapy target for LUAD.
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Affiliation(s)
- Tao Peng
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, China
| | - Fan Yang
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, China
| | - Zhanwen Sun
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, China
| | - Jie Yan
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital (Affiliated Hospital of Hubei Polytechnic University), Edong Healthcare Group, Huangshi, China
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Non-coding RNAs modulate function of extracellular matrix proteins. Biomed Pharmacother 2021; 136:111240. [PMID: 33454598 DOI: 10.1016/j.biopha.2021.111240] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/19/2020] [Accepted: 12/31/2020] [Indexed: 12/14/2022] Open
Abstract
The extracellular matrix (ECM) creates a multifaceted system for the interaction of diverse structural proteins, matricellular molecules, proteoglycans, hyaluronan, and various glycoproteins that collaborate and bind with each other to produce a bioactive polymer. Alterations in the composition and configuration of ECM elements influence the cellular phenotype, thus participating in the pathogenesis of several human disorders. Recent studies indicate the crucial roles of non-coding RNAs in the modulation of ECM. Several miRNAs such as miR-21, miR-26, miR-19, miR-140, miR-29, miR-30, miR-133 have been dysregulated in disorders that are associated with disruption or breakdown of the ECM. Moreover, expression of MALAT1, PVT1, SRA1, n379519, RMRP, PFL, TUG1, TM1P3, FAS-AS1, PART1, XIST, and expression of other lncRNAs is altered in disorders associated with the modification of ECM components. In the current review, we discuss the role of lncRNAs and miRNAs in the modification of ECM and their relevance with the pathophysiology of human disorders such as cardiac/ lung fibrosis, cardiomyopathy, heart failure, asthma, osteoarthritis, and cancers.
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Gao Y, Liu Y, Fu Y, Wang Q, Liu Z, Hu R, Yang X, Chen M. The potential regulatory role of hsa_circ_0004104 in the persistency of atrial fibrillation by promoting cardiac fibrosis via TGF-β pathway. BMC Cardiovasc Disord 2021; 21:25. [PMID: 33421993 PMCID: PMC7797150 DOI: 10.1186/s12872-021-01847-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 01/01/2021] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION The progression of paroxysmal AF (PAF) to persistent AF (PsAF) worsens the prognosis of AF, but its underlying mechanisms remain elusive. Recently, circular RNAs (circRNAs) were reported to be associated with cardiac fibrosis. In case of the vital role of cardiac fibrosis in AF persistency, we hypothesis that circRNAs may be potential regulators in the process of AF progression. MATERIALS AND METHODS 6 persistent and 6 paroxysmal AF patients were enrolled as derivation cohort. Plasma circRNAs expressions were determined by microarray and validated by RT-PCR. Fibrosis level, manifested by serum TGF-β, was determined by ELISA. Pathways and related non-coding RNAs involving in the progression of AF regulated were predicted by in silico analysis. RESULTS PsAF patients showed a distinct circRNAs expression profile with 92 circRNAs significantly dysregulated (fold change ≥ 2, p < 0.05), compared with PAF patients. The validity of the expression patterns was subsequently validated by RT-PCR in another 60 AF patients (30 PsAF and PAF, respectively). In addition, all the 5 up and down regulated circRNAs were clustered in MAPK and TGF-beta signaling pathway by KEGG pathway analysis. Among the 5 circRNAs, hsa_circ_0004104 was consistently downregulated in PsAF group (0.6 ± 0.33 vs 1.46 ± 0.41, p < 0.001) and predicted to target several AF and/or cardiac fibrosis related miRNAs reported by previous studies. In addition, TGF-β1 level was significantly higher in the PsAF group (5560.23 ± 1833.64 vs 2236.66 ± 914.89, p < 0.001), and hsa_circ_0004104 showed a significant negative correlation with TGF-β1 level (r = - 0.797, p < 0.001). CONCLUSION CircRNAs dysregulation plays vital roles in AF persistency. hsa_circ_0004104 could be a potential regulator and biomarker in AF persistency by promoting cardiac fibrosis via targeting MAPK and TGF-beta pathways.
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Affiliation(s)
- Yuanfeng Gao
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Ye Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Yuan Fu
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Qianhui Wang
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Zheng Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Roumu Hu
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Xinchun Yang
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China
| | - Mulei Chen
- Heart Center and Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China.
