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Tamkini M, Nourbakhsh M, Movahedi M, Golestani A. Unveiling the role of miR-186 in SIRT1 regulation in adipocytes: implications for adipogenesis and inflammation in obesity. J Diabetes Metab Disord 2025; 24:42. [PMID: 39801683 PMCID: PMC11711434 DOI: 10.1007/s40200-024-01525-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/19/2024] [Indexed: 01/16/2025]
Abstract
Objectives MicroRNAs (miRNAs) play a crucial role in the onset and progress of obesity. The inflammation of adipose tissue is deemed causative of the complications associated with obesity. This study delved into the potential mechanisms of miRNA-mediated SIRT1 regulation and inflammatory factors modulation in 3T3-L1 cells. Methods 3T3-L1 cells were differentiated into mature and hypertrophied adipocytes and the expression of selected miRNAs was evaluated by real-time PCR. 3T3-L1 cells were transfected with the mimic and inhibitor sequences of miR-186, together with the appropriate controls. Western blot analysis assessed the expression level of SIRT1 protein, and the interaction between miR-186 and SIRT1 was scrutinized through a luciferase reporter gene assay. Results Across all the mature and hypertrophied cells, the evaluated miRNAs exhibited a significant increase in expression, highlighting their involvement in fat accumulation at a cellular scale. Notably, miR-186-5p displayed the highest expression in differentiated cells and the hypertrophy model. Induction of miR-186 led to attenuation of SIRT1, while its inhibition by miR-186 inhibitor resulted in upregulation of SIRT1 expression. miR-186 caused a remarkable elevation in the expression of inflammatory genes, including IL-6, IL-1β, TNF-α, and MCP-1, indicating a noticeable pattern of relationship between miR-186-induced SIRT-1 inhibition and inflammation. Conclusions miR-186 emerges as a pivotal factor in amplifying inflammatory cytokines and down-regulates SIRT1, an effect that might highlight the involvement of SIRT1 in the inflammatory responses of adipocytes, as well as underscoring the crucial role of miR-186 in this process. These findings present miR-186 as a promising target for addressing health challenges related to obesity. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01525-0.
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Affiliation(s)
- Mahdieh Tamkini
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mitra Nourbakhsh
- Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Monireh Movahedi
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Abolfazl Golestani
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Ku HC, Kuo CC, Su TC, Yang MJ, Cheng CF, Kao YH. Molecular effects of green tea epigallocatechin gallate on the microRNA-143/MAPK7 and microRNA-let-7a/HMGA2 pathways. TEA IN HEALTH AND DISEASE PREVENTION 2025:571-580. [DOI: 10.1016/b978-0-443-14158-4.00074-9] [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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Ansarin A, Shanehbandi D, Zarredar H, Ostadrahimi A, Gilani N, Ansarin K. The synergistic impact of sleep duration and obesity on metabolic syndrome risk: exploring the role of microRNAs. BIOIMPACTS : BI 2024; 15:30593. [PMID: 40256243 PMCID: PMC12008491 DOI: 10.34172/bi.30593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/28/2024] [Accepted: 09/17/2024] [Indexed: 04/22/2025]
Abstract
Introduction Given the well-established association between metabolic syndrome (MetS) and obesity, this study elucidates the influences of sleep duration and weight on MetS risk and explores the potential role of miRNAs as underlying mechanisms. Methods According to sleep logs and biochemistry tests, this study investigated the association between MetS and its components, sleep duration, and weight in four subgroups: A: normal sleepers with normal weight (N = 145), B: normal sleepers with obesity (N = 140), C: short sleepers with normal weight (N = 130), and D: short sleepers with obesity (N = 142). Chi-square, one-way ANOVA, and Tukey's post hoc tests were used for statistical analysis. Furthermore, following total RNA isolation by TRIzol from blood samples, cDNA was synthesized using stem-loop technique. Quantitative real-time polymerase chain reaction (qRT-PCR) was then employed to evaluate the expression levels of miR-33a, miR-378a, miR-132-3p, and miR-181d. The data were analyzed using one-way ANOVA. Results Our findings revealed the strongest association between MetS prevalence and individuals in group D (short sleepers with obesity; Cramer's V = 0.649, P < 0.001). This observation underscores the synergistic effect of short sleep and obesity on MetS risk. Furthermore, there was an independent association between short sleep duration and elevated triglyceride levels (P < 0.05). MicroRNA expression analysis revealed downregulation of miR-33a and miR-181d in B, C, and D groups compared to the normal group. Conversely, miR-132-3p expression was upregulated in the B, C, and D groups. Conclusion Short sleep and obesity synergistically elevate MetS risk, potentially via miR-33a and miR-181d downregulation and miR-132-3p upregulation, impacting triglyceride metabolism.
