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Chen H, Tian T, Wang D. Dysregulation of miR-25-3p in Diabetic Nephropathy and Its Role in Inflammatory Response. Biochem Genet 2025; 63:1635-1646. [PMID: 38602597 DOI: 10.1007/s10528-024-10781-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/11/2024] [Indexed: 04/12/2024]
Abstract
To investigate the expression level of miR-25-3p in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), and its effect on proliferation, apoptosis and inflammatory response of mesangial cells cultured with high glucose. Blood samples of all clinical subjects were collected for RT-qPCR analysis to detect serum miR-25-3p levels. Human mesangial cells (HMCs) cultured with high glucose were used to construct DN model in vitro. MTT assay, flow cytometry and ELISA were used to evaluate the effects of miR-25-3p on the proliferation, apoptosis, and inflammatory response of DN cell models. Serum miR-25-3p was decreased in both T2DM group and DN group, but more in DN group. Serum miR-25-3p was positively correlated with eGFR and negatively correlated with UAER. The expression of miR-25-3p was reduced in HMCs induced by high glucose. Transfection of miR-25-3p mimic could significantly up-regulate the miR-25-3p level in HMCs. Besides, high glucose culture resulted in abnormal proliferation of HMCs, reduced apoptotic cells, and increased inflammation. The addition of miR-25-3p mimic significantly inhibited cell proliferation and promoted cell apoptosis and reduced the production of inflammatory factors. The abnormal reduction of serum miR-25-3p in DN indicates that it may be a potential biomarker for clinical diagnosis of DN. In in vitro experiments, miR-25-3p was involved in the progression of DN by regulating cell proliferation, apoptosis, and inflammatory response.
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Affiliation(s)
- Huanzhen Chen
- School of Medicine, Tongji University, No.500, Zhennan Road, Taopu Town, Shanghai, 200092, China.
- Department of Endocrinology and Metabolism, Shanghai Jiangong Hospital, No. 666 Zhongshan North 1st Road, Hongkou District, Shanghai, 200083, China.
| | - Tongguan Tian
- Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Dan Wang
- Department of Endocrinology and Metabolism, Shanghai Jiangong Hospital, No. 666 Zhongshan North 1st Road, Hongkou District, Shanghai, 200083, China
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Kachel M, Dola A, Kubiak M, Majewska W, Nowakowska J, Langwiński W, Hryhorowicz S, Szczepankiewicz A. MicroRNA Expression Profile Is Altered by Short-Term and Chronic Lithium Treatment in a Rat Model of Depression. J Mol Neurosci 2024; 74:116. [PMID: 39674983 DOI: 10.1007/s12031-024-02298-0] [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: 07/11/2024] [Accepted: 12/04/2024] [Indexed: 12/17/2024]
Abstract
Depression is a common disease that affects 3.8% of the global population. Despite various antidepressant treatments, one-third of patients do not respond to antidepressants, therefore augmentation with mood stabilizers such as lithium may be required in this group. One of the suggested pathomechanisms of depression is the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and recent reports showed that microRNAs (miRNA) can impact its activity by epigenetic regulation. We aimed to explore the miRNA expression profile in the depression model and its changes upon short-term and chronic lithium treatment in the rat brain (pituitary, hypothalamus, and hippocampus). We used a chronic mild stress rat model of depression and short- and long-term lithium treatment. The behavior was assessed by an open-field test. The miRNA expression profile in the pituitary was estimated by sequencing and validated in the hypothalamus and hippocampus with qPCR. We found several miRNAs in the pituitary that were significantly altered between CMS-exposed and control rats as well as after short- and long-term lithium treatment. MicroRNAs chosen for validation in the hypothalamus and hippocampus (rno-miR-146a-5p, rno-miR-127-3p) showed no significant changes in expression. We performed in silico analysis and estimated potential pathways involved in lithium action for miRNAs differentially expressed in the pituitary at different time points. Specific microRNA subsets showed altered expression in the pituitary in depression model upon short- and long-term lithium treatment. We identified that biological pathways of target genes for these altered miRNAs differ, with the Foxo pathway potentially involved in disease development.
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Affiliation(s)
- Maria Kachel
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
| | - Antonina Dola
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
| | - Mikołaj Kubiak
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
| | - Wiktoria Majewska
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
| | - Joanna Nowakowska
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
| | - Wojciech Langwiński
- Molecular and Cell Biology Unit, Poznan University of Medical Sciences, Poznan, Poland
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Garmaa G, Bunduc S, Kói T, Hegyi P, Csupor D, Ganbat D, Dembrovszky F, Meznerics FA, Nasirzadeh A, Barbagallo C, Kökény G. A Systematic Review and Meta-Analysis of microRNA Profiling Studies in Chronic Kidney Diseases. Noncoding RNA 2024; 10:30. [PMID: 38804362 PMCID: PMC11130806 DOI: 10.3390/ncrna10030030] [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: 04/08/2024] [Revised: 04/24/2024] [Accepted: 04/28/2024] [Indexed: 05/29/2024] Open
Abstract
Chronic kidney disease (CKD) represents an increasing health burden. Evidence suggests the importance of miRNA in diagnosing CKD, yet the reports are inconsistent. This study aimed to determine novel miRNA biomarkers and potential therapeutic targets from hypothesis-free miRNA profiling studies in human and murine CKDs. Comprehensive literature searches were conducted on five databases. Subgroup analyses of kidney diseases, sample types, disease stages, and species were conducted. A total of 38 human and 12 murine eligible studies were analyzed using Robust Rank Aggregation (RRA) and vote-counting analyses. Gene set enrichment analyses of miRNA signatures in each kidney disease were conducted using DIANA-miRPath v4.0 and MIENTURNET. As a result, top target genes, Gene Ontology terms, the interaction network between miRNA and target genes, and molecular pathways in each kidney disease were identified. According to vote-counting analysis, 145 miRNAs were dysregulated in human kidney diseases, and 32 were dysregulated in murine CKD models. By RRA, miR-26a-5p was significantly reduced in the kidney tissue of Lupus nephritis (LN), while miR-107 was decreased in LN patients' blood samples. In both species, epithelial-mesenchymal transition, Notch, mTOR signaling, apoptosis, G2/M checkpoint, and hypoxia were the most enriched pathways. These miRNA signatures and their target genes must be validated in large patient cohort studies.
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Affiliation(s)
- Gantsetseg Garmaa
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (G.G.); (A.N.)
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Department of Pathology, School of Medicine, Mongolian National University of Medical Sciences, Ulan-Bator 14210, Mongolia;
| | - Stefania Bunduc
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Dionisie Lupu Street 37, 020021 Bucharest, Romania
- Fundeni Clinical Institute, Fundeni Street 258, 022328 Bucharest, Romania
- Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Baross út 22-24, 1085 Budapest, Hungary
| | - Tamás Kói
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
| | - Péter Hegyi
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Baross út 22-24, 1085 Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Dezső Csupor
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary
- Institute of Clinical Pharmacy, University of Szeged, Szikra utca 8, 6725 Szeged, Hungary
| | - Dariimaa Ganbat
- Department of Pathology, School of Medicine, Mongolian National University of Medical Sciences, Ulan-Bator 14210, Mongolia;
- Department of Public Health, Graduate School of Medicine, International University of Health and Welfare, Tokyo 107-840, Japan
| | - Fanni Dembrovszky
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Baross út 22-24, 1085 Budapest, Hungary
| | - Fanni Adél Meznerics
- Center for Translational Medicine, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary; (S.B.); (T.K.); (P.H.); (D.C.); (F.D.); (F.A.M.)
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Mária utca 41, 1085 Budapest, Hungary
| | - Ailar Nasirzadeh
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (G.G.); (A.N.)
| | - Cristina Barbagallo
- Section of Biology and Genetics “G. Sichel”, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Gábor Kökény
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (G.G.); (A.N.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
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Liao Y, Huang J, Wang Z, Yang Z, Shu Y, Gan S, Wang Z, Lu W. The phosphokinase activity of IRE1ɑ prevents the oxidative stress injury through miR-25/Nox4 pathway after ICH. CNS Neurosci Ther 2024; 30:e14537. [PMID: 37994671 PMCID: PMC11017440 DOI: 10.1111/cns.14537] [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: 05/30/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress and oxidative stress are the major pathologies encountered after intracerebral hemorrhage (ICH). Inositol-requiring enzyme-1 alpha (IRE1α) is the most evolutionarily conserved ER stress sensor, which plays a role in monitoring and responding to the accumulation of unfolded/misfolded proteins in the ER lumen. Recent studies have shown that ER stress is profoundly related to oxidative stress in physiological or pathological conditions. The purpose of this study was to investigate the role of IRE1α in oxidative stress and the potential mechanism. METHODS A mouse model of ICH was established by autologous blood injection. The IRE1α phosphokinase inhibitor KIRA6 was administrated intranasally at 1 h after ICH, antagomiR-25 and agomiR-25 were injected intraventricularly at 24 h before ICH. Western blot analysis, RT-qPCR, immunofluorescence staining, hematoma volume, neurobehavioral tests, dihydroethidium (DHE) staining, H2O2 content, brain water content, body weight, Hematoxylin and Eosin (HE) staining, Nissl staining, Morris Water Maze (MWM) and Elevated Plus Maze (EPM) were performed. RESULTS Endogenous phosphorylated IRE1α (p-IRE1α), miR-25-3p, and Nox4 were increased in the ICH model. Administration of KIRA6 downregulated miR-25-3p expression, upregulated Nox4 expression, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, reduced body weight, aggravated spatial learning and memory deficits, and increased anxiety levels. Then antagomiR-25 further upregulated the expression of Nox4, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, whereas agomiR-25 reversed the effects promoted by KIRA6. CONCLUSION The IRE1α phosphokinase activity is involved in the oxidative stress response through miR-25/Nox4 pathway in the mouse ICH brain.