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Xue R, Tan W, Wu Y, Dong B, Xie Z, Huang P, He J, Dong Y, Liu C. Role of Exosomal miRNAs in Heart Failure. Front Cardiovasc Med 2020; 7:592412. [PMID: 33392270 PMCID: PMC7773699 DOI: 10.3389/fcvm.2020.592412] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/26/2020] [Indexed: 12/16/2022] Open
Abstract
Heart failure is the terminal outcome of the majority of cardiovascular diseases, which lacks specific diagnostic biomarkers and therapeutic targets. It contributes to most of cardiovascular hospitalizations and death despite of the current therapy. Therefore, it is important to explore potential molecules improving the diagnosis and treatment of heart failure. MicroRNAs (miRNAs) are small non-coding RNAs that have been reported to be involved in regulating processes of heart failure. After the discovery of miRNAs in exosomes, the subcellular distribution analysis of miRNAs is raising researchers' attention. Growing evidence demonstrates that exosomal miRNAs may be promising diagnostic and therapeutic molecules for heart failure. This review summarizes the role of exosomal miRNAs in heart failure in the prospect of molecular and clinical researches.
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Affiliation(s)
- Ruicong Xue
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Weiping Tan
- Department of Respiratory, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuzhong Wu
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Dong
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zengshuo Xie
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Peisen Huang
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiangui He
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yugang Dong
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chen Liu
- Department of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.,National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Florio MC, Magenta A, Beji S, Lakatta EG, Capogrossi MC. Aging, MicroRNAs, and Heart Failure. Curr Probl Cardiol 2020; 45:100406. [PMID: 30704792 PMCID: PMC10544917 DOI: 10.1016/j.cpcardiol.2018.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022]
Abstract
Aging is a major risk factor for heart failure, one of the leading causes of death in Western society. The mechanisms that underlie the different forms of heart failure have been elucidated only in part and the role of noncoding RNAs is still poorly characterized. Specifically, microRNAs (miRNAs), a class of small noncoding RNAs that can modulate gene expression at the posttranscriptional level in all cells, including myocardial and vascular cells, have been shown to play a role in heart failure with reduced ejection fraction. In contrast, miRNAs role in heart failure with preserved ejection fraction, the predominant form of heart failure in the elderly, is still unknown. In this review, we will focus on age-dependent miRNAs in heart failure and on some other conditions that are prevalent in the elderly and are frequently associated with heart failure with preserved ejection fraction.
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Song K, Li L, Quan Q, Wei Y, Hu S. Inhibited histone deacetylase 3 ameliorates myocardial ischemia-reperfusion injury in a rat model by elevating microRNA-19a-3p and reducing cyclin-dependent kinase 2. IUBMB Life 2020; 72:2696-2709. [PMID: 33217223 DOI: 10.1002/iub.2402] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Over the years, the roles of microRNAs (miRNAs) and histone deacetylase 3 (HDAC3) in human diseases have been investigated. This study focused on the effect of miR-19a-3p and HDAC3 in myocardial ischemia-reperfusion (I/R) injury (MIRI) by targeting cyclin-dependent kinase 2 (CDK2). METHODS The I/R rat models were established by coronary artery ligation, which were then treated with RGFP966 (an inhibitor of HDAC3), miR-19a-3p agomir or antagomir, or silenced CDK2 to explore their roles in the cardiac function, pathological changes of myocardial tissues, myocardial infarction area, inflammatory factors and oxidative stress factors in rats with MIRI. The expression of miR-19a-3p, HDAC3, and CDK2 was determined by RT-qPCR and western blot assay, and the interaction among which was also verified by online prediction, luciferase activity assay and ChIP assay. RESULTS The results indicated that HDAC3 and CDK2 were upregulated while miR-19a-3p was downregulated in myocardial tissues of I/R rats. The inhibited HDAC3/CDK2 or elevated miR-19a-3p could promote cardiac function, attenuate pathological changes, inflammatory reaction, oxidative stress, myocardial infarction area and apoptosis of myocardial tissues. HDAC3 mediates miR-19a-3p and CDK2 is targeted by miR-19a-3p. CONCLUSION Inhibited HDAC3 ameliorates MIRI in a rat model by elevating miR-19a-3p and reducing CDK2, which may contribute to the treatment of MIRI.