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Affiliation(s)
- Atefeh Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Gilani
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khalil Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Rahat Breath and Sleep Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Rahman MA, Islam MM, Ripon MAR, Islam MM, Hossain MS. Regulatory Roles of MicroRNAs in the Pathogenesis of Metabolic Syndrome. Mol Biotechnol 2024; 66:1599-1620. [PMID: 37393414 DOI: 10.1007/s12033-023-00805-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/17/2023] [Indexed: 07/03/2023]
Abstract
Metabolic syndrome refers to a group of several disease conditions together with high glucose triglyceride levels, high blood pressure, lower high-density lipoprotein level, and large waist circumference. About 400 million people worldwide, one-third of the Euro-American population and 27% Chinese population over age 50 have it. microRNAs, an abundant novel class of endogenous small, non-coding RNAs in eukaryotic cells, act as negative controllers of gene expression by promoting either degradation/translational repression of target messenger RNA. More than 2000 microRNAs in the human genome have been identified and they are implicated in various biological & pathophysiological processes, including glucose homeostasis, inflammatory response, and angiogenesis. Destruction of microRNAs has a crucial role in the pathogenesis of obesity, cardiovascular disease, and diabetes. Recently the discovery of circulating microRNAs in human serum may help to promote metabolic crosstalk between organs and serves as a novel approach for the identification of various diseases, like Type 2 diabetes & atherosclerosis. In this review, we will discuss the most recent and up-to-date research on the pathophysiology and histopathology of metabolic syndrome besides their historical background and epidemiological highlight. As well as search the methodologies employed in this field of research and the potential role of microRNAs as novel biomarkers and therapeutic targets for metabolic syndrome in the human body. Furthermore, the significance of microRNAs in promising strategies, like stem cell therapy, which holds enormous promise for regenerative medicine in the treatment of metabolic disorders will also be discussed.
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Affiliation(s)
- Md Abdur Rahman
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Monirul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh.
- Bangladesh Obesity Research Network (BORN), Noakhali, 3814, Bangladesh.
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Li S, Xiong F, Zhang S, Liu J, Gao G, Xie J, Wang Y. Oligonucleotide therapies for nonalcoholic steatohepatitis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102184. [PMID: 38665220 PMCID: PMC11044058 DOI: 10.1016/j.omtn.2024.102184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.
