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Aghaei-Zarch SM, Mahmoudieh L, Miryounesi M, Aghazadeh M, Reihani-Ardabili M, Zamani M, Motallebi M, Movafagh A. Investigation of TNF and related lncRNAs in diabetic nephropathy. Cytokine 2025; 188:156892. [PMID: 39970816 DOI: 10.1016/j.cyto.2025.156892] [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: 09/23/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a significant driver of end-stage renal disease, requiring kidney replacement therapies such as transplantation and dialysis. Given the critical importance of understanding the onset and progression of DN, we sought to explore the expression levels of tumor necrosis factor (TNF) and related long noncoding RNAs (lncRNAs) in diabetic patients with and without DN, as well as in pre-diabetic individuals, compared to healthy controls. We further explored the involvement of TNF and TNF-related lncRNAs in high glucose (HG)-induced apoptosis of human embryonic kidney (HEK)-293 cells. MATERIAL AND METHOD In the current cross-sectional investigation, we compare the expression levels of lncRNA myocardial infarction-associated transcript (MIAT), lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), and TNF in 50 healthy individuals, 50 people with prediabetes, 50 patients with type 2 diabetes mellitus (T2DM), and 50 patients with T2DM- DN. We cultured HEK293 cells in a HG condition (100 mM glucose) to establish a cellular model of DN, while HEK293 cells cultured in a normal-glucose environment (5 mM glucose) served as controls. We further assess apoptosis in HEK293 cells via flow cytometry analysis. Moreover, we evaluated the expression levels of lncRNA MIAT, lncRNA NEAT1, and TNF in HG and normal-glucose (NG) groups to investigate their potential involvement in HEK293 cell apoptosis and the pathogenesis of DN. RESULT Our findings reveal a significant upregulation of lncRNA MIAT, lncRNA NEAT1, and TNF in T2DM and T2DM-associated DN groups compared to prediabetic individuals and healthy controls (p < 0.05). Furthermore, HG conditions significantly increased the apoptotic rate of HEK293 cells. Additionally, the expression levels of TNF, lncRNA MIAT, and lncRNA NEAT1 were increased in HEK-293 cells cultured in a HG. CONCLUSION In conclusion, our findings indicate a significant role for the TNF gene and associated lncRNAs, such as lncRNA MIAT and lncRNA NEAT1, in podocyte apoptosis and the development of DN.
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Affiliation(s)
- Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Mahmoudieh
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Aghazadeh
- Department of Cell & Molecular Biology, Faculty of Life Sciences & Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mehran Reihani-Ardabili
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Zamani
- Shahid Akbarabadi Clinical Research Development Unit, Iran University of medical Science, Tehran, Iran
| | - Marzieh Motallebi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Movafagh
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Tian X, Zhou M, Zhang J, Huang X, Jiang D, Liu J, Zhang Q, Chen D, Hu Q. Mechanism of LncRNA-MiRNA in Renal Intrinsic Cells of Diabetic Kidney Disease and Potential Therapeutic Direction. DNA Cell Biol 2025. [PMID: 40117185 DOI: 10.1089/dna.2025.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2025] Open
Abstract
The occurrence of diabetic kidney disease (DKD), a critical microvascular issue in diabetes, is progressively on the rise. In recent years, long noncoding RNAs (lncRNAs) have garnered considerable attention as a novel and critical layer of biological regulation. Our knowledge regarding the roles and underlying mechanisms of lncRNAs in various diseases, including DKD, continues to evolve. Similarly, microRNAs (miRNAs), which are small noncoding RNAs, have been recognized as crucial contributors to cellular processes and disease pathogenesis. Emerging studies have highlighted the complex interactions between lncRNAs and miRNAs, particularly in the context of DKD, underscoring their importance in complex human diseases. Renal intrinsic cell damage is an important cause of inducing DKD. Persistent high glucose stimulation leads to remodeling of renal intrinsic cells and a cascade of pathological changes. This article aims to review recent literature on the lncRNAs-mediated regulation of miRNAs affecting renal intrinsic cells in DKD and to propose novel molecular-level therapeutic strategies for DKD. Through in-depth investigation of this dynamic molecular interaction, we can gain a profound understanding of the potential mechanisms underlying diabetic nephropathy, potentially identifying new targets for therapeutic intervention and paving the way for personalized and effective treatments.
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Affiliation(s)
- Xiyue Tian
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Min Zhou
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Jingbo Zhang
- School of Public Health, Southwest Medical University, Sichuan, China
| | - Xinchun Huang
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Dongyang Jiang
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Jian Liu
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Qiong Zhang
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Dingguo Chen
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
| | - Qiongdan Hu
- Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Sichuan, China
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Zhuang Y, Zhu L, Fu C, Ni H. miR-504-3p-HNF1B signaling axis aggravates podocyte injury in diabetic kidney disease. J Mol Histol 2025; 56:89. [PMID: 39954129 DOI: 10.1007/s10735-025-10369-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 02/04/2025] [Indexed: 02/17/2025]
Abstract
Recently, microRNAs (miRNAs) have been found to mediate the development of diabetic kidney disease (DKD) by regulating podocyte injury. The aim of this study was to investigate the influence of miR-504-3p on high glucose (HG)-treated mouse renal podocytes (MPC5) and its potential regulatory mechanisms. First, a DKD cell model was established. Next, RT-qPCR was performed to measure miR-504-3p and HNF1 Homeobox B (HNF1B) expression levels. Additionally, the proliferation and apoptosis of MPC5 cells were assessed using CCK-8 assay and Flow cytometry, respectively. The protein expression levels of cell fibrotic markers, podocyte injury marker, epithelial-mesenchymal transition (EMT) markers and HNF1B were measured by Western Blotting. ROS, MDA, SOD and GSH kits were used to assess oxidative stress levels. Furthermore, the interplay between miR-504-3p and HNF1B was confirmed by luciferase reporter experiments. The miR-504-3p expression was significantly upregulated in GEO database (GSE161884) and in HG-induced MPC5 cells. The results revealed that HG treatment decreased MPC5 cell proliferation, promoted cell apoptosis and fibrosis, and ultimately led to podocyte injury. However, miR-504-3p knockdown could reverse these phenotypes and reduce podocyte injury. Moreover, online database screening combined with dual luciferase reporter assay confirmed HNF1B as a specific target of miR-504-3p. Finally, overexpression of HNF1B mitigated the proliferation inhibition and apoptosis promotion induced by oxidative stress and inhibited EMT-mediated cell fibrosis, thereby counteracting the effects of miR-504-3p on podocyte injury under HG treatment. In summary, our data indicate that miR-504-3p regulates HG-induced podocyte injury by sponging HNF1B, providing a new direction for the treatment of DKD.