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Affiliation(s)
- Kaiyou Song
- Cardiovascular Department, Linyi People's Hospital, Linyi, China
| | - Lianting Li
- Internal Medicine Department, Junan County Hospital of Traditional Chinese Medicine, Linyi, China
| | - Qingqing Quan
- Department of Respiratory Medicine, Linyi People's Hospital, Linyi, China
| | - Yanjin Wei
- Cardiovascular Department, Linyi People's Hospital, Linyi, China
| | - Shunpeng Hu
- Cardiovascular Department, Linyi People's Hospital, Linyi, China
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Fu Q, Mo TR, Hu XY, Fu Y, Li J. miR-19a mitigates hypoxia/reoxygenation-induced injury by depressing CCL20 and inactivating MAPK pathway in human embryonic cardiomyocytes. Biotechnol Lett 2020; 43:393-405. [PMID: 33165673 DOI: 10.1007/s10529-020-03045-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/31/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Myocardial infarction (MI) is a prevalent cardiovascular puzzle and a mainspring of disease-induced mortality. We performed this investigation to detect the role of putative important miRNAs or genes in MI. RESULTS CCL20 may be a potential therapeutic target, which was directly targeted and negatively regulated by miR-19a. CCL20 expression was significantly increased in MI tissue samples, but miR-19a was expressed at lower levels in MI. H/R treatment inhibited cell viability and induced an increase of apoptotic rate compared with Sham group. However, miR-19a mimic relieved the H/R-stimulated injury to cardiomyocytes. Protective effect of miR-19a against H/R in cardiomyocytes was reversed by CCL20 enhancement, and MAPK pathway was inactivated during this progression. CONCLUSIONS miR-19a eliminates the H/R-induced injury in cardiomyocytes through directly targeting CCL20 and attenuating the activity of MAPK signaling pathway. These observations highlighted the therapeutic roles of miR-19a and CCL20 for MI treatment.
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Affiliation(s)
- Qiang Fu
- Department of Chinese Formulae, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang, China
| | - Tao-Ran Mo
- Department of Nephrology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang, China
| | - Xiao-Yang Hu
- Department of Chinese Formulae, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang, China
| | - Yin Fu
- Department of Chinese Formulae, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang, China
| | - Ji Li
- Department of Chinese Formulae, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang, China.
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Gao J, Chen X, Shan C, Wang Y, Li P, Shao K. Autophagy in cardiovascular diseases: role of noncoding RNAs. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:101-118. [PMID: 33335796 PMCID: PMC7732971 DOI: 10.1016/j.omtn.2020.10.039] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiovascular diseases (CVDs) remain the world's leading cause of death. Cardiomyocyte autophagy helps maintain normal metabolism and functioning of the heart. Importantly, mounting evidence has revealed that autophagy plays a dual role in CVD pathology. Under physiological conditions, moderate autophagy maintains cell metabolic balance by degrading and recycling damaged organelles and proteins, and it promotes myocardial survival, but excessive or insufficient autophagy is equally deleterious and contributes to disease progression. Noncoding RNAs (ncRNAs) are a class of RNAs transcribed from the genome, but most ncRNAs do not code for functional proteins. In recent years, increasingly, various ncRNAs have been identified, and they play important regulatory roles in the physiological and pathological processes of organisms, as well as in autophagy. Thus, determining whether ncRNA-regulated autophagy plays a protective role in CVDs or promotes their progression can help us to develop ncRNAs as therapeutic targets in autophagy-related CVDs. In this review, we briefly summarize the regulatory roles of several important ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the autophagy of various CVDs to provide a theoretical basis for the etiology and pathogenesis of CVDs and develop novel therapies to treat CVDs.