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Affiliation(s)
- Sixu Li
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
| | - Feng Xiong
- Department of Cardiology, The Third People’s Hospital of Chengdu, Chengdu 610031, China
| | - Songbo Zhang
- Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jinghua Liu
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Jun Xie
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Yi Wang
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
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Park I, Kim HJ, Shin J, Jung YJ, Lee D, Lim J, Park JM, Park JW, Kim J. AFM Imaging Reveals MicroRNA-132 to be a Positive Regulator of Synaptic Functions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306630. [PMID: 38493494 PMCID: PMC11077659 DOI: 10.1002/advs.202306630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/17/2024] [Indexed: 03/19/2024]
Abstract
The modification of synaptic and neural connections in adults, including the formation and removal of synapses, depends on activity-dependent synaptic and structural plasticity. MicroRNAs (miRNAs) play crucial roles in regulating these changes by targeting specific genes and regulating their expression. The fact that somatic and dendritic activity in neurons often occurs asynchronously highlights the need for spatial and dynamic regulation of protein synthesis in specific milieu and cellular loci. MicroRNAs, which can show distinct patterns of enrichment, help to establish the localized distribution of plasticity-related proteins. The recent study using atomic force microscopy (AFM)-based nanoscale imaging reveals that the abundance of miRNA(miR)-134 is inversely correlated with the functional activity of dendritic spine structures. However, the miRNAs that are selectively upregulated in potentiated synapses, and which can thereby support prospective changes in synaptic efficacy, remain largely unknown. Using AFM force imaging, significant increases in miR-132 in the dendritic regions abutting functionally-active spines is discovered. This study provides evidence for miR-132 as a novel positive miRNA regulator residing in dendritic shafts, and also suggests that activity-dependent miRNAs localized in distinct sub-compartments of neurons play bi-directional roles in controlling synaptic transmission and synaptic plasticity.
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Affiliation(s)
- Ikbum Park
- Technical Support Center for Chemical IndustryKorea Research Institute of Chemical Technology (KRICT)Ulsan44412Republic of Korea
| | - Hyun Jin Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)Pohang37673Republic of Korea
| | - Juyoung Shin
- Department of Life SciencesPohang University of Science and Technology (POSTECH)Pohang37673Republic of Korea
| | - Yu Jin Jung
- Center for Specialty ChemicalsKorea Research Institute of Chemical Technology (KRICT)Ulsan44412Republic of Korea
| | - Donggyu Lee
- Division of Electronics and Information SystemDaegu Gyeongbuk Institute of Science and Technology (DGIST)Daegu42988Republic of Korea
| | - Ji‐seon Lim
- Department of ChemistryPohang University of Science and Technology (POSTECH)Pohang37673Republic of Korea
| | - Jong Mok Park
- Technical Support Center for Chemical IndustryKorea Research Institute of Chemical Technology (KRICT)Ulsan44412Republic of Korea
| | - Joon Won Park
- Department of ChemistryPohang University of Science and Technology (POSTECH)Pohang37673Republic of Korea
| | - Joung‐Hun Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)Pohang37673Republic of Korea
- Institute of Convergence ScienceYonsei UniversitySeoul03722Republic of Korea
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Zhang L, Chen ZY, Wei XX, Li JD, Chen G. What are the changes in the hotspots and frontiers of microRNAs in hepatocellular carcinoma over the past decade? World J Clin Oncol 2024; 15:145-158. [PMID: 38292666 PMCID: PMC10823937 DOI: 10.5306/wjco.v15.i1.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/08/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Emerging research suggests that microRNAs (miRNAs) play an important role in the development of hepatocellular carcinoma (HCC). A comprehensive analysis of recent research concerning miRNAs in HCC development could provide researchers with a valuable reference for further studies. AIM To make a comprehensive analysis of recent studies concerning miRNAs in HCC. METHODS All relevant publications were retrieved from the Web of Science Core Collection database. Bibliometrix software, VOSviewer software and CiteSpace software were used to visually analyze the distribution by time, countries, institutions, journals, and authors, as well as the keywords, burst keywords and thematic map. RESULTS A total of 9426 publications on this topic were found worldwide. According to the keywords analysis, we found that the studies of miRNAs focused on their expression level, effects, and mechanisms on the biological behaviour of HCC. Keywords bursting analysis showed that in the early years (2013-2017), "microRNA expression", "gene expression", "expression profile", "functional polymorphism", "circulating microRNA", "susceptibility" and "mir 21" started to attract attention. In the latest phase (2018-2022), the hot topics turned to "sorafenib resistance", "tumor microenvironment" and so on. CONCLUSION This study provides a comprehensive overview of the role of miRNAs in HCC development based on bibliometric analysis. The hotspots in this field focus on miRNAs expression level, effects, and mechanisms on the biological behavior of HCC. The frontiers turned to sorafenib resistance, tumor microenvironment and so on.