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Affiliation(s)
- Yuhui Liao
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Medical CollegeSichuan University of Arts and ScienceDazhouChina
| | - Juan Huang
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Zhenhua Wang
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Zhengyu Yang
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Yue Shu
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Shengwei Gan
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Zhixu Wang
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
| | - Weitian Lu
- Department of Anatomy, Basic Medical CollegeChongqing Medical UniversityChongqingChina
- Institute of Neuroscience, Basic Medical CollegeChongqing Medical UniversityChongqingChina
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5
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Picchio V, Ferrero G, Cozzolino C, Pardini B, Floris E, Tarallo S, Dhori X, Nocella C, Loffredo L, Biondi-Zoccai G, Carnevale R, Frati G, Chimenti I, Pagano F. Effect of traditional or heat-not-burn cigarette smoking on circulating miRNAs in healthy subjects. Eur J Clin Invest 2024; 54:e14140. [PMID: 38050790 DOI: 10.1111/eci.14140] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/07/2023] [Accepted: 11/20/2023] [Indexed: 12/06/2023]
Abstract
BACKGROUND Traditional combustion cigarette (TCC) smoking is an established risk factor for several types of cancer and cardiovascular diseases. Circulating microRNAs (miRNAs) represent key molecules mediating pathogenetic mechanisms, and potential biomarkers for personalized risk assessment. TCC smoking globally changes the profile of circulating miRNAs. The use of heat-not-burn cigarettes (HNBCs) as alternative smoking devices is rising exponentially worldwide, and the circulating miRNA profile of chronic HNBC smokers is unknown. We aimed at defining the circulating miRNA profile of chronic exclusive HNBC smokers, and identifying potentially pathogenetic signatures. METHODS Serum samples were obtained from 60 healthy young subjects, stratified in chronic HNBC smokers, TCC smokers and nonsmokers (20 subjects each). Three pooled samples per group were used for small RNA sequencing, and the fourth subgroup constituted the validation set. RESULTS Differential expression analysis revealed 108 differentially expressed miRNAs; 72 exclusively in TCC, 10 exclusively in HNBC and 26 in both smoker groups. KEGG pathway analysis on target genes of the commonly modulated miRNAs returned cancer and cardiovascular disease associated pathways. Stringent abundance and fold-change criteria nailed down our functional bioinformatic analyses to a network where miR-25-3p and miR-221-3p are main hubs. CONCLUSION Our results define for the first time the miRNA profile in the serum of exclusive chronic HNBC smokers and suggest a significant impact of HNBCs on circulating miRNAs.
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Affiliation(s)
- Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Giulio Ferrero
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Claudia Cozzolino
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Barbara Pardini
- Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Erica Floris
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Sonia Tarallo
- Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Xhulio Dhori
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Cristina Nocella
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Loffredo
- Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Roberto Carnevale
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of Angio Cardio Neurology, Neuromed, Pozzilli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of Angio Cardio Neurology, Neuromed, Pozzilli, Italy
| | - Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Francesca Pagano
- Institute of Biochemistry and Cell Biology, Italian National Council of Research, Monterotondo, Rome, Italy
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Liebisch M, Wolf G. Role of Epigenetic Changes in the Pathophysiology of Diabetic Kidney Disease. GLOMERULAR DISEASES 2024; 4:211-226. [PMID: 39649441 PMCID: PMC11623970 DOI: 10.1159/000541923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/08/2024] [Indexed: 12/10/2024]
Abstract
Background Diabetic kidney disease (DKD) is a global health issue. Epigenetic changes play an important role in the pathogenesis of this disease. Summary DKD is currently the leading cause of kidney failure worldwide. Although much is known about the pathophysiology of DKD, the research field of epigenetics is relatively new. Several recent studies have demonstrated that diabetes-induced dysregulation of epigenetic mechanisms alters the expression of pathological genes in kidney cells. If these changes persist for a long time, the so-called "metabolic memory" could be established. In this review, we highlight diabetes-induced epigenetic modifications associated with DKD. While there is a substantial amount of literature on epigenetic changes, only a few studies describe the underlying molecular mechanisms. Detailed analyses have shown that epigenetic changes play an important role in known pathological features of DKD, such as podocyte injury, fibrosis, accumulation of extracellular matrix, or oxidative injury, all of which contribute to the pathophysiology of disease. The transforming growth factor-β plays a key role as it is involved in all-mentioned epigenetic types of regulation. Key Messages Epigenetic is crucial for the development and progression of DKD, but the detailed molecular mechanisms have to be further analyzed more in detail.
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Affiliation(s)
- Marita Liebisch
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
| | - Gunter Wolf
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
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Xiao M, Tang D, Luan S, Hu B, Gong W, Pommer W, Dai Y, Yin L. Dysregulated coagulation system links to inflammation in diabetic kidney disease. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1270028. [PMID: 38143793 PMCID: PMC10748384 DOI: 10.3389/fcdhc.2023.1270028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023]
Abstract
Diabetic kidney disease (DKD) is a significant contributor to end-stage renal disease worldwide. Despite extensive research, the exact mechanisms responsible for its development remain incompletely understood. Notably, patients with diabetes and impaired kidney function exhibit a hypercoagulable state characterized by elevated levels of coagulation molecules in their plasma. Recent studies propose that coagulation molecules such as thrombin, fibrinogen, and platelets are interconnected with the complement system, giving rise to an inflammatory response that potentially accelerates the progression of DKD. Remarkably, investigations have shown that inhibiting the coagulation system may protect the kidneys in various animal models and clinical trials, suggesting that these systems could serve as promising therapeutic targets for DKD. This review aims to shed light on the underlying connections between coagulation and complement systems and their involvement in the advancement of DKD.
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Affiliation(s)
- Mengyun Xiao
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Donge Tang
- Shenzhen People’s Hospital/The Second Clinical School of Jinan University, Shenzhen, Guangdong, China
| | - Shaodong Luan
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong, China
| | - Bo Hu
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Wenyu Gong
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Wolfgang Pommer
- KfH Kuratoriumfuer Dialyse und Nierentransplantatione.V., Bildungszentrum, Neu-Isenburg, Germany
| | - Yong Dai
- The First Affiliated Hospital, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China
| | - Lianghong Yin
- Institute of Nephrology and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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Li L, Shen Y, Tang Z, Yang Y, Fu Z, Ni D, Cai X. Engineered nanodrug targeting oxidative stress for treatment of acute kidney injury. EXPLORATION (BEIJING, CHINA) 2023; 3:20220148. [PMID: 38264689 PMCID: PMC10742205 DOI: 10.1002/exp.20220148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 04/23/2023] [Indexed: 01/25/2024]
Abstract
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function, and is associated with a high risk of death. Many pathological changes happen in the process of AKI, including crucial alterations to oxidative stress levels. Numerous efforts have thus been made to develop effective medicines to scavenge excess reactive oxygen species (ROS). However, researchers have encountered several significant challenges, including unspecific biodistribution, high biotoxicity, and in vivo instability. To address these problems, engineered nanoparticles have been developed to target oxidative stress and treat AKI. This review thoroughly discusses the methods that empower nanodrugs to specifically target the glomerular filtration barrier and presents the latest achievements in engineering novel ROS-scavenging nanodrugs in clustered sections. The analysis of each study's breakthroughs and imperfections visualizes the progress made in developing effective nanodrugs with specific biodistribution and oxidative stress-targeting capabilities. This review fills the blank of a comprehensive outline over current progress in applying nanotechnology to treat AKI, providing potential insights for further research.
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Affiliation(s)
- Liwen Li
- Department of Ultrasound in MedicineShanghai Jiao Tong University School of Medicine Affiliated Sixth People's HospitalShanghaiPeople's Republic of China
| | - Yining Shen
- Department of Ultrasound in MedicineShanghai Jiao Tong University School of Medicine Affiliated Sixth People's HospitalShanghaiPeople's Republic of China
| | - Zhongmin Tang
- Departments of Radiology and Medical PhysicsUniversity of Wisconsin‐MadisonWisconsinUSA
| | - Yuwen Yang
- Department of Ultrasound in MedicineShanghai Jiao Tong University School of Medicine Affiliated Sixth People's HospitalShanghaiPeople's Republic of China
| | - Zi Fu
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Dalong Ni
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Xiaojun Cai
- Department of Ultrasound in MedicineShanghai Jiao Tong University School of Medicine Affiliated Sixth People's HospitalShanghaiPeople's Republic of China
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Yang S, Jiang K, Li L, Xiang J, Li Y, Kang L, Yang G, Liang Z. MircroRNA-92b as a negative regulator of the TGF-β signaling by targeting the type I receptor. iScience 2023; 26:108131. [PMID: 37867958 PMCID: PMC10587525 DOI: 10.1016/j.isci.2023.108131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/30/2023] [Indexed: 10/24/2023] Open
Abstract
Transforming growth factor β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of chronic kidney disease (CKD). This study investigated the role of miR-92b-3p in the progression of renal fibrosis in unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (uIRI) mouse models, as well as explored its underlying mechanisms in human proximal tubular epithelial (HK2) cells. We found that renal fibrosis increased in UUO mice after miR-92b knockout, while it reduced in miR-92b overexpressing mice. MiR-92b knockout aggravated renal fibrosis in uIRI mice. RNA-sequencing analysis, the luciferase reporter assay, qPCR analysis, and western blotting confirmed that miR-92b-3p directly targeted TGF-β receptor 1, thereby ameliorating renal fibrosis by suppressing the TGF-β signaling pathway. Furthermore, we found that TGF-β suppressed miR-92b transcription through Snail family transcriptional repressors 1 and 2. Our results suggest that miR-92b-3p may serve as a novel therapeutic for mitigating fibrosis in CKD.
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Affiliation(s)
- Shu Yang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Kewei Jiang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Lixing Li
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Jiaqing Xiang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Yanchun Li
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Lin Kang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
- The Biobank of National Innovation Center for Advanced Medical Devices, Shenzhen People’s Hospital, Shenzhen 518000, China
| | - Guangyan Yang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
| | - Zhen Liang
- Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
- Guangdong Provincial Clinical Research Center for Geriatrics，Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518000 China
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10
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Ewees MGED, Orfali R, Rateb EE, Hassan HM, Hozzein WN, Alkhalfah DHM, Sree HTA, Abdel Rahman FEZS, Rateb ME, Mahmoud NI. Modulation of mi-RNA25/Ox-LDL/NOX4 signaling pathway by polyphenolic compound Hydroxytyrosol as a new avenue to alleviate cisplatin-induced acute kidney injury, a mechanistic study in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 103:104262. [PMID: 37699441 DOI: 10.1016/j.etap.2023.104262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/16/2023] [Accepted: 09/06/2023] [Indexed: 09/14/2023]
Abstract
Acute kidney injury (AKI) caused by Cis is considered one of the most severe adverse effects, which restricts its use and efficacy. This study seeks to examine the potential reno-protective impact of phenolic compound Hydroxytyrosol (HT) against Cis-induced AKI and the possible involvement of the mi-RNA25/Ox-LDL/NOX4 pathway elucidating the probable implicated molecular mechanisms. Forty rats were placed into 5 groups. Group I received saline only. Group II received Cis only. Group III, IV, and V received 20, 50, and 100 mg/kg b.w, of HT, respectively, with Cis delivery. NOX4, Ox-LDL, and gene expression of mi-RNA 25, TNF-α, and HO-1 in renal tissue were detected. HT showed reno-protective effect and significantly upregulated mi-RNA 25 and HO-1 as well as decreased the expression of NOX4, Ox-LDL, and TNF-α. In conclusion, HT may be promising in the fight against Cis-induced AKI through modulation of mi-RNA25/Ox-LDL/NOX4 pathway.