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Affiliation(s)
- Yibo Zhuang
- Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, 213000, People's Republic of China
| | - Lingtao Zhu
- Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, 213000, People's Republic of China
| | - Chenlu Fu
- Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, 213000, People's Republic of China
| | - Huiping Ni
- Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, 213000, People's Republic of China.
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Kotey SK, Tan X, Kinser AL, Liu L, Cheng Y. Host Long Noncoding RNAs as Key Players in Mycobacteria-Host Interactions. Microorganisms 2024; 12:2656. [PMID: 39770858 PMCID: PMC11728548 DOI: 10.3390/microorganisms12122656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Mycobacterial infections, caused by various species within the Mycobacterium genus, remain one of the main challenges to global health across the world. Understanding the complex interplay between the host and mycobacterial pathogens is essential for developing effective diagnostic and therapeutic strategies. Host long noncoding RNAs (lncRNAs) have emerged as key regulators in cellular response to bacterial infections within host cells. This review provides an overview of the intricate relationship between mycobacterial infections and host lncRNAs in the context of Mycobacterium tuberculosis and non-tuberculous mycobacterium (NTM) infections. Accumulation of evidence indicates that host lncRNAs play a critical role in regulating cellular response to mycobacterial infection within host cells, such as macrophages, the primary host cells for mycobacterial intracellular survival. The expression of specific host lncRNAs has been implicated in the pathogenesis of mycobacterial infections, providing potential targets for the development of novel host-directed therapies and biomarkers for TB diagnosis. In summary, this review aims to highlight the current state of knowledge regarding the involvement of host lncRNAs in mycobacterial infections. It also emphasizes their potential application as novel diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Stephen K. Kotey
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Xuejuan Tan
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Audrey L. Kinser
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Lin Liu
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Yong Cheng
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
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Zhang K, Wu D, Huang C. Crosstalk between non-coding RNA and apoptotic signaling in diabetic nephropathy. Biochem Pharmacol 2024; 230:116621. [PMID: 39542182 DOI: 10.1016/j.bcp.2024.116621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/18/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024]
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.
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Affiliation(s)
- Kejia Zhang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Di Wu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
| | - Chunjie Huang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
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Ren Y, Zheng J, Cao Y, Zhu Y, Ling Z, Zhang Z, Huang M. Diagnostic significance of LncRNA MIAT in periodontitis and the molecular mechanisms influencing periodontal ligament fibroblasts via the miR-204-5p/DKK1 axis. Arch Oral Biol 2024; 168:106066. [PMID: 39190957 DOI: 10.1016/j.archoralbio.2024.106066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024]
Abstract
OBJECTIVE This study investigated the clinical importance of long noncoding RNA myocardial infarction-associated transcript (MIAT) in periodontitis and its impact on the functional regulation of human periodontal ligament fibroblasts (hPDLFs). METHODS Ninety-eight periodontitis patients and 74 healthy controls were enrolled. In vitro cellular models were created using Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) to stimulate hPDLFs. Real-time quantitative polymerase chain reaction was used to measure mRNA levels of MIAT and osteogenic factors. Inflammation factor concentration was assessed using an enzyme-linked immunosorbent assay. Cell viability and apoptosis were examined by cell counting kit -8 and flow cytometry assay. The targeting relationship was verified by the dual-luciferase reporter and RNA Immunoprecipitation assay. RESULTS Highly expressed MIAT and Dicckopf-1 (DDK1), and lowly expressed miR-204-5p were found in the gingival crevicular fluid of periodontitis patients and Pg-LPS induced hPDLFs. MIAT has a sensitivity of 76.53 % and a specificity of 86.49 % for identifying patients with periodontitis among healthy individuals. MIAT acts as a sponge for miR-204-5p and upregulates DDK1 mRNA expression. Silencing of MIAT diminished the promotion of apoptosis and inflammation in hPDLFs by Pg-LPS and enhanced osteogenic differentiation. However, a miR-204-5p inhibitor significantly reversed the effect of silenced MIAT. CONCLUSIONS MIAT may act as a promising biomarker for periodontitis. It modulates apoptosis, inflammation, and osteogenic differentiation of PDLFs by focusing on the miR-204-5p/DKK1 axis, indicating its potential as a new therapeutic target for treating periodontitis.
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Affiliation(s)
- Yu Ren
- Department of stomatology, Dental Well Institute of Temporomandibular Joint Research, Chengdu, China; LESHAN Vocational and Technical College, Leshan, China
| | - Jiwen Zheng
- LESHAN Vocational and Technical College, Leshan, China; Department of stomatology, Leshan Weiduo Dental, Leshan, China
| | - Yang Cao
- Department of stomatology, Leshan Jiajiang Weiduo Dental, Leshan, China
| | - Yu Zhu
- Department of stomatology, Leshan Weiduo Dental, Leshan, China
| | - Zhuo Ling
- Department of stomatology, Dental Well Institute of Temporomandibular Joint Research, Chengdu, China
| | - Zhiqiang Zhang
- Department of stomatology, Dental Well Institute of Temporomandibular Joint Research, Chengdu, China
| | - Mingke Huang
- LESHAN Vocational and Technical College, Leshan, China; Department of stomatology, Leshan Weiduo Dental, Leshan, China.
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Sun L, Yang K, Wang L, Wu S, Wen D, Wang J. LncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by promoting autophagy through miR-30a-5p/SOCS1 axi. Sci Rep 2024; 14:22608. [PMID: 39349964 PMCID: PMC11442610 DOI: 10.1038/s41598-024-73607-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Accumulated data implicate that long noncoding RNA (lncRNA) plays a pivotal role in rheumatoid arthritis (RA), potentially serving as a competitive endogenous RNA (ceRNA) for microRNAs (miRNAs). The lncRNA myocardial infarction-associated transcript (MIAT) has been demonstrated to regulate inflammation. However, the role of MIAT in the inflammation of RA remains inadequately explored. This study aims to elucidate MIAT's role in the inflammation of lipopolysaccharide (LPS)-induced macrophages and to uncover the underlying molecular mechanisms. We observed heightened MIAT expression in LPS-induced J774A.1 cells and collagen-induced arthritis mouse models, in contrast to the expression pattern of miR-30a-5p. Silencing MIAT resulted in increased expression of the inflammatory cytokines IL-1β and TNF-α. Simultaneously, MIAT interference significantly impeded macrophage autophagy, evidenced by decreased expression of autophagy-related markers LC3-II and Beclin-1, alongside increased levels of p62 in LPS-induced J774A.1 cells. Notably, MIAT functioned as a ceRNA, sponging miR-30a-5p and exerting a negative regulatory influence on its expression. SOCS1 emerged as a target of miR-30a-5p, modulated by MIAT. Mechanistically, inhibiting miR-30a-5p reversed the impact of MIAT deficiency in promoting LPS-induced inflammation, while SOCS1 knockdown countered the cytokine inhibitory effect induced by silencing miR-30a-5p. In summary, this study indicates that lncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by stimulating autophagy through the miR-30a-5p/SOCS1 axis. This suggests that MIAT holds promise as a potential therapeutic target for RA inflammation.