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Affiliation(s)
- Jinning Gao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiatian Chen
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Chan Shan
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kai Shao
- Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 266035, China
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Nuclear miR-30b-5p suppresses TFEB-mediated lysosomal biogenesis and autophagy. Cell Death Differ 2020; 28:320-336. [PMID: 32764647 DOI: 10.1038/s41418-020-0602-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/12/2020] [Accepted: 07/23/2020] [Indexed: 01/07/2023] Open
Abstract
Lysosome is a crucial organelle in charge of degrading proteins and damaged organelles to maintain cellular homeostasis. Transcription factor EB (TFEB) is the master transcription factor regulating lysosomal biogenesis and autophagy. Under external stimuli such as starvation, dephosphorylated TFEB transports into the nucleus to specifically recognize and bind to the coordinated lysosomal expression and regulation (CLEAR) elements at the promotors of autophagy and lysosomal biogenesis-related genes. The function of TFEB in the nucleus is fine regulated but the molecular mechanism is not fully elucidated. In this study, we discovered that miR-30b-5p, a small RNA which is known to regulate a series of genes through posttranscriptional regulation in the cytoplasm, was translocated into the nucleus, bound to the CLEAR elements, suppressed the transcription of TFEB-dependent downstream genes, and further inhibited the lysosomal biogenesis and the autophagic flux; meanwhile, knocking out the endogenous miR-30b-5p by CRISPR/Cas9 technique significantly increased the TFEB-mediated transactivation, resulting in the increased expression of autophagy and lysosomal biogenesis-related genes. Overexpressing miR-30b-5p in mice livers showed a decrease in lysosomal biogenesis and autophagy. These in vitro and in vivo data indicate that miR-30b-5p may inhibit the TFEB-dependent transactivation by binding to the CLEAR elements in the nucleus to regulate the lysosomal biogenesis and autophagy. This novel mechanism of nuclear miRNA regulating gene transcription is conducive to further elucidating the roles of miRNAs in the lysosomal physiological functions and helps to understand the pathogenesis of abnormal autophagy-related diseases.
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Li F, Long TY, Bi SS, Sheikh SA, Zhang CL. circPAN3 exerts a profibrotic role via sponging miR-221 through FoxO3/ATG7-activated autophagy in a rat model of myocardial infarction. Life Sci 2020; 257:118015. [PMID: 32629000 DOI: 10.1016/j.lfs.2020.118015] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Cardiac fibrosis is the scarring process occurs commonly with CVDs impairing the function and structure of heart. Herein, we investigated the role of circPAN3 in the pathogenesis of cardiac fibrosis. METHODS A rat myocardial infarction (MI) model was constructed to evaluate the role of circPAN3. Expression of circPAN3 in MI was determined, and si-circPAN3 was applied to verify its profibrotic effects. With an in vitro model, cardiac fibroblasts were stimulated by transforming growth factor beta 1 (TGFβ1). Immunofluorescent staining was employed to assess the fibrosis-related markers, as well as autophagy activity. CCK-8 and transwell assays were performed to determine cell proliferation and migration. Luciferase reporter assay and RNA pull-down were subjected to verify the interaction of circPAN3/miR-221. The enrichment of FoxO3 on the promoter region of ATG7 was detected using CHIP assay. RESULTS Elevated circPAN3 was found in rat MI heart tissue, of which knockdown attenuated cardiac fibrosis after MI. In an in vitro model exposing with TGFβ1, increasing cell proliferation and migration were observed, whereas these effects were abolished by circPAN3 knockdown, as well as autophagy activity. miR-221 was identified as a target to be involved in circPAN3-mediated cardiac fibrosis after MI. miR-221 negatively regulated FoxO3, thus causing the inhibition of ATG7 transcription. The regulatory network of circPAN3/miR-221/FoxO3/ATG7 in cardiac fibrosis was further determined in vivo. CONCLUSION circPAN3 exhibited profibrotic effects during autophagy-mediated cardiac fibrosis via miR-221/FoxO3/ATG7 axis, which may serve as potential biomarkers for cardiac fibrosis therapeutics.
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Affiliation(s)
- Fei Li
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Tian-Yi Long
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Si-Si Bi
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Sayed Ali Sheikh
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Internal Medicine Department, Cardiology, College of Medicine, Jouf University, Saudi Arabia
| | - Cheng-Long Zhang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China.
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Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Am J Cancer Res 2020; 10:7993-8017. [PMID: 32724454 PMCID: PMC7381749 DOI: 10.7150/thno.47826] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/16/2020] [Indexed: 01/18/2023] Open
Abstract
Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.
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Hashem T, Kammala AK, Thaxton K, Griffin RM, Mullany K, Panettieri RA, Subramanian H, Das R. CD2 Regulates Pathogenesis of Asthma Induced by House Dust Mice Extract. Front Immunol 2020; 11:881. [PMID: 32477356 PMCID: PMC7235426 DOI: 10.3389/fimmu.2020.00881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/16/2020] [Indexed: 01/13/2023] Open
Abstract
Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated Cd2-/- mice. Interestingly, Il13 but not Il4 or Il5 gene expression in the lungs was dramatically decreased in HDME-exposed Cd2-/- mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed Cd2-/- mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed Cd2-/- mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.