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Affiliation(s)
- Mohamed Gamal El-Din Ewees
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 11787, Egypt.
| | - Raha Orfali
- Department of Pharmacognosy, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
| | - Enas Ezzat Rateb
- Department of Physiology, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt.
| | - Hossam M Hassan
- Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, Beni-Suef 11787, Egypt.
| | - Wael N Hozzein
- Botany and Microbiology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
| | - Dalal Hussien M Alkhalfah
- Department of Biology. College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
| | - Haidy Tamer Abo Sree
- Department of Basic Sciences Department, Biochemistry, Faculty of Oral and Dental Medicine, Nahda University, Beni-Suef 11787, Egypt.
| | - Fatema El-Zahraa S Abdel Rahman
- Department of Basic Sciences Department, Physiology, Faculty of Oral and Dental Medicine, Nahda University, Beni-Suef 11787, Egypt.
| | - Mostafa E Rateb
- School of Computing, Engineering & Physical Sciences, University of the West of Scotland, Paisley PA1 2BE, UK.
| | - Nesreen Ishak Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 11787, Egypt.
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11
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Lee YC, Chiou JT, Wang LJ, Chen YJ, Chang LS. Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway. Toxicol Appl Pharmacol 2023; 474:116625. [PMID: 37451322 DOI: 10.1016/j.taap.2023.116625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Accumulating evidence indicates that the anticancer activity of acridine derivatives is mediated through the regulation of anti-apoptotic and pro-apoptotic BCL2 protein expression. Therefore, we investigated whether the cytotoxicity of amsacrine with an acridine structural scaffold in human chronic myeloid leukemia (CML) K562 cells was mediated by BCL2 family proteins. Amsacrine induced apoptosis, mitochondrial depolarization, and BCL2L1 (also known as BCL-XL) downregulation in K562 cells. BCL2L1 overexpression inhibited amsacrine-induced cell death and mitochondrial depolarization. Amsacrine treatment triggered SIDT2-mediated miR-25 downregulation, leading to increased NOX4-mediated ROS production. ROS-mediated inactivation of ERK triggered miR-22 expression, leading to increased HuR mRNA decay. As HuR is involved in stabilizing BCL2L1 mRNA, downregulation of BCL2L1 was noted in K562 cells after amsacrine treatment. In contrast, amsacrine-induced BCL2L1 downregulation was alleviated by restoring ERK phosphorylation and HuR expression. Altogether, the results of this study suggest that amsacrine triggers apoptosis in K562 cells by inhibiting BCL2L1 expression through the SIDT2/NOX4/ERK-mediated downregulation of HuR. Furthermore, a similar pathway also explains the cytotoxicity of amsacrine in CML MEG-01 and KU812 cells.
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Affiliation(s)
- Yuan-Chin Lee
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Jing-Ting Chiou
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Liang-Jun Wang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Ying-Jung Chen
- Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Long-Sen Chang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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12
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Barreiro K, Dwivedi OP, Rannikko A, Holthöfer H, Tuomi T, Groop PH, Puhka M. Capturing the Kidney Transcriptome by Urinary Extracellular Vesicles-From Pre-Analytical Obstacles to Biomarker Research. Genes (Basel) 2023; 14:1415. [PMID: 37510317 PMCID: PMC10379145 DOI: 10.3390/genes14071415] [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: 05/26/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Urinary extracellular vesicles (uEV) hold non-invasive RNA biomarkers for genitourinary tract diseases. However, missing knowledge about reference genes and effects of preanalytical choices hinder biomarker studies. We aimed to assess how preanalytical variables (urine storage temperature, isolation workflow) affect diabetic kidney disease (DKD)-linked miRNAs or kidney-linked miRNAs and mRNAs (kidney-RNAs) in uEV isolates and to discover stable reference mRNAs across diverse uEV datasets. We studied nine raw and normalized sequencing datasets including healthy controls and individuals with prostate cancer or type 1 diabetes with or without albuminuria. We focused on kidney-RNAs reviewing literature for DKD-linked miRNAs from kidney tissue, cell culture and uEV/urine experiments. RNAs were analyzed by expression heatmaps, hierarchical clustering and selecting stable mRNAs with normalized counts (>200) and minimal coefficient of variation. Kidney-RNAs were decreased after urine storage at -20 °C vs. -80 °C. Isolation workflows captured kidney-RNAs with different efficiencies. Ultracentrifugation captured DKD -linked miRNAs that separated healthy and diabetic macroalbuminuria groups. Eleven mRNAs were stably expressed across the datasets. Hence, pre-analytical choices had variable effects on kidney-RNAs-analyzing kidney-RNAs complemented global correlation, which could fade differences in some relevant RNAs. Replicating prior DKD-marker results and discovery of candidate reference mRNAs encourages further uEV biomarker studies.
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Affiliation(s)
- Karina Barreiro
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, 00290 Helsinki, Finland
- Institute for Molecular Medicine Finland FIMM, EV and HiPREP Core, University of Helsinki, 00290 Helsinki, Finland
| | - Om Prakash Dwivedi
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, 00290 Helsinki, Finland
| | - Antti Rannikko
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
- Department of Urology, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland
| | - Harry Holthöfer
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, 00290 Helsinki, Finland
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tiinamaija Tuomi
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, 00290 Helsinki, Finland
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 214 28 Malmö, Sweden
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland
- Endocrinology, Abdominal Centre, Helsinki University Hospital, 00029 Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland
- Department of Nephrology, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3800, Australia
| | - Maija Puhka
- Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, 00290 Helsinki, Finland
- Institute for Molecular Medicine Finland FIMM, EV and HiPREP Core, University of Helsinki, 00290 Helsinki, Finland
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13
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Saikia BJ, Bhardwaj J, Paul S, Sharma S, Neog A, Paul SR, Binukumar BK. Understanding the Roles and Regulation of Mitochondrial microRNAs (MitomiRs) in Neurodegenerative Diseases: Current Status and Advances. Mech Ageing Dev 2023:111838. [PMID: 37329989 DOI: 10.1016/j.mad.2023.111838] [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: 12/27/2022] [Revised: 06/13/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21 - 22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.
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Affiliation(s)
- Bhaskar Jyoti Saikia
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Juhi Bhardwaj
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sangita Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Srishti Sharma
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Anindita Neog
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - Swaraj Ranjan Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - B K Binukumar
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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14
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Wang D, Li J, Luo G, Zhou J, Wang N, Wang S, Zhao R, Cao X, Ma Y, Liu G, Hao L. Nox4 as a novel therapeutic target for diabetic vascular complications. Redox Biol 2023; 64:102781. [PMID: 37321060 PMCID: PMC10363438 DOI: 10.1016/j.redox.2023.102781] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/03/2023] [Accepted: 06/08/2023] [Indexed: 06/17/2023] Open
Abstract
Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.
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Affiliation(s)
- Dongxia Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China; Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Jiaying Li
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Luo
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Juan Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Ning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Shanshan Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Rui Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Xin Cao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Yuxia Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang, 050000, China.
| | - Liping Hao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China.
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15
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Szostak J, Gorący A, Durys D, Dec P, Modrzejewski A, Pawlik A. The Role of MicroRNA in the Pathogenesis of Diabetic Nephropathy. Int J Mol Sci 2023; 24:ijms24076214. [PMID: 37047185 PMCID: PMC10094215 DOI: 10.3390/ijms24076214] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Diabetic nephropathy is one of the most common and severe complications of diabetes mellitus, affecting one in every five patients suffering from diabetes. Despite extensive research, the exact pathogenesis of diabetic nephropathy is still unclear. Several factors and pathways are known to be involved in the development of the disease, such as reactive oxygen species or the activation of the renin–angiotensin–aldosterone system. The expression of those proteins might be extensively regulated by microRNA. Recent research suggests that in diabetic nephropathy patients, the profile of miRNA is significantly changed. In this review, we focus on the actions of miRNA in various pathways involved in the pathogenesis of diabetic nephropathy and the clinical usage of miRNAs as biomarkers and therapeutic targets.
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Affiliation(s)
- Joanna Szostak
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Anna Gorący
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Damian Durys
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Paweł Dec
- Plastic and Reconstructive Surgery Department, 109 Military Hospital, 71-422 Szczecin, Poland
| | | | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
- Correspondence:
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16
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Su QS, Zhuang DL, Nasser MI, Sai X, Deng G, Li G, Zhu P. Stem Cell Therapies for Restorative Treatments of Central Nervous System Ischemia-Reperfusion Injury. Cell Mol Neurobiol 2023; 43:491-510. [PMID: 35129759 PMCID: PMC11415191 DOI: 10.1007/s10571-022-01204-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 02/01/2022] [Indexed: 11/27/2022]
Abstract
Ischemic damage to the central nervous system (CNS) is a catastrophic postoperative complication of aortic occlusion subsequent to cardiovascular surgery that can cause brain impairment and sometimes even paraplegia. Over recent years, numerous studies have investigated techniques for protecting and revascularizing the nervous system during intraoperative ischemia; however, owing to a lack of knowledge of the physiological distinctions between the brain and spinal cord, as well as the limited availability of testing techniques and treatments for ischemia-reperfusion injury, the cause of brain and spinal cord ischemia-reperfusion injury remains poorly understood, and no adequate response steps are currently available in the clinic. Given the limited ability of the CNS to repair itself, it is of great clinical value to make full use of the proliferative and differentiation potential of stem cells to repair nerves in degenerated and necrotic regions by stem cell transplantation or mobilization, thereby introducing a novel concept for the treatment of severe CNS ischemia-reperfusion injury. This review summarizes the most recent advances in stem cell therapy for ischemia-reperfusion injury in the brain and spinal cord, aiming to advance basic research and the clinical use of stem cell therapy as a promising treatment for this condition.
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Affiliation(s)
- Qi-Song Su
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China
| | - Dong-Lin Zhuang
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China
| | - Moussa Ide Nasser
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
| | - Xiyalatu Sai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China
| | - Gang Deng
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Ge Li
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
| | - Ping Zhu
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China.
- Guangdong Provincial Key Laboratory of Structural Heart Disease, Guangzhou, 510100, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China.