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Affiliation(s)
- Linqian Sun
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Kun Yang
- Medical Research Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liqin Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Si Wu
- Department of Infectious Disease, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Dawei Wen
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jibo Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Sun T, Guo Y, Su Y, Shan S, Qian W, Zhang F, Li M, Zhang Z. Molecular mechanisms of diabetic nephropathy: A narrative review. Cell Biol Int 2024; 48:1240-1253. [PMID: 38946126 DOI: 10.1002/cbin.12212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/01/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024]
Abstract
Diabetic nephropathy (DN) is the predominant secondary nephropathy resulting in global end-stage renal disease. It is attracting significant attention in both domestic and international research due to its widespread occurrence, fast advancement, and limited choices for prevention and treatment. The pathophysiology of this condition is intricate and involves multiple molecular and cellular pathways at various levels. This article provides a concise overview of the molecular processes involved in the development of DN. It discusses various factors, such as signaling pathways, cytokines, inflammatory responses, oxidative stress, cellular damage, autophagy, and epigenetics. The aim is to offer clinicians a valuable reference for DN's diagnosis, treatment, and intervention.
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Affiliation(s)
- Tian Sun
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yina Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yanting Su
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Shigang Shan
- School of Public Health and Nursing, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wenbin Qian
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Feixue Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Mengxi Li
- School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology, Xianning, China
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
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Hou Q, Yi B. The role of long non-coding RNAs in the development of diabetic kidney disease and the involved clinical application. Diabetes Metab Res Rev 2024; 40:e3809. [PMID: 38708843 DOI: 10.1002/dmrr.3809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 03/03/2024] [Accepted: 04/03/2024] [Indexed: 05/07/2024]
Abstract
Diabetic kidney disease (DKD), one of the common microvascular complications of diabetes, is increasing in prevalence worldwide and can lead to End-stage renal disease. However, there are still gaps in our understanding of the pathophysiology of DKD, and both current clinical diagnostic methods and treatment strategies have drawbacks. According to recent research, long non-coding RNAs (lncRNAs) are intimately linked to the developmental process of DKD and could be viable targets for clinical diagnostic decisions and therapeutic interventions. Here, we review recent insights gained into lncRNAs in pathological changes of DKD such as mesangial expansion, podocyte injury, renal tubular injury, and interstitial fibrosis. We also discuss the clinical applications of DKD-associated lncRNAs as diagnostic biomarkers and therapeutic targets, as well as their limitations and challenges, to provide new methods for the prevention, diagnosis, and treatment of DKD.
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Affiliation(s)
- Qizhuo Hou
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Bin Yi
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Xia J, Huang Y, Ma M, Liu F, Cao B. Downregulating lncRNA MIAT attenuates apoptosis of podocytes exposed to high glucose. Acta Diabetol 2024; 61:451-460. [PMID: 38072843 DOI: 10.1007/s00592-023-02213-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 11/08/2023] [Indexed: 03/27/2024]
Abstract
AIMS Diabetic nephropathy (DN), a destructive complication of diabetes mellitus (DM), is one of the leading causes of end-stage renal disease (ESRD). This study aimed to investigate the role of long non-coding RNA (lncRNA) MIAT in high-glucose (HG)-induced podocyte injury associated with DN. METHODS Three human kidney podocyte (HKP) cultures were treated with HG to mimic DN. Expression of lncRNA MIAT, podocyte-specific and injury-related proteins, and apoptosis were assessed before and after MIAT knockdown using MIAT shRNAs. RESULTS MIAT expression was upregulated in HKPs in response to glucose stress. HG treatment resulted in a significant increase in the apoptotic rate, Bax level, and levels of injury-related proteins desmin, fibroblast-specific protein 1 (FSP-1), and smooth muscle α-actin (α-SMA), and a significant reduction in Bcl-2 levels and the levels of podocyte-specific proteins synaptopodin and podocin. Transfection of HKPs with shRNAs significantly reduced MIAT levels (p < 0.05) and attenuated apoptosis in HG-medium. Correspondingly, the levels of synaptopodin and podocin were upregulated, and desmin, FSP-1, and α-SMA were reduced (p < 0.05). Western blot analysis also showed that anti-apoptotic active caspase-3 and Bax and proapoptotic Bcl-2 were elevated and decreased, respectively, after MIAT knockdown, suggesting that apoptosis pathways are deactivated after MIAT downregulation. CONCLUSIONS High glucose upregulates MIAT level in HKPs and induces cellular injury. Knockdown of MIAT alleviates the injury likely via deactivating apoptosis pathways.
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Affiliation(s)
- Jiayi Xia
- Department of Endocrinology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Yan Huang
- Department of Medical Insurance, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Min Ma
- Department of Gynecology, Graduate School of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Fang Liu
- Department of Coloproctology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.
| | - Bo Cao
- Department of Coloproctology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.
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He YX, Wang T, Li WX, Chen YX. Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p. World J Diabetes 2024; 15:260-274. [PMID: 38464366 PMCID: PMC10921158 DOI: 10.4239/wjd.v15.i2.260] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/13/2023] [Accepted: 01/15/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy (DN). The regulatory relationship between long noncoding RNAs (lncRNAs) and podocyte apoptosis has recently become another research hot spot in the DN field. AIM To investigate whether lncRNA protein-disulfide isomerase-associated 3 (Pdia3) could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism. METHODS Using normal glucose or high glucose (HG)-cultured podocytes, the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress (ERS) were explored. LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction. Relative cell viability was detected through the cell counting kit-8 colorimetric assay. The podocyte apoptosis rate in each group was measured through flow cytometry. The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay. Finally, western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p. RESULTS The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes. Next, lncRNA Pdia3 was involved in HG-induced podocyte apoptosis. Furthermore, the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p. LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes. CONCLUSION Taken together, this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p, which might provide a potential therapeutic target for DN.