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Affiliation(s)
- Tanwir Hashem
- Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Ananth K. Kammala
- College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Kanedra Thaxton
- Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Ryan M. Griffin
- Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Kellie Mullany
- Department of Chemical Engineering and Material Science, College of Engineering, Michigan State University, East Lansing, MI, United States
| | - Reynold A. Panettieri
- Rutgers Institute for Translational Medicine and Science, New Brunswick, NJ, United States
| | - Hariharan Subramanian
- College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Rupali Das
- College of Human Medicine, Michigan State University, East Lansing, MI, United States
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Diagnostic Role of Plasma MicroRNA-21 in Stable and Unstable Angina Patients and Association with Aging. Cardiol Res Pract 2020; 2020:9093151. [PMID: 32351734 PMCID: PMC7174930 DOI: 10.1155/2020/9093151] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 03/22/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
The present study explored the clinical value of plasma microRNA-21 as a novel biomarker for early prediction of stable and unstable angina patients and its relationship with aging. A total of 255 participants, 123 patients with chronic stable angina, 82 patients with unstable angina, and 50 healthy subjects, were included in our study. Stable coronary and unstable coronary patients were confirmed following AHA/ACC clinical protocols. Total RNA was extracted from plasma by using miRNA-based TRIzol reagent. Plasma miR-21 expression levels were determined by real-time polymerase chain reaction. To evaluate the diagnosis accuracy, the receiver operating characteristic (ROC) curves were used. Plasma microRNA-21 concentration levels were significantly elevated in stable and unstable angina patients as compared with control subjects (P < 0.001). The area under the ROC curves of circulating microRNA-21 was accurately distinguished in stable angina patients (AUC 0.921) and unstable angina patients (AUC 0.944) from healthy subjects. MicroRNA-21 expression gradually elevated with increasing aging in all the populations. Moreover, the current study also demonstrated that the expression of plasma miR-21 levels was significantly associated with different age groups within healthy subjects and stable and unstable angina patients (P < 0.001). This research finding suggested that plasma microRNA-21 may be considered as a suitable new biomarker for early detection of stable and unstable angina patients, and it has a strong correlation with aging.
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Ahkin Chin Tai JK, Freeman JL. Zebrafish as an integrative vertebrate model to identify miRNA mechanisms regulating toxicity. Toxicol Rep 2020; 7:559-570. [PMID: 32373477 PMCID: PMC7195498 DOI: 10.1016/j.toxrep.2020.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Zebrafish are an established vertebrate model for toxicity studies. Zebrafish have a fully sequenced genome and the capability to create genetic models. Zebrafish have over 80 % homology for genes related to human disease. Functions of miRNAs in the zebrafish genome are being characterized. Zebrafish are ideal for mechanistic studies on how miRNAs regulate toxicity. Zebrafish (Danio rerio) are an integrative vertebrate model ideal for toxicity studies. The zebrafish genome is sequenced with detailed characterization of all life stages. With their genetic similarity to humans, zebrafish models are established to study biological processes including development and disease mechanisms for translation to human health. The zebrafish genome, similar to other eukaryotic organisms, contains microRNAs (miRNAs) which function along with other epigenetic mechanisms to regulate gene expression. Studies have now established that exposure to toxins and xenobiotics can change miRNA expression profiles resulting in various physiological and behavioral alterations. In this review, we cover the intersection of miRNA alterations from toxin or xenobiotic exposure with a focus on studies using the zebrafish model system to identify miRNA mechanisms regulating toxicity. Studies to date have addressed exposures to toxins, particulate matter and nanoparticles, various environmental contaminants including pesticides, ethanol, and pharmaceuticals. Current limitations of the completed studies and future directions for this research area are discussed.
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Affiliation(s)
| | - Jennifer L Freeman
- School of Health Sciences, Purdue University, West Lafayette, IN 47907 USA
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Yu FB, Sheng J, Yu JM, Liu JH, Qin XX, Mou B. MiR-19a-3p regulates the Forkhead box F2-mediated Wnt/β-catenin signaling pathway and affects the biological functions of colorectal cancer cells. World J Gastroenterol 2020; 26:627-644. [PMID: 32103872 PMCID: PMC7029353 DOI: 10.3748/wjg.v26.i6.627] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/03/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies worldwide.