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17
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Urinary microRNA in Diabetic Kidney Disease: A Literature Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59020354. [PMID: 36837555 PMCID: PMC9962090 DOI: 10.3390/medicina59020354] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/31/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023]
Abstract
Diabetic kidney disease is the most common primary disease of end-stage kidney disease globally; however, a sensitive and accurate biomarker to predict this disease remains awaited. microRNAs are endogenous single-stranded noncoding RNAs that have intervened in different post-transcriptional regulations of various cellular biological functions. Previous literatures have reported its potential role in the pathophysiology of diabetic kidney disease, including regulation of Transforming Growth Factor-β1-mediated fibrosis, extracellular matrix and cell adhesion proteins, cellular hypertrophy, growth factor, cytokine production, and redox system activation. Urinary microRNAs have emerged as a novel, non-invasive liquid biopsy for disease diagnosis. In this review, we describe the available experimental and clinical evidence of urinary microRNA in the context of diabetic kidney disease and discuss the future application of microRNA in routine practice.
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18
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Pediatric Diabetic Nephropathy: Novel Insights from microRNAs. J Clin Med 2023; 12:jcm12041447. [PMID: 36835983 PMCID: PMC9961327 DOI: 10.3390/jcm12041447] [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: 12/30/2022] [Revised: 02/05/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Diabetic nephropathy (DN) represents the most common microvascular complication in patients with diabetes. This progressive kidney disease has been recognized as the major cause of end-stage renal disease with higher morbidity and mortality. However, its tangled pathophysiology is still not fully known. Due to the serious health burden of DN, novel potential biomarkers have been proposed to improve early identification of the disease. In this complex landscape, several lines of evidence supported a critical role of microRNAs (miRNAs) in regulating posttranscriptional levels of protein-coding genes involved in DN pathophysiology. Indeed, intriguing data showed that deregulation of certain miRNAs (e.g., miRNAs 21, -25, -92, -210, -126, -216, and -377) were pathogenically linked to the onset and the progression of DN, suggesting not only a role as early biomarkers but also as potential therapeutic targets. To date, these regulatory biomolecules represent the most promising diagnostic and therapeutic options for DN in adult patients, while similar pediatric evidence is still limited. More, findings from these elegant studies, although promising, need to be deeper investigated in larger validation studies. In an attempt to provide a comprehensive pediatric overview in the field, we aimed to summarize the most recent evidence on the emerging role of miRNAs in pediatric DN pathophysiology.
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Dauth A, Bręborowicz A, Ruan Y, Tang Q, Zadeh JK, Böhm EW, Pfeiffer N, Khedkar PH, Patzak A, Vujacic-Mirski K, Daiber A, Gericke A. Sulodexide Prevents Hyperglycemia-Induced Endothelial Dysfunction and Oxidative Stress in Porcine Retinal Arterioles. Antioxidants (Basel) 2023; 12:antiox12020388. [PMID: 36829947 PMCID: PMC9952154 DOI: 10.3390/antiox12020388] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/27/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated with highly concentrated glucose solution (HG, 25 mM D-glucose) +/- sulodexide (50/5/0.5 μg/mL) or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/- sulodexide for two hours. Endothelium-dependent and endothelium-independent vasodilatation were measured by videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory, inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent responses were not affected. In the HG group, ROS formation was markedly increased in the vascular wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction. Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia-induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression.
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Affiliation(s)
- Alice Dauth
- Department of Neurosurgery, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
- Correspondence:
| | - Andrzej Bręborowicz
- Department of Pathophysiology, Poznań University of Medical Sciences, 60-512 Poznań, Poland
| | - Yue Ruan
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Qi Tang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Jenia K. Zadeh
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
- AbbVie Germany GmbH & Co. KG, 65189 Wiesbaden, Germany
| | - Elsa W. Böhm
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Pratik H. Khedkar
- Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Andreas Patzak
- Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Ksenija Vujacic-Mirski
- Department of Cardiology, Cardiology 1, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Cardiology 1, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
- Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), 55131 Mainz, Germany
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
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20
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Pecchillo Cimmino T, Ammendola R, Cattaneo F, Esposito G. NOX Dependent ROS Generation and Cell Metabolism. Int J Mol Sci 2023; 24:ijms24032086. [PMID: 36768405 PMCID: PMC9916913 DOI: 10.3390/ijms24032086] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023] Open
Abstract
Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, the superoxide anion radical (O2·-) is a key redox signaling molecule prominently generated by the NADPH oxidase (NOX) enzyme family and by the mitochondrial electron transport chain. Notably, altered redox balance and deregulated redox signaling are recognized hallmarks of cancer and are involved in malignant progression and resistance to drugs treatment. Since oxidative stress and metabolism of cancer cells are strictly intertwined, in this review, we focus on the emerging roles of NOX enzymes as important modulators of metabolic reprogramming in cancer. The NOX family includes seven isoforms with different activation mechanisms, widely expressed in several tissues. In particular, we dissect the contribute of NOX1, NOX2, and NOX4 enzymes in the modulation of cellular metabolism and highlight their potential role as a new therapeutic target for tumor metabolism rewiring.
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Affiliation(s)
- Tiziana Pecchillo Cimmino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Rosario Ammendola
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Fabio Cattaneo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
- Correspondence: (F.C.); (G.E.)
| | - Gabriella Esposito
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore S.c.a.r.l., 80131 Naples, Italy
- Correspondence: (F.C.); (G.E.)
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21
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Wallace SR, Pagano PJ, Kračun D. MicroRNAs in the Regulation of NADPH Oxidases in Vascular Diabetic and Ischemic Pathologies: A Case for Alternate Inhibitory Strategies? Antioxidants (Basel) 2022; 12:70. [PMID: 36670932 PMCID: PMC9854786 DOI: 10.3390/antiox12010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/24/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022] Open
Abstract
Since their discovery in the vasculature, different NADPH oxidase (NOX) isoforms have been associated with numerous complex vascular processes such as endothelial dysfunction, vascular inflammation, arterial remodeling, and dyslipidemia. In turn, these often underlie cardiovascular and metabolic pathologies including diabetes mellitus type II, cardiomyopathy, systemic and pulmonary hypertension and atherosclerosis. Increasing attention has been directed toward miRNA involvement in type II diabetes mellitus and its cardiovascular and metabolic co-morbidities in the search for predictive and stratifying biomarkers and therapeutic targets. Owing to the challenges of generating isoform-selective NOX inhibitors (NOXi), the development of specific NOXis suitable for therapeutic purposes has been hindered. In that vein, differential regulation of specific NOX isoforms by a particular miRNA or combina-tion thereof could at some point become a reasonable approach for therapeutic targeting under some circumstances. Whereas administration of miRNAs chronically, or even acutely, to patients poses its own set of difficulties, miRNA-mediated regulation of NOXs in the vasculature is worth surveying. In this review, a distinct focus on the role of miRNAs in the regulation of NOXs was made in the context of type II diabetes mellitus and ischemic injury models.
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Affiliation(s)
- Sean R. Wallace
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Patrick J. Pagano
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Damir Kračun
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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22
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Mortazavi-Jahromi SS, Aslani M. Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation. Int Immunopharmacol 2022; 110:109040. [PMID: 35839566 PMCID: PMC9271492 DOI: 10.1016/j.intimp.2022.109040] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022]
Abstract
Known as a pivotal immunohemostatic response, immunothrombosis is activated to restrict the diffusion of pathogens. This beneficial intravascular defensive mechanism represents the close interaction between the immune and coagulation systems. However, its uncontrolled form can be life-threatening to patients with the critical coronavirus disease 2019 (COVID-19). Hyperinflammation and ensuing cytokine storm underlie the activation of the coagulation system, something which results in the provocation of more immune-inflammatory responses by the thrombotic mediators. This vicious cycle causes grave clinical complications and higher risks of mortality. Classified as an evolutionarily conserved family of the small non-coding RNAs, microRNAs (miRNAs) serve as the fine-tuners of genes expression and play a key role in balancing the pro/anticoagulant and pro-/anti-inflammatory factors maintaining homeostasis. Therefore, any deviation from their optimal expression levels or efficient functions can lead to severe complications. Despite their extensive effects on the molecules and processes involved in uncontrolled immunothrombosis, some genetic agents and uncontrolled immunothrombosis-induced interfering factors (e.g., miRNA-single nucleotide polymorphysms (miR-SNPs), the complement system components, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and reactive oxygen species (ROS)) have apparently disrupted their expressions/functions. This review study aims to give an overview of the role of miRNAs in the context of uncontrolled immunothrombosis/thromboinflammation accompanied by some presumptive interfering factors affecting their expressions/functions in the critical COVID-19. Detecting, monitoring, and resolving these interfering agents mafy facilitate the design and development of the novel miRNAs-based therapeutic approaches to the reduction of complications incidence and mortality in patients with the critical COVID-19.
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Affiliation(s)
- Seyed Shahabeddin Mortazavi-Jahromi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Department of Cellular and Molecular Biology, Kish International Campus, University of Tehran, Kish, Iran.
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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23
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Carboxyl Group-Modified Myoglobin Induces TNF-α-Mediated Apoptosis in Leukemia Cells. Pharmaceuticals (Basel) 2022; 15:ph15091066. [PMID: 36145287 PMCID: PMC9501283 DOI: 10.3390/ph15091066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Previous studies have shown that chemical modification may increase the activity of proteins or confer novel activity to proteins. Some studies have indicated that myoglobin (Mb) is cytotoxic; however, the underlying mechanisms remain unclear. In this study, we investigated whether chemical modification of the carboxyl group by semicarbazide could promote the Mb cytotoxicity in human leukemia U937 cells and the underlying mechanism of semicarbazide-modified myoglobin (SEM-Mb)-induced U937 cell death. The semicarbazide-modified Mb (SEM-Mb) induced U937 cell apoptosis via the production of cleaved caspase-8 and t-Bid, while silencing of FADD abolished this effect. These findings suggest that SEM-Mb can induce U937 cell death by activating the death receptor-mediated pathway. The SEM-Mb inhibited miR-99a expression, leading to increased NOX4 mRNA and protein expression, which promoted SIRT3 degradation, and, in turn, induced ROS-mediated p38 MAPK phosphorylation. Activated p38 MAPK stimulated miR-29a-dependent tristetraprolin (TTP) mRNA decay. Downregulation of TTP slowed TNF-α mRNA turnover, thereby increasing TNF-α protein expression. The SEM-Mb-induced decrease in cell viability and TNF-α upregulation were alleviated by abrogating the NOX4/SIRT3/ROS/p38 MAPK axis or ectopic expression of TTP. Taken together, our results demonstrated that the NOX4/SIRT3/p38 MAPK/TTP axis induces TNF-α-mediated apoptosis in U937 cells following SEM-Mb treatment. A pathway regulating p38 MAPK-mediated TNF-α expression also explains the cytotoxicity of SEM-Mb in the human leukemia cell lines HL-60, THP-1, K562, Jurkat, and ABT-199-resistant U937. Furthermore, these findings suggest that the carboxyl group-modified Mb is a potential structural template for the generation of tumoricidal proteins.