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Affiliation(s)
- Yin-Xi He
- Department of Orthopaedic Trauma, The Third Hospital of Shijiazhuang, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Wen-Xian Li
- Department of Endocrinology, The First Hospital of Zhangjiakou, Zhangjiakou 075000, Hebei Province, China
| | - Yan-Xia Chen
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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12
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Wang L, Wang H, Luo Y, Wu W, Gui Y, Zhao J, Xiong R, Li X, Yuan D, Yuan C. Role of LncRNA MIAT in Diabetic Complications. Curr Med Chem 2024; 31:1716-1725. [PMID: 37711129 DOI: 10.2174/0929867331666230914091944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/21/2023] [Accepted: 07/25/2023] [Indexed: 09/16/2023]
Abstract
Long non-coding RNA (LncRNA) refers to a large class of RNAs with over 200 nucleotides that do not have the function of encoding proteins. In recent years, more and more literature has revealed that lncRNA is involved in manipulating genes related to human health and disease, playing outstanding biological functions, which has attracted widespread attention from researchers. The newly discovered long-stranded non-coding RNA myocardial infarction-related transcript (LncRNA MIAT) is abnormally expressed in a variety of diseases, especially in diabetic complications, and has been proven to have a wide range of effects. This review article aimed to summarize the importance of LncRNA MIAT in diabetic complications, such as diabetic cardiomyopathy, diabetic nephropathy, and diabetic retinopathy, and highlight the latest findings on the pathway and mechanism of its participation in regulating diabetic complications, which may aid in finding new intervention targets for the treatment of diabetic complications. LncRNA MIAT competitively binds microRNAs to regulate gene expression as competitive endogenous RNAs. Thus, this review article has reviewed the biological function and pathogenesis of LncRNA MIAT in diabetic complications and described its role in diabetic complications. This paper will help in finding new therapeutic targets and intervention strategies for diabetes complications.
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Affiliation(s)
- Lijun Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Hailin Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Yiyang Luo
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Wei Wu
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Yibei Gui
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Jiale Zhao
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Ruisi Xiong
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Xueqin Li
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Ding Yuan
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Chengfu Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
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Chen J, Li G, Liu X, Chen K, Wang Y, Qin J, Yang F. Delivery of miR-130a-3p Through Adipose-Derived Stem Cell-Secreted EVs Protects Against Diabetic Peripheral Neuropathy via DNMT1/NRF2/HIF1α/ACTA1 Axis. Mol Neurobiol 2023; 60:3678-3694. [PMID: 36933145 DOI: 10.1007/s12035-023-03297-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 03/05/2023] [Indexed: 03/19/2023]
Abstract
Peripheral neuropathy is common in diabetic patients and can lead to amputations or foot ulcers. microRNAs (miRNAs) possess crucial roles in diabetic peripheral neuropathy (DPN). This study aims to investigate the role miR-130a-3p played in DPN and its underlying molecular mechanisms. miR-130a-3p expression in clinical tissue samples, established DPN rat models, and extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSCs) were determined. Schwann cells (SCs) were co-cultured with ADSC-derived EVs and treated with high glucose. The direct relationship and functional significance of miR-130a-3p, DNMT1, nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor-1α (HIF1α), and skeletal muscle actin alpha 1 (ACTA1) was identified. The in vitro and in vivo implication of ADSC-derived EVs carrying miR-130a-3p was assessed. miR-130a-3p was poorly expressed in DPN patients and rats but highly expressed in ADSC-derived EVs. miR-130a-3p could be delivered to SCs through ADSC-derived EVs to inhibit SC apoptosis and promote proliferation under a high-glucose environment. miR-130a-3p activated NRF2/HIF1α/ACTA1 axis through down-regulating DNMT1. In vivo injection of ADSC-derived EVs activated NRF2/HIF1α/ACTA11 axis to promote angiogenesis in DPN rat model. These data together supported that ADSC-derived EVs carrying miR-130a-3p could alleviate DPN by accelerating SC proliferation and inhibiting apoptosis, providing a potential treatment against DPN.
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Affiliation(s)
- Ji Chen
- Department of Endocrinology, The First People's Hospital of Huaihua, Huaihua, 418000, People's Republic of China
| | - Gengzhang Li
- Department of Anesthesiology, The First Affiliated Hospital, Shaoyang College, Shaoyang, 422001, People's Republic of China
| | - Xinxin Liu
- Department of Anesthesiology, The First People's Hospital of Huaihua, No. 144, Jinxi South Road, Huaihua, 418000, Hunan Province, People's Republic of China
| | - Kemin Chen
- Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
| | - Yuxia Wang
- Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
| | - Jie Qin
- Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
| | - Fengrui Yang
- Department of Anesthesiology, The First People's Hospital of Huaihua, No. 144, Jinxi South Road, Huaihua, 418000, Hunan Province, People's Republic of China.
- Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
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Dieter C, Lemos NE, Girardi E, Ramos DT, Pellenz FM, Canani LH, Assmann TS, Crispim D. The rs3931283/PVT1 and rs7158663/MEG3 polymorphisms are associated with diabetic kidney disease and markers of renal function in patients with type 2 diabetes mellitus. Mol Biol Rep 2023; 50:2159-2169. [PMID: 36565414 DOI: 10.1007/s11033-022-08122-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/14/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are key regulators of gene expression. Some studies have reported the association of polymorphisms in lncRNA genes with diabetes mellitus (DM) and its chronic complications, including diabetic kidney disease (DKD); however, the results are still inconclusive. Thus, we investigated the association of the rs3200401/MALAT1, rs1894720/MIAT, rs3931283/PVT1, rs11993333/PVT1, rs5749201/TUG1, and rs7158663/MEG3 polymorphisms with DKD in patients with type 2 DM (T2DM). METHODS AND RESULTS This study comprised 902 patients with T2DM and DKD (cases) and 394 patients with T2DM without DKD (controls). The six polymorphisms of interest were genotyped by real-time PCR using TaqMan probes. Frequency of the rs3931283/PVT1 G/G genotype was 36.2% in cases and 31.9% in controls (P = 0.331). After adjustment for gender, glycated hemoglobin, HDL cholesterol, ethnicity, hypertension, and diabetic retinopathy, the G/G genotype was associated with risk for DKD (OR = 1.625, 95% CI 1.020-2.588; P = 0.041). The rs3931283/PVT1 G/G genotype was also associated with higher urinary albumin excretion levels compared to A allele carriers (P = 0.017). No difference was found in rs7158663/MEG3 genotype frequencies between T2DM controls and DKD patients (OR = 1.087, 95% CI 0.686-1.724; P = 0.722). However, the rs7158663/MEG3 G/G genotype was associated with protection against severe DKD (OR = 0.694, 95% CI 0.488-0.989; P = 0.043, for patients with severe DKD vs. T2DM controls). The rs7158663/MEG3 G/G genotype was also associated with lower creatinine levels (P = 0.007) and higher estimated glomerular filtration rate (P = 0.010) compared to A allele carriers. No association was found between the rs11993333/PVT1, rs3200401/MALAT1, rs1894720/MIAT, and rs5749201/TUG1 polymorphisms and DKD or its laboratory markers. CONCLUSION The rs3931283/PVT1 G/G and rs7158663/MEG3 G/G are associated with DKD and markers of renal function in T2DM patients from a Brazilian population.