AIM To explore the expression of microRNA miR-19a-3p and Forkhead box F2 (FOXF2) in patients with CRC and the relevant mechanisms.
METHODS Sixty-two CRC patients admitted to the hospital were enrolled into the study group, and sixty healthy people from the same period were assigned to the control group. Elbow venous blood was sampled from the patients and healthy individuals, and blood serum was saved for later analysis. MiR-19a-3p mimics, miR-19a-3p inhibitor, miR-negative control, small interfering-FOXF2, and short hairpin-FOXF2 were transfected into HT29 and HCT116 cells. Then quantitative polymerase chain reaction was performed to quantify the expression of miR-19a-3p and FOXF2 in HT29 and HCT116 cells, and western blot (WB) analysis was conducted to evaluate the levels of FOXF2, glycogen synthase kinase 3 beta (GSK-3β), phosphorylated GSK-3β (p-GSK-3β), β-catenin, p-β-catenin, α-catenin, N-cadherin, E-cadherin, and vimentin. The MTT, Transwell, and wound healing assays were applied to analyze cell proliferation, invasion, and migration, respectively, and the dual luciferase reporter assay was used to determine the correlation of miR-19a-3p with FOXF2.
RESULTS The patients showed high serum levels of miR-19a-3p and low levels of FOXF2, and the area under the curves of miR-19a-3p and FOXF2 were larger than 0.8. MiR-19a-3p and FOXF2 were related to sex, tumor size, age, tumor-node-metastasis staging, lymph node metastasis, and differentiation of CRC patients. Silencing of miR-19a-3p and overexpression of FOXF2 suppressed the epithelial-mesenchymal transition, invasion, migration, and proliferation of cells. WB analysis revealed that silencing of miR-19a-3p and FOXF2 overexpression significantly suppressed the expression of p-GSK-3β, β-catenin, N-cadherin, and vimentin; and increased the levels of GSK-3β, p-β-catenin, α-catenin, and E-cadherin. The dual luciferase reporter assay confirmed that there was a targeted correlation of miR-19a-3p with FOXF2. In addition, a rescue experiment revealed that there were no differences in cell proliferation, invasion, and migration in HT29 and HCT116 cells co-transfected with miR-19a-3p-mimics+sh-FOXF2 and miR-19a-3p-inhibitor+si-FOXF2 compared to the miR-negative control group.
CONCLUSION Inhibiting miR-19a-3p expression can upregulate the FOXF2-mediated Wnt/β-catenin signaling pathway, thereby affecting the epithelial-mesenchymal transition, proliferation, invasion, and migration of cells. Thus, miR-19a-3p is likely to be a therapeutic target in CRC.
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Affiliation(s)
- Fu-Bing Yu
- Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming 650021, Yunnan Province, China
| | - Juan Sheng
- Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming 650021, Yunnan Province, China
| | - Jia-Man Yu
- Department of Clinical Laboratory, The Geriatrics Hospital of Yunnan Province, Kunming 650011, Yunnan Province, China
| | - Jing-Hua Liu
- Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming 650021, Yunnan Province, China
| | - Xiang-Xin Qin
- Department of Clinical Nutrition, The Fourth Affiliated Hospital of Kunming Medical University, Kunming 650021, Yunnan Province, China
| | - Bo Mou
- Department of Clinical Nutrition, The Fourth Affiliated Hospital of Kunming Medical University, Kunming 650021, Yunnan Province, China
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Tao J, Wang J, Li C, Wang W, Yu H, Liu J, Kong X, Chen Y. MiR-216a accelerates proliferation and fibrogenesis via targeting PTEN and SMAD7 in human cardiac fibroblasts. Cardiovasc Diagn Ther 2019; 9:535-544. [PMID: 32038943 DOI: 10.21037/cdt.2019.11.06] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Heart failure (HF) is a progressive disease with relatively poor prognosis and lacks effective therapy, and the discovery of dysregulated microRNAs (miRNAs) and their role in cardiac fibroblasts have provided a new avenue for elucidating the mechanism involved in HF. Methods Two datasets of GSE53080 and GSE57338 were used to screen the miRNAs profiling and analysis the differentially expressed genes (DEGs) in HF. QRT-PCR was used to detect miR-216a between HF and healthy controls (HC). Cell counting kit-8 (CCK-8) assay and clonogenic assay were used to analyze the effect of proliferation and fibrogenesis. Then dual-luciferase activity assay and western blotting were used to confirm the key mechanism. Results In this study, the results showed that miR-216a was significantly up-regulated in HF and over-expression of miR-216a promoted proliferation and enhanced the fibrogenesis in the human cardiac fibroblasts (HCF) cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were both validated as the direct target genes of miR-216a, which were confirmed by the dual-luciferase reporter assay. MiR-216a decreased the expression of PTEN and SMAD7 leading to the activation of Akt/mTOR and TGF-βRI/Smad2 in the HCF cells, which might act as a promoter of cardiac fibrosis. Conclusions Our study might provide a promising approach for the treatment of HF in the future.