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24
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Cung T, Wang H, Hartnett ME. The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity. Cells 2022; 11:cells11121951. [PMID: 35741081 PMCID: PMC9222209 DOI: 10.3390/cells11121951] [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: 05/17/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 01/27/2023] Open
Abstract
Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.
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25
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The Role of Epigenetic Modifications in Late Complications in Type 1 Diabetes. Genes (Basel) 2022; 13:genes13040705. [PMID: 35456511 PMCID: PMC9029845 DOI: 10.3390/genes13040705] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022] Open
Abstract
Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late complications. These include diabetic retinopathy, chronic renal failure, diabetic neuropathy, and cardiovascular diseases. The impact of long-term hyperglycemia has been shown to persist long after the normalization of blood glucose levels, a phenomenon known as metabolic memory. It is believed that epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs, play an important role in metabolic memory. The aim of this review is to address the impact of long-term hyperglycemia on epigenetic marks in late complications of type 1 diabetes.
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26
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Wonnacott A, Denby L, Coward RJM, Fraser DJ, Bowen T. MicroRNAs and their delivery in diabetic fibrosis. Adv Drug Deliv Rev 2022; 182:114045. [PMID: 34767865 DOI: 10.1016/j.addr.2021.114045] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/21/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022]
Abstract
The global prevalence of diabetes mellitus was estimated to be 463 million people in 2019 and is predicted to rise to 700 million by 2045. The associated financial and societal costs of this burgeoning epidemic demand an understanding of the pathology of this disease, and its complications, that will inform treatment to enable improved patient outcomes. Nearly two decades after the sequencing of the human genome, the significance of noncoding RNA expression is still being assessed. The family of functional noncoding RNAs known as microRNAs regulates the expression of most genes encoded by the human genome. Altered microRNA expression profiles have been observed both in diabetes and in diabetic complications. These transcripts therefore have significant potential and novelty as targets for therapy, therapeutic agents and biomarkers.
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Affiliation(s)
- Alexa Wonnacott
- Wales Kidney Research Unit, Division of Infection & Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Laura Denby
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Richard J M Coward
- Bristol Renal, Dorothy Hodgkin Building, Bristol Medical School, University of Bristol, Bristol BS1 3NY, UK
| | - Donald J Fraser
- Wales Kidney Research Unit, Division of Infection & Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Timothy Bowen
- Wales Kidney Research Unit, Division of Infection & Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
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27
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Aparicio-Trejo OE, Aranda-Rivera AK, Osorio-Alonso H, Martínez-Klimova E, Sánchez-Lozada LG, Pedraza-Chaverri J, Tapia E. Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease. Antioxidants (Basel) 2022; 11:antiox11020356. [PMID: 35204238 PMCID: PMC8868440 DOI: 10.3390/antiox11020356] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/26/2022] [Accepted: 02/03/2022] [Indexed: 12/17/2022] Open
Abstract
Chronic kidney disease (CKD) is a world health problem increasing dramatically. The onset of CKD is driven by several mechanisms; among them, metabolic reprogramming and changes in redox signaling play critical roles in the advancement of inflammation and the subsequent fibrosis, common pathologies observed in all forms of CKD. Extracellular vesicles (EVs) are cell-derived membrane packages strongly associated with cell-cell communication since they transfer several biomolecules that serve as mediators in redox signaling and metabolic reprogramming in the recipient cells. Recent studies suggest that EVs, especially exosomes, the smallest subtype of EVs, play a fundamental role in spreading renal injury in CKD. Therefore, this review summarizes the current information about EVs and their cargos’ participation in metabolic reprogramming and mitochondrial impairment in CKD and their role in redox signaling changes. Finally, we analyze the effects of these EV-induced changes in the amplification of inflammatory and fibrotic processes in the progression of CKD. Furthermore, the data suggest that the identification of the signaling pathways involved in the release of EVs and their cargo under pathological renal conditions can allow the identification of new possible targets of injury spread, with the goal of preventing CKD progression.
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Affiliation(s)
- Omar Emiliano Aparicio-Trejo
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
| | - Ana Karina Aranda-Rivera
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Horacio Osorio-Alonso
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
| | - Elena Martínez-Klimova
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Laura Gabriela Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
| | - José Pedraza-Chaverri
- Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Edilia Tapia
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
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28
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Wang LJ, Chiou JT, Lee YC, Chang LS. Docetaxel-triggered SIDT2/NOX4/JNK/HuR signaling axis is associated with TNF-α-mediated apoptosis of cancer cells. Biochem Pharmacol 2021; 195:114865. [PMID: 34863979 DOI: 10.1016/j.bcp.2021.114865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/29/2021] [Accepted: 11/29/2021] [Indexed: 11/15/2022]
Abstract
Previous studies have confirmed that docetaxel (DTX) treatment increases TNF-α production in cancer cells, but its mechanism of action remains unclear. Therefore, this study aimed to determine the signaling axis by which DTX induced the expression of TNF-α in U937 leukemia and MCF-7 breast carcinoma cells. DTX treatment promoted Ca2+-controlled autophagy and SIDT2 expression, resulting in lysosomal degradation of miR-25 in U937 cells. Downregulation of miR-25 increased NOX4 mRNA stability and protein expression. NOX4-stimulated ROS generation led to JNK-mediated phosphorylation of cytosolic HuR at Ser221, thereby increasing TNF-α protein expression by stabilizing TNF-α mRNA. Consequently, DTX induced TNF-α-dependent death in U937 cells. Depletion of HuR using siRNA or abolishment of JNK activation reduced TNF-α expression and eliminated DTX-mediated cytotoxicity. Knockdown of SIDT2 or pretreatment with chloroquine (a lysosome inhibitor) reduced DTX-induced NOX4 and TNF-α expression and mitigated JNK-mediated HuR phosphorylation. Altogether, our data indicate that DTX triggers HuR-mediated TNF-α mRNA stabilization through the Ca2+/SIDT2/NOX4/ROS/JNK axis, thereby inducing TNF-α-dependent apoptosis in U937 cells. In addition, DTX induces apoptosis in MCF-7 cells through SIDT2/NOX4/JNK/HuR axis-mediated TNF-α expression.
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Affiliation(s)
- Liang-Jun Wang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Jing-Ting Chiou
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Yuan-Chin Lee
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Long-Sen Chang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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29
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Viswambharan H, Yuldasheva NY, Imrie H, Bridge K, Haywood NJ, Skromna A, Hemmings KE, Clark ER, Gatenby VK, Cordell P, Simmons KJ, Makava N, Abudushalamu Y, Endesh N, Brown J, Walker AMN, Futers ST, Porter KE, Cubbon RM, Naseem K, Shah AM, Beech DJ, Wheatcroft SB, Kearney MT, Sukumar P. Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat. Circ Res 2021; 129:720-734. [PMID: 34420367 PMCID: PMC8448413 DOI: 10.1161/circresaha.121.319517] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Hema Viswambharan
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Nadira Y Yuldasheva
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Helen Imrie
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Katherine Bridge
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Natalie J Haywood
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Anna Skromna
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Karen E Hemmings
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Emily R Clark
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - V Kate Gatenby
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Paul Cordell
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Katie J Simmons
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Natallia Makava
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Yilizila Abudushalamu
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Naima Endesh
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Jane Brown
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Andrew M N Walker
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Simon T Futers
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Karen E Porter
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Richard M Cubbon
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Khalid Naseem
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Ajay M Shah
- British Heart Foundation Centre of Research Excellence, King's College London (A.M.S.)
| | - David J Beech
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Stephen B Wheatcroft
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Mark T Kearney
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
| | - Piruthivi Sukumar
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.)
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Brown OI, Bridge KI, Kearney MT. Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction. Cells 2021; 10:cells10092315. [PMID: 34571964 PMCID: PMC8469180 DOI: 10.3390/cells10092315] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress within the vascular endothelium, due to excess generation of reactive oxygen species (ROS), is thought to be fundamental to the initiation and progression of the cardiovascular complications of type 2 diabetes mellitus. The term ROS encompasses a variety of chemical species including superoxide anion (O2•-), hydroxyl radical (OH-) and hydrogen peroxide (H2O2). While constitutive generation of low concentrations of ROS are indispensable for normal cellular function, excess O2•- can result in irreversible tissue damage. Excess ROS generation is catalysed by xanthine oxidase, uncoupled nitric oxide synthases, the mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Amongst enzymatic sources of O2•- the Nox2 isoform of NADPH oxidase is thought to be critical to the oxidative stress found in type 2 diabetes mellitus. In contrast, the transcriptionally regulated Nox4 isoform, which generates H2O2, may fulfil a protective role and contribute to normal glucose homeostasis. This review describes the key roles of Nox2 and Nox4, as well as Nox1 and Nox5, in glucose homeostasis, endothelial function and oxidative stress, with a key focus on how they are regulated in health, and dysregulated in type 2 diabetes mellitus.
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Su Z, Ren N, Ling Z, Sheng L, Zhou S, Guo C, Ke Z, Xu T, Qin Z. Differential expression of microRNAs associated with neurodegenerative diseases and diabetic nephropathy in protein l-isoaspartyl methyltransferase-deficient mice. Cell Biol Int 2021; 45:2316-2330. [PMID: 34314072 DOI: 10.1002/cbin.11679] [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: 04/10/2021] [Revised: 07/15/2021] [Accepted: 07/24/2021] [Indexed: 11/05/2022]
Abstract
Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), an enzyme repairing isoaspartate residues in peptides and proteins that result from the spontaneous decomposition of normal l-aspartyl and l-asparaginyl residues during aging, has been revealed to be involved in neurodegenerative diseases (NDDs) and diabetes. However, the molecular mechanisms for a putative association of PIMT dysfunction with these diseases have not been clarified. Our study aimed to identify differentially expressed microRNAs (miRNAs) in the brain and kidneys of PIMT-deficient mice and uncover the epigenetic mechanism of PIMT-involved NDDs and diabetic nephropathy (DN). Differentially expressed miRNAs by sequencing underwent target prediction and enrichment analysis in the brain and kidney of PIMT knockout (KO) mice and age-matched wild-type (WT) littermates. Sequence analysis revealed 40 differentially expressed miRNAs in the PIMT KO mouse brain including 25 upregulated miRNAs and 15 downregulated miRNAs. In the PIMT KO mouse kidney, there were 80 differentially expressed miRNAs including 40 upregulated miRNAs and 40 downregulated miRNAs. Enrichment analysis and a systematic literature review of differentially expressed miRNAs indicated the involvement of PIMT deficiency in the pathogenesis in NDDs and DN. Some overlapped differentially expressed miRNAs between the brain and kidney were quantitatively assessed in the brain, kidney, and serum-derived exosomes, respectively. Despite being preliminary, these results may aid in investigating the pathological hallmarks and identify the potential therapeutic targets and biomarkers for PIMT dysfunction-related NDDs and DN.