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Affiliation(s)
- Cristine Dieter
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Natália Emerim Lemos
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Eliandra Girardi
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil
| | - Denise Taurino Ramos
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil
| | - Felipe Mateus Pellenz
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Luís Henrique Canani
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Taís Silveira Assmann
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Daisy Crispim
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil. .,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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Cheng Y, Wu X, Xia Y, Liu W, Wang P. The role of lncRNAs in regulation of DKD and diabetes-related cancer. Front Oncol 2022; 12:1035487. [PMID: 36313695 PMCID: PMC9606714 DOI: 10.3389/fonc.2022.1035487] [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: 09/02/2022] [Accepted: 09/19/2022] [Indexed: 11/23/2022] Open
Abstract
Diabetes mellitus often results in several complications, such as diabetic kidney disease (DKD) and end-stage renal diseases (ESRDs). Cancer patients often have the dysregulated glucose metabolism. Abnormal glucose metabolism can enhance the tumor malignant progression. Recently, lncRNAs have been reported to regulate the key proteins and signaling pathways in DKD development and progression and in cancer patients with diabetes. In this review article, we elaborate the evidence to support the function of lncRNAs in development of DKD and diabetes-associated cancer. Moreover, we envisage that lncRNAs could be diagnosis and prognosis biomarkers for DKD and cancer patients with diabetes. Furthermore, we delineated that targeting lncRNAs might be an alternative approach for treating DKD and cancer with dysregulated glucose metabolism.
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Affiliation(s)
- Yawei Cheng
- Department of Disease Prevention, Hainan Province Hospital of Traditional Chinese Medicine, Haikou, China
- Hainan Clinical Research Center for Preventive Treatment of Diseases, Haikou, China
- *Correspondence: Yawei Cheng, ; Peter Wang,
| | - Xiaowen Wu
- Department of Disease Prevention, Hainan Province Hospital of Traditional Chinese Medicine, Haikou, China
| | - Yujie Xia
- Department of Food Science and Technology Centers, National University of Singapore (Suzhou) Research Institute, Suzhou, China
| | - Wenjun Liu
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, China
| | - Peter Wang
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, China
- *Correspondence: Yawei Cheng, ; Peter Wang,
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lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis. J Immunol Res 2022; 2022:8098001. [PMID: 35910856 PMCID: PMC9334040 DOI: 10.1155/2022/8098001] [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: 05/13/2022] [Accepted: 07/01/2022] [Indexed: 02/07/2023] Open
Abstract
Objective The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.
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Zhao Y, Yan G, Mi J, Wang G, Yu M, Jin D, Tong X, Wang X. The Impact of lncRNA on Diabetic Kidney Disease: Systematic Review and In Silico Analyses. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:8400106. [PMID: 35528328 PMCID: PMC9068318 DOI: 10.1155/2022/8400106] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/07/2022] [Accepted: 04/13/2022] [Indexed: 12/17/2022]
Abstract
Background Long noncoding RNA (lncRNA) is involved in the occurrence and development of diabetic kidney disease (DKD). It is necessary to identify the expression of lncRNA from DKD patients through systematic reviews, and then carry out silico analyses to recognize the dysregulated lncRNA and their associated pathways. Methods The study searched Pubmed, Embase, Cochrane Library, WanFang, VIP, CNKI, and CBM to find lncRNA studies on DKD published before March 1, 2021. Systematic review of the literature on this topic was conducted to determine the expression of lncRNA in DKD and non-DKD controls. For the dysregulated lncRNA in DKD patients, silico analysis was performed, and lncRNA2Target v2.0 and starBase were used to search for potential target genes of lncRNA. The Encyclopedia of Genomics (KEGG) pathway enrichment analysis was performed to better identify dysregulated lncRNAs in DKD and determine the associated signal pathways. Results According to the inclusion and exclusion criteria, 28 publications meeting the eligibility criteria were included in the systematic evaluation. A total of 3,394 patients were enrolled in this study, including 1,238 patients in DKD group, and 1,223 diabetic patients, and 933 healthy adults in control group. Compared with the control, there were eight lncRNA disorders in DKD patients (MALAT1, GAS5, MIAT, CASC2, NEAT1, NR_033515, ARAP1-AS2, and ARAP1-AS1). In addition, five lncRNAs (MALAT1, GAS5, MIAT, CASC2, and NEAT1) participated in disease-related signal pathways, indicating their role in DKD. Discussion. This study showed that there were eight lncRNAs in DKD that were persistently dysregulated, especially five lncRNAs which were closely related to the disease. Although systematic review included 28 studies that analyzed the expression of lncRNA in DKD-related tissues, the potential of these dysregulated lncRNAs as biomarkers or therapeutic targets for DKD remains to be further explored. Trial registration. PROSPERO (CRD42021248634).
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Affiliation(s)
- Yunyun Zhao
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Guanchi Yan
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jia Mi
- Endocrinology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Guoqiang Wang
- Endocrinology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Miao Yu
- Endocrinology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Di Jin
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaolin Tong
- Northeast Asian Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Xiuge Wang
- Endocrinology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
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Hu M, Ma Q, Liu B, Wang Q, Zhang T, Huang T, Lv Z. Long Non-Coding RNAs in the Pathogenesis of Diabetic Kidney Disease. Front Cell Dev Biol 2022; 10:845371. [PMID: 35517509 PMCID: PMC9065414 DOI: 10.3389/fcell.2022.845371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/08/2022] [Indexed: 01/09/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus, with relatively high morbidity and mortality globally but still in short therapeutic options. Over the decades, a large body of data has demonstrated that oxidative stress, inflammatory responses, and hemodynamic disorders might exert critical influence in the initiation and development of DKD, whereas the delicate pathogenesis of DKD remains profoundly elusive. Recently, long non-coding RNAs (lncRNAs), extensively studied in the field of cancer, are attracting increasing attentions on the development of diabetes mellitus and its complications including DKD, diabetic retinopathy, and diabetic cardiomyopathy. In this review, we chiefly focused on abnormal expression and function of lncRNAs in major resident cells (mesangial cell, endothelial cell, podocyte, and tubular epithelial cell) in the kidney, summarized the critical roles of lncRNAs in the pathogenesis of DKD, and elaborated their potential therapeutic significance, in order to advance our knowledge in this field, which might help in future research and clinical treatment for the disease.