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Affiliation(s)
- Jinsong Tao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,Department of Cardiology, The Affiliated Hospital of Southeast University Medical College, Jiangyin 214400, China
| | - Jingyi Wang
- Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Chunyu Li
- Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Weiwei Wang
- Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hao Yu
- Emergency Center, Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux 845350, China
| | - Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiangqing Kong
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yan Chen
- Emergency Center, Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux 845350, China.,Emergency Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Yan Y, Chen D, Han X, Liu M, Hu W. MiRNA-19a and miRNA-19b regulate proliferation of antler cells by targeting TGFBR2. MAMMAL RES 2019. [DOI: 10.1007/s13364-019-00469-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Ye YL, Yin J, Hu T, Zhang LP, Wu LY, Pang Z. Increased circulating circular RNA_103516 is a novel biomarker for inflammatory bowel disease in adult patients. World J Gastroenterol 2019; 25:6273-6288. [PMID: 31749597 PMCID: PMC6848015 DOI: 10.3748/wjg.v25.i41.6273] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/23/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Increasing evidence demonstrates that by acting as microRNA sponges modulating gene expression at the transcriptional or post-transcriptional level, circular RNAs (circRNAs) participate in the pathogenesis of a variety of diseases and are considered ideal biomarkers of human disease.
AIM To examine the expression of circRNA_103516 in inflammatory bowel disease (IBD) and its associations with clinical phenotypes and inflammatory cytokines.
METHODS Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IBD, healthy controls (HCs), and patient controls (PCs). Expression of circRNA_103516 and hsa-miR-19b-1-5p was assessed by quantitative reverse transcription-polymerase chain reaction. Crohn's disease activity index (CDAI), Mayo score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were measured. To assess the inflammatory cytokines tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10), blood samples were analysed by flow cytometry.
RESULTS Ninety Crohn’s disease (CD) and 90 ulcerative colitis (UC) patients, 80 HCs, and 35 PCs were included in the study. CircRNA_103516 was upregulated in CD and UC patients compared with HCs and PCs (P < 0.05). The area under the curve of circRNA_103516 for diagnosing CD and UC was 0.790 and 0.687, respectively. In addition, circRNA_103516 levels were increased in active CD and UC compared with remittent groups (P = 0.027, P = 0.045). Furthermore, in CD, circRNA_103516 correlated positively with CDAI (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNFα (P < 0.001), and IFN-γ (P < 0.001) and negatively correlated with IL-10 (P = 0.006). In UC patients, circRNA_103516 correlated with Mayo score (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNFα (P < 0.001), IFN-γ (P =0.011), and IL-10 (P = 0.002). Additionally, circRNA_103516 correlated positively with stricturing (P = 0.018) and penetrating (P = 0.031) behaviour. Moreover, hsa-miR-19b-1-5p correlated negatively with circRNA_103516 in CD.
CONCLUSION CircRNA_103516 levels in PBMCs can be considered an ideal candidate biomarker for diagnosing IBD. Dysregulation of circRNA_103516 may participate in the molecular mechanism of IBD through hsa-miR-19b-1-5p sponging.