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Affiliation(s)
- Zhonghao Su
- Department of Febrile Disease, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Na Ren
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zicheng Ling
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lanyue Sheng
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Sirui Zhou
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunxia Guo
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zunji Ke
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tiefeng Xu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenxia Qin
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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He X, Kuang G, Zuo Y, Li S, Zhou S, Ou C. The Role of Non-coding RNAs in Diabetic Nephropathy-Related Oxidative Stress. Front Med (Lausanne) 2021; 8:626423. [PMID: 33959621 PMCID: PMC8093385 DOI: 10.3389/fmed.2021.626423] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/25/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the main complications of diabetes and the main cause of diabetic end-stage renal disease, which is often fatal. DN is usually characterized by progressive renal interstitial fibrosis, which is closely related to the excessive accumulation of extracellular matrix and oxidative stress. Non-coding RNAs (ncRNAs) are RNA molecules expressed in eukaryotic cells that are not translated into proteins. They are widely involved in the regulation of biological processes, such as, chromatin remodeling, transcription, post-transcriptional modification, and signal transduction. Recent studies have shown that ncRNAs play an important role in the occurrence and development of DN and participate in the regulation of oxidative stress in DN. This review clarifies the functions and mechanisms of ncRNAs in DN-related oxidative stress, providing valuable insights into the prevention, early diagnosis, and molecular therapeutic targets of DN.
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Affiliation(s)
- Xiaoyun He
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Gaoyan Kuang
- Department of Orthopedics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yi Zuo
- Department of Endocrinology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Shuangxi Li
- Department of Pathophysiology, Hunan University of Medicine, Huaihua, China
| | - Suxian Zhou
- Department of Endocrinology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Chunlin Ou
- Department of Pathology, 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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Chang J, Yan J, Li X, Liu N, Zheng R, Zhong Y. Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:661076. [PMID: 33859992 PMCID: PMC8042139 DOI: 10.3389/fmed.2021.661076] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.
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Affiliation(s)
- Jingsheng Chang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiayi Yan
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xueling Li
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ni Liu
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Zheng
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Zhong
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zhou Y, Yang J. Implications of microRNA in kidney metabolic disorders. EXRNA 2020; 2:4. [DOI: 10.1186/s41544-019-0042-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/31/2019] [Indexed: 05/11/2025]
Abstract
AbstractThe kidney requires large amount of energy to regulate the balance of fluid, electrolytes and acid-base homeostasis. Mitochondria provide indispensible energy to drive these functions. Diverse energy sources such as fatty acid and glucose are fueled for ATP production at different renal sites controlled by a fine-tuned regulation mechanism. microRNAs (miRNAs) have been implicated in the pathogenesis of various kidney diseases. Recent studies have highlighted their contributions to metabolic abnormalities. Characterization of the miRNAs in renal metabolic disorders may promote a better understanding of the molecular mechanism of these diseases and potentially serve as therapeutic targets.
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Włodarski A, Strycharz J, Wróblewski A, Kasznicki J, Drzewoski J, Śliwińska A. The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress. Int J Mol Sci 2020; 21:ijms21186902. [PMID: 32962281 PMCID: PMC7555602 DOI: 10.3390/ijms21186902] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress (OxS) is the cause and the consequence of metabolic syndrome (MetS), the incidence and economic burden of which is increasing each year. OxS triggers the dysregulation of signaling pathways associated with metabolism and epigenetics, including microRNAs, which are biomarkers of metabolic disorders. In this review, we aimed to summarize the current knowledge regarding the interplay between microRNAs and OxS in MetS and its components. We searched PubMed and Google Scholar to summarize the most relevant studies. Collected data suggested that different sources of OxS (e.g., hyperglycemia, insulin resistance (IR), hyperlipidemia, obesity, proinflammatory cytokines) change the expression of numerous microRNAs in organs involved in the regulation of glucose and lipid metabolism and endothelium. Dysregulated microRNAs either directly or indirectly affect the expression and/or activity of molecules of antioxidative signaling pathways (SIRT1, FOXOs, Keap1/Nrf2) along with effector enzymes (e.g., GPx-1, SOD1/2, HO-1), ROS producers (e.g., NOX4/5), as well as genes of numerous signaling pathways connected with inflammation, insulin sensitivity, and lipid metabolism, thus promoting the progression of metabolic imbalance. MicroRNAs appear to be important epigenetic modifiers in managing the delicate redox balance, mediating either pro- or antioxidant biological impacts. Summarizing, microRNAs may be promising therapeutic targets in ameliorating the repercussions of OxS in MetS.
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Affiliation(s)
- Adam Włodarski
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 92-213 Lodz, Poland;
- Correspondence: (A.W.); (J.S.); (A.Ś.)
| | - Justyna Strycharz
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
- Correspondence: (A.W.); (J.S.); (A.Ś.)
| | - Adam Wróblewski
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Jacek Kasznicki
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 92-213 Lodz, Poland;
| | - Józef Drzewoski
- Central Teaching Hospital of the Medical University of Lodz, 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland
- Correspondence: (A.W.); (J.S.); (A.Ś.)
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Peters LJF, Floege J, Biessen EAL, Jankowski J, van der Vorst EPC. MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application. Int J Mol Sci 2020; 21:6547. [PMID: 32906849 PMCID: PMC7555601 DOI: 10.3390/ijms21186547] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies.
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Affiliation(s)
- Linsey J. F. Peters
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University Hospital, 52074 Aachen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, 52074 Aachen, Germany;
| | - Erik A. L. Biessen
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University Hospital, 52074 Aachen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany
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Karthika CL, Ahalya S, Radhakrishnan N, Kartha CC, Sumi S. Hemodynamics mediated epigenetic regulators in the pathogenesis of vascular diseases. Mol Cell Biochem 2020; 476:125-143. [PMID: 32844345 DOI: 10.1007/s11010-020-03890-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/14/2020] [Indexed: 12/19/2022]
Abstract
Endothelium of blood vessels is continuously exposed to various hemodynamic forces. Flow-mediated epigenetic plasticity regulates vascular endothelial function. Recent studies have highlighted the significant role of mechanosensing-related epigenetics in localized endothelial dysfunction and the regional susceptibility for lesions in vascular diseases. In this article, we review the epigenetic mechanisms such as DNA de/methylation, histone modifications, as well as non-coding RNAs in promoting endothelial dysfunction in major arterial and venous diseases, consequent to hemodynamic alterations. We also discuss the current challenges and future prospects for the use of mechanoepigenetic mediators as biomarkers of early stages of vascular diseases and dysregulated mechanosensing-related epigenetic regulators as therapeutic targets in various vascular diseases.
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Affiliation(s)
- C L Karthika
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - S Ahalya
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - N Radhakrishnan
- St.Thomas Institute of Research on Venous Diseases, Changanassery, Kerala, India
| | - C C Kartha
- Society for Continuing Medical Education & Research (SOCOMER), Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, India
| | - S Sumi
- Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India.
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Pathomthongtaweechai N, Chutipongtanate S. AGE/RAGE signaling-mediated endoplasmic reticulum stress and future prospects in non-coding RNA therapeutics for diabetic nephropathy. Biomed Pharmacother 2020; 131:110655. [PMID: 32853909 DOI: 10.1016/j.biopha.2020.110655] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/01/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022] Open
Abstract
Disturbance of endoplasmic reticulum (ER) homeostasis triggered by the accumulation of unfolded proteins and advanced glycation end-products (AGEs) plays a major role in pathophysiology of diabetic nephropathy. Activation of receptor for AGEs (RAGE) stimulates NADPH oxidase-mediated reactive oxygen species (ROS) production, leading to ER stress, inflammation, glomerular hypertrophy, podocyte injury, and renal fibrosis. A growing body of evidence indicates that non-coding RNAs (ncRNAs) could rescue ER stress and renal inflammation by the epigenetic modification. This review summarizes ncRNA regulation in AGE/RAGE signaling-mediated ER stress, and discusses the opportunities and challenges of ncRNA-loaded extracellular vesicle therapy in diabetic nephropathy.
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Affiliation(s)
- Nutthapoom Pathomthongtaweechai
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand.
| | - Somchai Chutipongtanate
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand; Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
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Effects of Functionalized Fullerenes on ROS Homeostasis Determine Their Cytoprotective or Cytotoxic Properties. NANOMATERIALS 2020; 10:nano10071405. [PMID: 32707664 PMCID: PMC7407884 DOI: 10.3390/nano10071405] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Functionalized fullerenes (FF) can be considered regulators of intracellular reactive oxygen species (ROS) homeostasis; their direct oxidative damage-as well as regulation of oxidant enzymes and signaling pathways-should be considered. METHODS Uptake of two water-soluble functionalized C70 fullerenes with different types of aromatic addends (ethylphenylmalonate and thienylacetate) in human fetal lung fibroblasts, intracellular ROS visualization, superoxide scavenging potential, NOX4 expression, NRF2 expression, oxidative DNA damage, repair genes, cell proliferation and cell cycle were studied. RESULTS & CONCLUSION The intracellular effects of ethylphenylmalonate C70 derivative (FF1) can be explained in terms of upregulated NOX4 activity. The intracellular effects of thienylacetate C70 derivative (FF2) can be probably resulted from its superoxide scavenging potential and inhibition of lipid peroxidation. FF1 can be considered a NOX4 upregulator and potential cytotoxicant and FF2, as a superoxide scavenger and a potential cytoprotector.