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Affiliation(s)
- Mengsi Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qiqi Ma
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianhui Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tongtong Huang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Zhimei Lv,
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Zhang G, Liu SL, Yi WT, Dong YP, Wan YX. Long noncoding RNA ZFPM2-AS1 regulates renal cell carcinoma progression via miR-130a-3p/ESCO2. Kaohsiung J Med Sci 2022; 38:530-541. [PMID: 35258173 DOI: 10.1002/kjm2.12527] [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: 09/15/2021] [Revised: 02/05/2022] [Accepted: 02/17/2022] [Indexed: 11/07/2022] Open
Abstract
Previous studies reported that long noncoding RNA (lncRNA) ZFPM2-AS1 is upregulated in renal cell carcinoma (RCC). However, the biological role of lncRNA ZFPM2-AS1 in RCC has not been explored. In this study, we investigated the role of lncRNA ZFPM2-AS1 in the progression of RCC. Quantitative real-time polymerase chain reaction was used for gene expression analysis, and functional assays including Cell Counting Kit-8 assay, flow cytometry-based apoptosis assay and transwell migration assays were performed to examine the malignant phenotypes. The functional interaction between ZFPM2-AS1 or miR-130A-3P and their targets was detected by dual-luciferase reporter assay. We found that the expressions of ZFPM2-AS1 and ESCO2 were upregulated in RCC tissues and cells, whereas miR-130a-3p was downregulated. The expression level of ZFPM2-AS1 is significantly associated with advanced TNM, distant metastasis, lymphatic metastasis, and a poor overall survival in RCC patients. Silencing ZFPM2-AS1 in RCC cells suppressed cell proliferation, invasion, and migration, and induced cell apoptosis. ZFPM2-AS1 interacted with miR-130A-3P and negatively regulated its expression in RCC cells. We further showed that ESCO2 was a downstream target of miR-130a-3p. Both miR-130a-3p inhibitor and ESCO2 overexpression could rescue the inhibitory effects of ZFPM2-AS1 knockdown in RCC cells. Together, our study demonstrates that ZFPM2-AS1 plays an oncogenic role in RCC progression via the miR-130a-3p/ESCO2 axis.
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Affiliation(s)
- Gang Zhang
- Department of Urology section, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Song-Lin Liu
- Department of Urology section, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Wen-Ting Yi
- Department of Medical Laboratory, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Yu-Ping Dong
- Department of Hematopathology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Yin-Xu Wan
- Department of Urology section, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
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Zhang H, He F, Zhou L, Shi M, Li F, Jia H. Activation of TLR4 induces inflammatory muscle injury via mTOR and NF-κB pathways in experimental autoimmune myositis mice. Biochem Biophys Res Commun 2022; 603:29-34. [PMID: 35276460 DOI: 10.1016/j.bbrc.2022.03.004] [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] [Received: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 11/02/2022]
Abstract
Idiopathic inflammatory myopathy (IIM) is an autoimmune disease that invades skeletal muscle; however, the etiology of IIM is still poorly understood. Toll-like receptor (TLR) 4 has been widely reported to take part in the autoimmune inflammation of IIMs. The mammalian target of rapamycin, mTOR, is a key central substance which mediates immune responses and metabolic changes, and also has been confirmed to be involved in the pathogenesis of IIMs. However, the interconnectedness between TLR4 and mTOR in IIM inflammation has not been fully elucidated. We hypothesized that TLR4 may play an important role in IIM inflammatory muscle injury by regulating mTOR. Mice were divided into four groups: a normal control group, IIM animal model (experimental autoimmune myositis, EAM) group, TAK242 intervention group and rapamycin (RAPA) intervention group. The results of EAM mice showed that TLR4, mTOR, nuclear factor-kappa B (NF-κB) and inflammatory factors interleukin-17A (IL-17A) and interferon γ (IFN-γ) mRNA levels were significantly upregulated. These factors were positively correlated with the degree of muscle inflammatory injury. When EAM mice were given the antagonist TAK242 to inhibit the TLR4 pathway, the results demonstrated that both mTOR and NF-κB were downregulated in the muscle of the mice. Muscle staining showed that the inflammatory injury was alleviated and the EAM mouse muscle strength was improved. Then, RAPA was used to inhibit the mTOR pathway, and the inflammatory factors IL-17A and IFN-γ were downregulated in EAM mouse muscle and serum. Consistently, muscle inflammatory injury was significantly reduced, and muscle strength was significantly improved. Our results suggest that TLR4 may regulate inflammatory muscle injury in EAM by activating the mTOR and NF-κB pathways, which provides both an experimental complement for the pathological mechanism of IIM and an encouraging target for the selection of effective treatments.
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Affiliation(s)
- Hongya Zhang
- Air Force Medical University, Xi'an, China; Department of Neurology, Shenzhen University General Hospital, Shenzhen, China
| | - Fangyuan He
- Department of Neurology, Xi'an Children's Hospital, Xi'an, China
| | - Linfu Zhou
- Department of Neurology, Northwestern University School of Medicine, Xi'an, China
| | - Ming Shi
- Air Force Medical University, Xi'an, China
| | - Fangming Li
- Department of Neurology, Shenzhen University General Hospital, Shenzhen, China.
| | - Hongge Jia
- Department of Neurology, Shenzhen Hospital of Southern Medical University, Shenzhen, China.
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21
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Gu W, Wang L, Deng G, Gu X, Tang Z, Li S, Jin W, Yang J, Guo X, Li Q. Knockdown of long noncoding RNA MIAT attenuates cigarette smoke-induced airway remodeling by downregulating miR-29c-3p-HIF3A axis. Toxicol Lett 2021; 357:11-19. [PMID: 34953943 DOI: 10.1016/j.toxlet.2021.12.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/29/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a global public health issue and is defined as persistent airflow limitation. COPD is a major cause of morbidity and mortality worldwide. Long noncoding RNAs are involved in the course of pulmonary diseases. Here, we revealed that a long noncoding RNA called myocardial-infarction-associated transcript (MIAT) is upregulated in lung tissues of cigarette smoke (CS)-exposed mice. Knockdown of MIAT attenuated CS or CS-extract-induced inflammatory processes, epithelial-mesenchymal transition (EMT), and collagen deposition. Moreover, according to bioinformatic analyses and luciferase reporter assays, MIAT binds to microRNA-29c-3p (miR-29c-3p) and upregulates hypoxia-inducible factor 3 alpha (HIF3A), a target gene of miR-29c-3p. When the MIAT-specific short hairpin RNA and an miR-29c-3p inhibitor were cotransfected into cells, the inhibitor reversed the effects of MIAT knockdown on cell proliferation, apoptosis, inflammation, EMT, and collagen deposition. Overall, these results indicate that MIAT participates in CS-induced EMT and airway remodeling in COPD by upregulating miR-29c-3p-HIF3A axis output, thereby offering a novel promising biomarker for the assessment of COPD exacerbation induced by CS exposure.