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Affiliation(s)
- Yu-Lan Ye
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Juan Yin
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Tong Hu
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Li-Ping Zhang
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Long-Yun Wu
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
| | - Zhi Pang
- Department of Gastroenterology, the North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
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Yang Y, Qin X, Meng X, Zhu X, Zhang X, Li Y, Zhang Z. MicroRNA Expression Profile in Peripheral Blood Lymphocytes of Sheep Vaccinated with Nigeria 75/1 Peste Des Petits Ruminants Virus. Viruses 2019; 11:v11111025. [PMID: 31694166 PMCID: PMC6893480 DOI: 10.3390/v11111025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 10/25/2019] [Accepted: 10/31/2019] [Indexed: 12/15/2022] Open
Abstract
Peste des petits ruminants (PPR) is one of the highly contagious transboundary viral diseases of small ruminants. Host microRNA (miRNA) expression patterns may change in response to virus infection, and it mainly works as a post-transcriptional moderator in gene expression and affects viral pathogenesis and replication. In this study, the change of miRNA expression profile in peripheral blood lymphocyte (PBMC) from sheep inoculated with PPR vaccine virus in vivo as well as primary sheep testicular (ST) cells inoculated with PPR vaccine virus in vitro were determined via deep sequencing technology. In PBMC cells, 373 and 115 differentially expressed miRNAs (DEmiRNAs) were identified 3 days and 5 days post inoculated (dpi), respectively. While, 575 DEmiRNAs were identified when comparing miRNA profiles on 5 dpi with 3 dpi. Some of the DEmiRNAs were found to change significantly via time-course during PPR vaccine virus inoculated. Similarly, in ST cells, 136 DEmiRNAs were identified at 3 dpi in comparison with mock-inoculation. A total of 12 DEmiRNAs were validated by real-time quantitative PCR (RT-qPCR). The oar-miR-150, oar-miR-370-3p and oar-miR-411b-3p were found common differentially expressed in both PPR vaccine virus-inoculated PBMC cells and ST cells. Targets prediction and functional analysis of the DEmiRNAs uncovered mainly gathering in antigen processing and presentation pathways, protein processing in endoplasmic reticulum pathways and cell adhesion molecules pathways. Our study supplies information about the DEmiRNAs in PPR vaccine virus-inoculated PBMC cells and ST cells, and provides clues for further understanding the function of miRNAs in PPR vaccine virus replication.
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Affiliation(s)
| | | | | | | | | | - Yanmin Li
- Correspondence: ; Tel.: +86-0931-8374622
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Zhou T, Lin D, Chen Y, Peng S, Jing X, Lei M, Tao E, Liang Y. α-synuclein accumulation in SH-SY5Y cell impairs autophagy in microglia by exosomes overloading miR-19a-3p. Epigenomics 2019; 11:1661-1677. [PMID: 31646884 DOI: 10.2217/epi-2019-0222] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aims: To reveal whether miRNAs in exosomes from α-synuclein transgenic SH-SY5Y cells are able to regulate autophagy in recipient microglia. Materials & methods: Microarray analysis and experimental verification were adopted to assess the significance of autophagy-associated miRNAs in exosomes from neuronal model of α-synucleinopathies. Results: We found that miR-19a-3p increased remarkably in the exosomes from α-synuclein gene transgenic SH-SY5Y cells. Further study inferred that α-synuclein gene transgenic SH-SY5Y cell-derived exosomes and miR-19a-3p mimic consistently inhibited the expression of phosphatase and tensin homolog and increased the phosphorylation of AKT and mTOR, both of which ultimately lead to the dysfunction of autophagy in recipient microglia. Conclusion: The data suggested that enhanced expression of miR-19a-3p in exosomes suppress autophagy in recipient microglia by targeting the phosphatase and tensin homolog/AKT/mTOR signaling pathway.
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Affiliation(s)
- Tianen Zhou
- Department of Emergency, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Danyu Lin
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, PR China
| | - Ying Chen
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Sudan Peng
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Xiuna Jing
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Ming Lei
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Enxiang Tao
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Yanran Liang
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China
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Zhao Y, Wang Z, Zhang W, Zhang L. MicroRNAs play an essential role in autophagy regulation in various disease phenotypes. Biofactors 2019; 45:844-856. [PMID: 31418958 PMCID: PMC6916288 DOI: 10.1002/biof.1555] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 07/31/2019] [Indexed: 12/16/2022]
Abstract
Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.
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Affiliation(s)
- Yunyi Zhao
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
| | - Ze Wang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
| | - Wenhui Zhang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
- Ministry of Education, Engineering Research Center for Bioreactor and Pharmaceutical DevelopmentJilin Agricultural UniversityChangchunChina
| | - Linbo Zhang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
- Ministry of Education, Engineering Research Center for Bioreactor and Pharmaceutical DevelopmentJilin Agricultural UniversityChangchunChina
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