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Zhang YL, Wang JM, Yin H, Wang SB, He CL, Liu J. DACH1, a novel target of miR-218, participates in the regulation of cell viability, apoptosis, inflammatory response, and epithelial-mesenchymal transition process in renal tubule cells treated by high-glucose. Ren Fail 2020; 42:463-473. [PMID: 32408786 PMCID: PMC7269034 DOI: 10.1080/0886022x.2020.1762647] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objective: This report was designed to assess the functional role of miR-218/dachshund family transcription factor 1 (DACH1) in diabetic kidney disease (DKD) and investigate its possible molecular mechanism.Materials and Methods: From the GEO database, we downloaded different datasets for analyzing the expression of miR-218 and DACH1 in DKD. TargetScan was adopted to predict the binding sites between miR-218 and DACH1, which was further verified by dual-luciferase reporter assays. The renal proximal tubule cells (HK-2) treated with high glucose (HG) were used as an in vitro model. QRT-PCR and western blot were used to determine the expression of DACH1 and other relative factors. Cell counting kit-8 and flow cytometer were applied to detect cell viability and apoptosis. The levels of inflammatory cytokines were determined by an ELISA assay.Results: A prominent raise of miR-218 was observed in DKD through bioinformatics analysis, which was further confirmed in the HG-induced model. DACH1 is a target of miR-218. miR-218 reduced cell viability and induced apoptosis by negatively regulating DACH1. Moreover, upregulating miR-218 in HG models increased the concentrations of pro-inflammatory cytokines TNF-α and IL-1β, reduced the level of anti-inflammatory cytokine IL-10, and promoted the epithelial-mesenchymal transition (EMT) process, which is possibly achieved by targeting DACH1. While downregulating miR-218 showed the opposite results.Conclusion: These data demonstrated that, under an in vitro HG environment, miR-218 suppressed the HK-2 cells proliferation, promoted apoptosis, caused an inflammatory response, and facilitated the EMT process largely by targeting DACH1, providing an insight into the therapeutic intervention of DKD.
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Affiliation(s)
- Ying-Li Zhang
- Department of Endocrinology, The First People's Hospital of Lanzhou City, Lanzhou, Gansu, P. R. China
| | - Jie-Min Wang
- Department of Endocrinology, The First People's Hospital of Lanzhou City, Lanzhou, Gansu, P. R. China
| | - Hong Yin
- Department of Endocrinology, The First People's Hospital of Lanzhou City, Lanzhou, Gansu, P. R. China
| | - Shou-Bao Wang
- Department of Endocrinology, The First People's Hospital of Lanzhou City, Lanzhou, Gansu, P. R. China
| | - Cai-Ling He
- Department of Endocrinology, The First People's Hospital of Lanzhou City, Lanzhou, Gansu, P. R. China
| | - Jing Liu
- Department of Endocrinology, The People's Hospital of Gansu Province, Lanzhou, Gansu, P. R. China
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Muñoz P, Ardiles ÁO, Pérez-Espinosa B, Núñez-Espinosa C, Paula-Lima A, González-Billault C, Espinosa-Parrilla Y. Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease. Mech Ageing Dev 2020; 189:111250. [PMID: 32433996 DOI: 10.1016/j.mad.2020.111250] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/05/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.
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Affiliation(s)
- Pablo Muñoz
- Department of Pathology and Physiology, Medical School, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Translational Neurology Center, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Biomedical Research Center, Universidad de Valparaíso, Valparaíso, Chile; Thematic Task Force on Healthy Aging, CUECH Research Network.
| | - Álvaro O Ardiles
- Department of Pathology and Physiology, Medical School, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Translational Neurology Center, Faculty of Medicine, Universidad de Valparaíso, Valparaíso, Chile; Thematic Task Force on Healthy Aging, CUECH Research Network; Interdisciplinary Center of Neuroscience of Valparaíso, Universidad de Valparaíso, Valparaíso, Chile; Interdisciplinary Center for Health Studies, Universidad de Valparaíso, Valparaíso, Chile
| | - Boris Pérez-Espinosa
- Thematic Task Force on Healthy Aging, CUECH Research Network; Laboratorio biología de la Reproduccion, Departamento Biomédico, Facultad Ciencias de la Salud, Universidad de Antofagasta, Antofagasta, Chile
| | - Cristian Núñez-Espinosa
- Thematic Task Force on Healthy Aging, CUECH Research Network; School of Medicine, Universidad de Magallanes, Punta Arenas, Chile
| | - Andrea Paula-Lima
- Thematic Task Force on Healthy Aging, CUECH Research Network; Institute for Research in Dental Sciences, Faculty of Dentistry; Universidad de Chile, Santiago, Chile; Biomedical Neuroscience Institute (BNI) and Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Christian González-Billault
- Thematic Task Force on Healthy Aging, CUECH Research Network; Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile; FONDAP Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, USA.
| | - Yolanda Espinosa-Parrilla
- Thematic Task Force on Healthy Aging, CUECH Research Network; School of Medicine, Universidad de Magallanes, Punta Arenas, Chile; Laboratory of Molecular Medicine - LMM, Center for Education, Healthcare and Investigation - CADI, University of Magallanes, Punta Arenas, Chile.
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Loganathan TS, Sulaiman SA, Abdul Murad NA, Shah SA, Abdul Gafor AH, Jamal R, Abdullah N. Interactions Among Non-Coding RNAs in Diabetic Nephropathy. Front Pharmacol 2020; 11:191. [PMID: 32194418 PMCID: PMC7062796 DOI: 10.3389/fphar.2020.00191] [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: 08/02/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetic Nephropathy (DN) is the most common cause of End-stage renal disease (ESRD). Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden. Recent findings showed that noncoding RNAs (ncRNAs) play an important role in DN progression, potentially can be used as biomarkers and therapeutic targets. NcRNAs refers to the RNA species that do not encode for any protein, and the most known ncRNAs are the microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Dysregulation of these ncRNAs was reported before in DN patients and animal models of DN. Importantly, there are some interactions between these ncRNAs to regulate the crucial steps in DN progression. Here, we aimed to discuss the reported ncRNAs in DN and their interactions with critical genes in DN progression. Elucidating these ncRNAs regulatory network will allow for a better understanding of the molecular mechanisms in DN and how they can act as new biomarkers for DN and also as the potential targets for treatment.
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Affiliation(s)
- Tamil Selvi Loganathan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Shamsul Azhar Shah
- Department of Community Health, UKM Medical Centre, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Abdul Halim Abdul Gafor
- Nephrology Unit, Faculty of Medicine, UKM Medical Centre, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Abdelghaffar S, Shora H, Abdelatty S, Elmougy F, El Sayed R, Abdelrahman H, Soliman H, Algebaly H, Ahmed S, Alfy P, Elshiwy Y. MicroRNAs and Risk Factors for Diabetic Nephropathy in Egyptian Children and Adolescents with Type 1 Diabetes. Diabetes Metab Syndr Obes 2020; 13:2485-2494. [PMID: 32765027 PMCID: PMC7367734 DOI: 10.2147/dmso.s247062] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/18/2020] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Currently available markers for early detection of diabetic nephropathy (DN), the leading cause of end stage renal disease, have some limitations. There is insufficient evidence from previous studies about the role of several circulating microRNAs (miRNAs) in the early development of DN. This study aimed to describe the expression of miRNA-377, miRNA-93, miRNA-25, miRNA-216a, and miRNA-21 in a sample of type 1 diabetic children and adolescents to explore their association with DN and some indices of kidney injury. PATIENTS AND METHODS Seventy type 1 diabetic patients, with 5 years' duration of diabetes or more, were recruited from Children's Hospital, Faculty of Medicine, Cairo University. Quantitative real-time reverse-transcription PCR (qRT-PCR) was used to measure the expression of the above mentioned miRNAs in serum and to assess its association with DN, and the studied risk factors. RESULTS There was a significantly higher percentage of up-regulation of miRNA-377 and miRNA-93 (P=0.03, 0.02, respectively) in addition to significant down-regulation of miRNA-25 (P=0.01) in patients with DN than in patients without DN. In patients with DN, expression of miR-216a was significantly negatively correlated with creatinine (r=-0.4, P=0.04) and positively correlated with eGFR using creatinine (r=0.5, P=0.03). In the same group, expression of miR-21 was positively correlated with urinary cystatin C (r=0.6, P=0.01) and was negatively correlated with e-GFR using cystatin c (r=-0.6, P=0.01). miRNA-93 was associated with increased risk (odds ratio=15, 95% CI=12.03-24.63, P=0.01), while miRNA-25 was associated with decreased risk for albuminuria (odds ratio=0.15, 95% CI=0.08-0.55, P=0.03). CONCLUSION miRNA-377, miRNA-93, miRNA-216a, and miRNA-21 may be implicated in the pathogenesis of DN, while miRNA-25 may have a reno-protective role. More studies are needed to document the value of these miRNAs as diagnostic biomarkers as well as therapeutic targets in DN.
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Affiliation(s)
- Shereen Abdelghaffar
- Department of Pediatrics, Cairo University, Cairo, Egypt
- Correspondence: Shereen Abdelghaffar Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, EgyptTel +201005859252Fax +201272202209 Email
| | - Hassan Shora
- Department of Molecular Biology/Biochemistry, Port Said University, Port Said, Egypt
| | - Sahar Abdelatty
- Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt
| | - Fatma Elmougy
- Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt
| | - Reham El Sayed
- Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt
| | - Heba Abdelrahman
- Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt
| | - Hend Soliman
- Department of Pediatrics, Cairo University, Cairo, Egypt
| | | | | | - Peter Alfy
- Department of Pediatrics, Cairo University, Cairo, Egypt
| | - Yasmine Elshiwy
- Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt
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Miguel V, Lamas S. Redox distress in organ fibrosis: The role of noncoding RNAs. OXIDATIVE STRESS 2020:779-820. [DOI: 10.1016/b978-0-12-818606-0.00037-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Grieco GE, Brusco N, Licata G, Nigi L, Formichi C, Dotta F, Sebastiani G. Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes. Int J Mol Sci 2019; 20:ijms20246358. [PMID: 31861156 PMCID: PMC6940935 DOI: 10.3390/ijms20246358] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/09/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases.
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Affiliation(s)
- Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
- UO Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
- UO Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
- UO Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy
- Correspondence: ; Tel.: +39-0577-586269
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (L.N.); (C.F.); (G.S.)
- Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, 53100 Siena, Italy
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Kalinina EV, Ivanova-Radkevich VI, Chernov NN. Role of MicroRNAs in the Regulation of Redox-Dependent Processes. BIOCHEMISTRY (MOSCOW) 2019; 84:1233-1246. [DOI: 10.1134/s0006297919110026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Zemskov EA, Lu Q, Ornatowski W, Klinger CN, Desai AA, Maltepe E, Yuan JXJ, Wang T, Fineman JR, Black SM. Biomechanical Forces and Oxidative Stress: Implications for Pulmonary Vascular Disease. Antioxid Redox Signal 2019; 31:819-842. [PMID: 30623676 PMCID: PMC6751394 DOI: 10.1089/ars.2018.7720] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Oxidative stress in the cell is characterized by excessive generation of reactive oxygen species (ROS). Superoxide (O2-) and hydrogen peroxide (H2O2) are the main ROS involved in the regulation of cellular metabolism. As our fundamental understanding of the underlying causes of lung disease has increased it has become evident that oxidative stress plays a critical role. Recent Advances: A number of cells in the lung both produce, and respond to, ROS. These include vascular endothelial and smooth muscle cells, fibroblasts, and epithelial cells as well as the cells involved in the inflammatory response, including macrophages, neutrophils, eosinophils. The redox system is involved in multiple aspects of cell metabolism and cell homeostasis. Critical Issues: Dysregulation of the cellular redox system has consequential effects on cell signaling pathways that are intimately involved in disease progression. The lung is exposed to biomechanical forces (fluid shear stress, cyclic stretch, and pressure) due to the passage of blood through the pulmonary vessels and the distension of the lungs during the breathing cycle. Cells within the lung respond to these forces by activating signal transduction pathways that alter their redox state with both physiologic and pathologic consequences. Future Directions: Here, we will discuss the intimate relationship between biomechanical forces and redox signaling and its role in the development of pulmonary disease. An understanding of the molecular mechanisms induced by biomechanical forces in the pulmonary vasculature is necessary for the development of new therapeutic strategies.
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Affiliation(s)
- Evgeny A Zemskov
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Qing Lu
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Wojciech Ornatowski
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Christina N Klinger
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Ankit A Desai
- Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Emin Maltepe
- Department of Pediatrics, University of California, San Francisco, San Francisco, California
| | - Jason X-J Yuan
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
| | - Ting Wang
- Department of Internal Medicine, The University of Arizona Health Sciences, Phoenix, Arizona
| | - Jeffrey R Fineman
- Department of Pediatrics, University of California, San Francisco, San Francisco, California
| | - Stephen M Black
- Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona
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Massaro JD, Polli CD, Costa E Silva M, Alves CC, Passos GA, Sakamoto-Hojo ET, Rodrigues de Holanda Miranda W, Bispo Cezar NJ, Rassi DM, Crispim F, Dib SA, Foss-Freitas MC, Pinheiro DG, Donadi EA. Post-transcriptional markers associated with clinical complications in Type 1 and Type 2 diabetes mellitus. Mol Cell Endocrinol 2019; 490:1-14. [PMID: 30926524 DOI: 10.1016/j.mce.2019.03.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/08/2019] [Accepted: 03/20/2019] [Indexed: 01/10/2023]
Abstract
The delayed diagnosis and the inadequate treatment of diabetes increase the risk of chronic complications. The study of regulatory molecules such as miRNAs can provide expression profiles of diabetes and diabetes complications. We evaluated the mononuclear cell miRNA profiles of 63 Type 1 and Type 2 diabetes patients presenting or not microvascular complications, and 40 healthy controls, using massive parallel sequencing. Gene targets, enriched pathways, dendograms and miRNA-mRNA networks were performed for the differentially expressed miRNAs. Six more relevant miRNAs were validated by RT-qPCR and data mining analysis. MiRNAs associated with specific complications included: i) neuropathy (miR-873-5p, miR-125a-5p, miR-145-3p and miR-99b-5p); ii) nephropathy (miR-1249-3p, miR-193a-5p, miR-409-5p, miR-1271-5p, miR-501-3p, miR-148b-3p and miR-9-5p); and iii) retinopathy (miR-143-3p, miR-1271-5p, miR-409-5p and miR-199a-5p). These miRNAs mainly targeted gene families and specific genes associated with advanced glycation end products and their receptors. Sets of miRNAs were also defined as potential targets for diabetes/diabetes complication pathogenesis.
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Affiliation(s)
- Juliana Doblas Massaro
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil.
| | - Claudia Danella Polli
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Matheus Costa E Silva
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Cinthia Caroline Alves
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Geraldo Aleixo Passos
- Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil; Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, 14040-900, Ribeirão Preto, SP, Brazil
| | - Elza Tiemi Sakamoto-Hojo
- Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, 14040-900, Ribeirão Preto, SP, Brazil
| | - Wallace Rodrigues de Holanda Miranda
- Division of Endocrinology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Nathalia Joanne Bispo Cezar
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Diane Meyre Rassi
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Felipe Crispim
- Endocrinology and Diabetes Division, Department of Medicine, Federal University of São Paulo, 04039-032, São Paulo, SP, Brazil
| | - Sergio Atala Dib
- Endocrinology and Diabetes Division, Department of Medicine, Federal University of São Paulo, 04039-032, São Paulo, SP, Brazil
| | - Maria Cristina Foss-Freitas
- Division of Endocrinology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil
| | - Daniel Guariz Pinheiro
- Department of Technology, Faculty of Agriculture and Veterinary Sciences, University of the State of São Paulo, 14884-900, Jaboticabal, SP, Brazil
| | - Eduardo Antônio Donadi
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, 14048-900, Ribeirão Preto, SP, Brazil.
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Cao Q, Chen X, Huang C, Pollock CA. MicroRNA as novel biomarkers and therapeutic targets in diabetic kidney disease: An update. FASEB Bioadv 2019; 1:375-388. [PMID: 32123840 PMCID: PMC6996361 DOI: 10.1096/fba.2018-00064] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 11/28/2018] [Accepted: 03/22/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a life-limiting condition characterized by progressive and irreversible loss of renal function. Currently, the estimated glomerular filtration rate (eGFR) and albuminuria are used as key markers to define DKD. However, they may not accurately indicate the degree of renal dysfunction and injury. Current therapeutic approaches for DKD, including attainment of blood pressure goals, optimal control of blood glucose and lipid levels, and the use of agents to block the renin-angiotensin-aldosterone system (RAAS) can only slow the progression of DKD. Hence, early diagnosis and innovative strategies are needed to both prevent and treat DKD. In recent years, a novel class of noncoding RNA, microRNAs (miRNAs) are reported to be involved in all biological processes, including cellular proliferation, apoptosis, and differentiation. miRNAs are small noncoding RNAs that regulate gene expression by posttranscriptional and epigenetic mechanisms. They are found to be in virtually all body fluids and used successfully as biomarkers for various diseases. Urinary miRNAs correlate with clinical and histologic parameters in DKD and differential urinary miRNA expression patterns have been reported. Kidney fibrosis is the common end stage of various CKD including DKD. Transforming growth factor-β(TGF-β) is regarded as the master regulator of kidney fibrosis, which is likely at least in part through regulating miRNA expression. miRNA are widely involved in the progression of DKD via many molecular mechanisms. In this review, the involvement of miRNA in fibrosis, inflammation, hypertrophy, autophagy, endoplasmic reticulum (ER) stress, oxidative stress, insulin resistance, and podocyte injury will be discussed, as these mechanisms are believed to offer new therapeutic targets that can be exploited to develop important treatments for DKD over the next decade.
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Affiliation(s)
- Qinghua Cao
- Renal Research LaboratoryKolling Institute of Medical Research, The University of Sydney, Royal North Shore hospitalSt Leonards, SydneyNew South WalesAustralia
| | - Xin‐Ming Chen
- Renal Research LaboratoryKolling Institute of Medical Research, The University of Sydney, Royal North Shore hospitalSt Leonards, SydneyNew South WalesAustralia
| | - Chunling Huang
- Renal Research LaboratoryKolling Institute of Medical Research, The University of Sydney, Royal North Shore hospitalSt Leonards, SydneyNew South WalesAustralia
| | - Carol A. Pollock
- Renal Research LaboratoryKolling Institute of Medical Research, The University of Sydney, Royal North Shore hospitalSt Leonards, SydneyNew South WalesAustralia
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50
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Zhang B, Zhang G, Wei T, Yang Z, Tan W, Mo Z, Liu J, Li D, Wei Y, Zhang L, Webster KA, Wei J. MicroRNA-25 Protects Smooth Muscle Cells against Corticosterone-Induced Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2691514. [PMID: 30992737 PMCID: PMC6434288 DOI: 10.1155/2019/2691514] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/17/2018] [Accepted: 01/01/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Vascular smooth muscle cells (VSMCs) are central components of atherosclerotic plaque. Loss of VSMCs through apoptotic cell death can cause fibrous cap thinning, necrotic core formation, and calcification that may destabilize plaque. Elevated glucocorticoid levels caused by psychological stress promote VSMC apoptosis and can exacerbate atherosclerosis in mice and humans. Changes in the levels of antiapoptosis microRNA-25 (miR-25) have been linked with heart disease, inflammation, VSMC phenotype, oxidative stress, and apoptosis. Here, we investigated the pathways and mechanisms of glucocorticoid-induced apoptosis of mouse VSMCs and the protective role of miR-25. METHODS Primary mouse VSMCs were cultured +/- corticosterone for 48 h. Apoptosis, ROS, apoptotic protein activities, miR-25, MOAP1, a miR-25 target, and p70S6 kinase were quantified at intervals. The roles of miR-25 were assessed by treating cells with lenti-pre-miR-25 and anti-miR-25. RESULTS VSMC apoptosis, caspase-3 activity, and Bax were increased by corticosterone, and cell death was paralleled by marked loss of miR-25. Protection was conferred by pre-miR-25 and exacerbated by anti-miR-25. Pre-miR-25 conferred reduced expression of the proapoptotic protein MOAP1, and the protective effects of pre-miR-25 were abrogated by overexpressing MOAP1. The antiapoptotic effects of miR-25 were paralleled by inhibition of the p70S6K pathway, a convergence target for the survival signaling pathways, and protection by pre-miR-25 was abrogated by the p70S6k inhibitor rapamycin. CONCLUSIONS MicroRNA-25 blocks corticosterone-induced VSMC apoptosis by targeting MOAP1 and the p70S6k pathway. Therapeutic manipulation of miR-25 may reduce atherosclerosis and unstable plaque formation associated with chronic stress.
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Affiliation(s)
- Bin Zhang
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Gaoxing Zhang
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Tianlu Wei
- Department of Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
| | - Zhen Yang
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
- Department of Cardiovascular, Sun Yat-Sen University, Guangzhou 510080, China
| | - Wenfeng Tan
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Ziqing Mo
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Jinxue Liu
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Dong Li
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
- Department of Intensive Care Unit, The Jiangmen Central Hospital, Jiangmen 529030, China
| | - Yidong Wei
- Youjiang Medical University for Nationalities, Chengxiang Rd, Baise, Guangxi 533000, China
| | - Lukun Zhang
- Department of Infection, Third People's Hospital of Shenzhen, 29 Bulan Road, Shenzhen 518112, China
| | - Keith A. Webster
- Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute, Miller School of Medicine, University of Miami, FL 33136, USA
| | - Jianqin Wei
- Department of Medicine, Division of Cardiology, Miller School of Medicine, University of Miami, FL 33136, USA
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