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Affiliation(s)
- Wenchao Gu
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Linxuan Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Guoping Deng
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Xiaolong Gu
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Zhijun Tang
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Shanshan Li
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Wenjing Jin
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Junxia Yang
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Xiaoxia Guo
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Qiang Li
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.
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22
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Li X, Li N, Li B, Feng Y, Zhou D, Chen G. Noncoding RNAs and RNA-binding proteins in diabetic wound healing. Bioorg Med Chem Lett 2021; 50:128311. [PMID: 34438011 DOI: 10.1016/j.bmcl.2021.128311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]
Abstract
Poor wound healing is a common complication in diabetic patients. It often leads to intractable infections and lower limb amputations and is associated with cardiovascular morbidity and mortality. NcRNAs, which can regulate gene expression, have emerged as important regulators of various physiological processes. Herein, we summarize the diverse roles of ncRNAs in the key stages of diabetic wound healing, including inflammation, angiogenesis, re-epithelialization, and extracellular matrix remodeling. Meanwhile, the potential use of ncRNAs as novel therapeutic targets for wound healing in diabetic patients is also discussed. In addition, we summarize the role of RNA-binding proteins (RBPs) in the regulation of gene expression and signaling pathways during skin repair, which may provide opportunities for therapeutic intervention for this potentially devastating disease. However, so far, research on the modulated drug based on ncRNAs that lead to significantly altered gene expression in diabetic patients is scarce. We have compiled some drugs that may be able to modulate ncRNAs, which significantly regulate the gene expression in diabetic patients.
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Affiliation(s)
- Xue Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Bingxin Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China; Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, People's Republic of China.
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23
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Dong J, Xia R, Zhang Z, Xu C. lncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis. Aging (Albany NY) 2021; 13:23004-23019. [PMID: 34609952 PMCID: PMC8544300 DOI: 10.18632/aging.203592] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/20/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Long non-coding RNAs (lncRNAs) exert a critical function in mediating neuropathic pain (NP). MEG3, a novel lncRNA, contributes to astrocyte activation and inflammation. However, its role in NP remains unclear. METHODS The chronic constriction injury (CCI) method was employed to construct an NP rat model. Astrocyte activation was induced by lipopolysaccharide (LPS). The profiles of MEG3, microRNA (miR)-130a-5p, CXC motif chemokine receptor 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4), and the Rac1/NF-κB pathway in CCI rats' spinal cord tissues and astrocytes were monitored by reverse transcription-quantitative PCR (RT-qPCR) and western blot (WB). Pain scores of CCI rats were assessed. Enzyme-linked immunosorbent assay (ELISA) was adopted to monitor neuroinflammation alteration. The glial fibrillary acidic protein (GFAP)-labeled astrocytes were tested by immunohistochemistry (IHC). Bioinformatics, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were utilized to verify the molecular mechanism between MEG3 and miR-130a-3p. RESULTS MEG3, CXCL12 and CXCR4 were overexpressed and miR-130a-5p was knocked down in CCI rats and LPS-induced astrocytes. Up-regulating MEG3 aggravated NP, enhanced inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, and interleukin-6 (IL-6) expression and release in CCI rats and LPS-induced astrocytes. Up-regulating miR-130-5p repressed LPS-induced inflammation in astrocytes. AS verified by the dual-luciferase reporter assay and RIP assay, MEG3 sponged miR-130a-5p as a competitive endogenous RNA (ceRNA). What's more, miR-130a-5p up-regulation weakened the MEG3-induced proinflammatory effects on LPS-induced astrocytes. CONCLUSIONS MEG3 aggravates NP and astrocyte activation via the miR-130a-5p/CXCL12/CXCR4 axis, which is a potential therapeutic target for NP.
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Affiliation(s)
- Jiacai Dong
- Department of Anesthesiology, Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University, Qianjiang 433100, Hubei, China
| | - Rui Xia
- Department of Anesthesiology, The First People's Hospital of Jingzhou, Jingzhou 434000, Hubei, China
| | - Zhonggui Zhang
- Department of Pain, The First People's Hospital of Jingzhou, Jingzhou 434000, Hubei, China
| | - Cheng Xu
- Department of Pain, The First People's Hospital of Jingzhou, Jingzhou 434000, Hubei, China
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Dong Q, Wang Q, Yan X, Wang X, Li Z, Zhang L. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis. Open Med (Wars) 2021; 16:1336-1349. [PMID: 34553078 PMCID: PMC8422979 DOI: 10.1515/med-2021-0328] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background Diabetic nephropathy (DN) is a common diabetic complication. Long noncoding RNAs (lncRNAs) have been identified as essential regulators in DN progression. This study is devoted to the research of lncRNA-myocardial infarction-associated transcript (MIAT) in DN. Methods DN cell model was established by high glucose (HG) treatment for human renal tubular epithelial cells (HK-2). Cell viability and colonizing capacity were analyzed by Cell Counting Kit-8 (CCK-8) and colony formation assay. Apoptosis was assessed via caspase-3 detection and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used for evaluating inflammation. The protein determination was completed using western blot. MIAT, microRNA-182-5p (miR-182-5p), and G protein-coupled receptor class C group 5 member A (GPRC5A) levels were all examined via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Intergenic binding was verified using dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. Results HG induced the inhibition of cell growth, but accelerated apoptosis and inflammation as well as the activation of nuclear factor kappa B (NF-κB) pathway. MIAT reestablishment prevented the HG-induced cell damages and NF-κB signal activation. Mechanistically, MIAT was proved as a miR-182-5p sponge and regulated the expression of GPRC5A that was a miR-182-5p target. The rescued experiments demonstrated that MIAT downregulation or miR-182-5p upregulation aggravated the HG-induced cell damages and activated the NF-κB pathway via the respective regulation of miR-182-5p or GPRC5A. Conclusion Taken together, MIAT functioned as an inhibitory factor in the pathogenesis to impede the development of DN and inactivate the NF-κB pathway via regulating the miR-182-5p/GPRC5A axis.
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Affiliation(s)
- Qianlan Dong
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
| | - Qiong Wang
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
| | - Xiaohui Yan
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
| | - Xiaoming Wang
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
| | - Zhenjiang Li
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
| | - Linping Zhang
- Kidney Disease and Dialysis Center, Shaanxi Provincial People's Hospital, Beilin District, Xi'an, Shaanxi, 710068, China
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25
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Jiang F, Lou J, Zheng XM, Yang XY. LncRNA MIAT regulates autophagy and apoptosis of macrophage infected by Mycobacterium tuberculosis through the miR-665/ULK1 signaling axis. Mol Immunol 2021; 139:42-49. [PMID: 34454184 DOI: 10.1016/j.molimm.2021.07.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/23/2021] [Accepted: 07/29/2021] [Indexed: 12/26/2022]
Abstract
Accumulating lines of evidence have revealed the involvement of long non-coding RNAs (lncRNAs) in the control and elimination of invading Mycobacterium tuberculosis (Mtb) by macrophage. In this study, we sought to elucidate the role of MIAT on autophagy and apoptosis of Mtb-infected macrophage and to reveal the molecular mechanism. We observed that the expression of MIAT was heightened while miR-665 level was declined in THP-1 cells with Bacillus Calmette-Guerin (BCG) infection in a time-dependent manner. Functionally, disruption of MIAT effectively facilitated cell viability and restricted apoptosis ability concomitant with the downregulation of Bax and cleaved caspase-3 along with an accumulation of Bcl-2 in BCG-infected THP-1 cells. Concurrently, the interference of MIAT dramatically disinhibited macrophage autophagy as characterized by diminution of autophagy related markers LC3-II and Beclin-1 as well as increment of p62 in THP-1 cells following BCG infection. Concordantly, depletion of MIAT was found to noticeably aggrandize Mtb survival. Importantly, MIAT served as a ceRNA for sponging miR-665 and negatively regulated its expression. ULK1 was identified as an authentic target of miR-665 and modulated by MIAT. Mechanistically, the functional role of MIAT depletion in macrophage apoptosis and autophagy were tremendously abrogated by the depression of miR-665 and enrichment of ULK1. Overall, the preceding observations clearly illuminated that MIAT was elevated in human macrophage response to BCG infection, and functioned as a negative regulator in autophagy and antimicrobial effects by manipulating miR-665/ULK1 axis during Mtb infection, which may provide a promising target for developing an anti-bacterial against TB.
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Affiliation(s)
- Fang Jiang
- Clinical Laboratory, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
| | - Jun Lou
- Clinical Laboratory, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China
| | - Xi-Ming Zheng
- Clinical Laboratory, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China
| | - Xi-Yong Yang
- Clinical Laboratory, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China
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26
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Shao BY, Zhang SF, Li HD, Meng XM, Chen HY. Epigenetics and Inflammation in Diabetic Nephropathy. Front Physiol 2021; 12:649587. [PMID: 34025445 PMCID: PMC8131683 DOI: 10.3389/fphys.2021.649587] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/12/2021] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN) leads to high morbidity and disability. Inflammation plays a critical role in the pathogenesis of DN, which involves renal cells and immune cells, the microenvironment, as well as extrinsic factors, such as hyperglycemia, chemokines, cytokines, and growth factors. Epigenetic modifications usually regulate gene expression via DNA methylation, histone modification, and non-coding RNAs without altering the DNA sequence. During the past years, numerous studies have been published to reveal the mechanisms of epigenetic modifications that regulate inflammation in DN. This review aimed to summarize the latest evidence on the interplay of epigenetics and inflammation in DN, and highlight the potential targets for treatment and diagnosis of DN.
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Affiliation(s)
- Bao-Yi Shao
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Shao-Fei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hai-Di Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hai-Yong Chen
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Ding X, Xu X, He XF, Yuan Y, Chen C, Shen XY, Su S, Chen Z, Xu ST, Huang YH. Muscleblind-like 1 antisense RNA 1 inhibits cell proliferation, invasion, and migration of prostate cancer by sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR signaling. Bioengineered 2021; 12:803-814. [PMID: 33648424 PMCID: PMC8806234 DOI: 10.1080/21655979.2021.1890383] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to investigate the role and underlying mechanisms of long non-coding RNA (lncRNA) muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) in the progression of Prostate cancer (PCa). MBNL1-AS1 and microRNA (miR)-181a-5p expression in PCa tissues and several human PCa cell lines were analyzed, respectively, using StarBasev3.0 project and RT-qPCR assay. After MBNL1-AS1 overexpression, cell proliferation, invasion and migration were, respectively, evaluated using CCK-8, colony formation, transwell and wound healing assays. Dual luciferase assay were used for analysis of the interactions among MBNL1-AS1, miR-181a-5p, and phosphatase and tensin homolog (PTEN). Subsequently, the expression of PTEN and proteins in PI3K/AKT/mTOR signaling was examined using western blot analysis after transfection with miR-181a-5p mimic. The rescue assays were performed to investigate the effects of MBNL1-AS1 and miR-181a-5p on the functions of PCa cells and the expression of PTEN/PI3K/AKT/mTOR signaling by co-transfection with MBNL1-AS1 plasmid and miR-181a-5p mimic. Results indicated that MBNL1-AS1 was conspicuously downregulated while miR-181a-5p upregulating in PCa tissues and cell lines. MBNL1-AS1 overexpression decreased the abilities of cell proliferation, invasion, and migration. Further study revealed that MBNL1-AS1 acted as a sponge for miR-181a-5p and positively regulated PTEN by a sponge effect. Additionally, rescue assays proved that the effect of MBNL1-AS1-upregulation on the proliferation, invasion, and migration of PCa cells was dependent on miR-181a-5p. Furthermore, miR-181a-5p overexpression counteracted the expression of PTEN and proteins in PI3K/AKT/mTOR signaling exerted by MBNL1-AS1-upregulation in PCa cells. This study suggests that MBNL1-AS1 inhibits the progression of PCa via sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Xiang Ding
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xu Xu
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xue-Feng He
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ye Yuan
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chuang Chen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin-Yu Shen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Sai Su
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhang Chen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Song-Tao Xu
- Department of Clinical Medicine, Luohe Medical College, Luohe, China
| | - Yu-Hua Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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28
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Huang L, Hu X. Molecular Mechanisms and Functions of lncRNAs in the Inflammatory Reaction of Diabetes Mellitus. Int J Endocrinol 2021; 2021:2550399. [PMID: 34712322 PMCID: PMC8548175 DOI: 10.1155/2021/2550399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 10/08/2021] [Indexed: 12/28/2022] Open
Abstract
Diabetes is a chronic inflammatory state, and several studies have shown that the mechanisms of insulin resistance and abnormal islet β-cell function in diabetes are closely related to inflammatory reactions. Inflammation plays a critical role in diabetic complications. Long noncoding RNAs (lncRNAs), a new area of genomic research for gene regulation, have complex biological functions in various aspects of cellular biological activity. Recent studies have shown that lncRNAs are associated with the regulation of inflammatory responses in various ways, including at the epigenetic, transcriptional, and posttranscriptional levels. This paper presents a brief review of studies on the mechanisms of lncRNAs in diabetic inflammation. The purpose of this article is to determine the role of lncRNAs in the process of diabetic inflammation and to provide new strategies for the use of lncRNAs in the treatments for diabetic inflammation.
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Affiliation(s)
- Linjuan Huang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Xiaolei Hu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
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