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Affiliation(s)
- Lu Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zu-Yuan Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Xian Wei
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jian-Di Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Mehta P, Swaminathan A, Yadav A, Chattopadhyay P, Shamim U, Pandey R. Integrative genomics important to understand host-pathogen interactions. Brief Funct Genomics 2024; 23:1-14. [PMID: 35909219 DOI: 10.1093/bfgp/elac021] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/30/2022] [Accepted: 07/11/2022] [Indexed: 01/21/2024] Open
Abstract
Infectious diseases are the leading cause of morbidity and mortality worldwide. Causative pathogenic microbes readily mutate their genome and lead to outbreaks, challenging the healthcare and the medical support. Understanding how certain symptoms manifest clinically is integral for therapeutic decisions and vaccination efficacy/protection. Notably, the interaction between infecting pathogens, host response and co-presence of microbes influence the trajectories of disease progression and clinical outcome. The spectrum of observed symptomatic patients (mild, moderate and severe) and the asymptomatic infections highlight the challenges and the potential for understanding the factors driving protection/susceptibility. With the increasing repertoire of high-throughput tools, such as cutting-edge multi-omics profiling and next-generation sequencing, genetic drivers of factors linked to heterogeneous disease presentations can be investigated in tandem. However, such strategies are not without limits in terms of effectively integrating host-pathogen interactions. Nonetheless, an integrative genomics method (for example, RNA sequencing data) for exploring multiple layers of complexity in host-pathogen interactions could be another way to incorporate findings from high-throughput data. We further propose that a Holo-transcriptome-based technique to capture transcriptionally active microbial units can be used to elucidate functional microbiomes. Thus, we provide holistic perspective on investigative methodologies that can harness the same genomic data to investigate multiple seemingly independent but deeply interconnected functional domains of host-pathogen interaction that modulate disease severity and clinical outcomes.
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Engin AB, Engin A. MicroRNAs as Epigenetic Regulators of Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:595-627. [PMID: 39287866 DOI: 10.1007/978-3-031-63657-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Mu C, Gao M, Xu W, Sun X, Chen T, Xu H, Qiu H. Mechanisms of microRNA-132 in central neurodegenerative diseases: A comprehensive review. Biomed Pharmacother 2024; 170:116029. [PMID: 38128185 DOI: 10.1016/j.biopha.2023.116029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
MicroRNA-132 (miR-132) is a highly conserved molecule that plays a crucial regulatory role in central nervous system (CNS) disorders. The expression levels of miR-132 exhibit variability in various neurological disorders and have been closely linked to disease onset and progression. The expression level of miR-132 in the CNS is regulated by a diverse range of stimuli and signaling pathways, including neuronal migration and integration, dendritic outgrowth, and complexity, synaptogenesis, synaptic plasticity, as well as inflammation and apoptosis activation. The aberrant expression of miR-132 in various central neurodegenerative diseases has garnered widespread attention. Clinical studies have revealed altered miR-132 expression levels in both chronic and acute CNS diseases, positioning miR-132 as a potential biomarker or therapeutic target. An in-depth exploration of miR-132 holds the promise of enhancing our understanding of the mechanisms underlying CNS diseases, thereby offering novel insights and strategies for disease diagnosis and treatment. It is anticipated that this review will assist researchers in recognizing the potential value of miR-132 and in generating innovative ideas for clinical trials related to CNS degenerative diseases.
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Affiliation(s)
- Chenxi Mu
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Meng Gao
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Weijing Xu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China; School of Public Health, Jiamusi University, Jiamusi 154007, Heilongjiang, China
| | - Xun Sun
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Tianhao Chen
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Hui Xu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China.
| | - Hongbin Qiu
- School of Public Health, Jiamusi University, Jiamusi 154007, Heilongjiang, China.
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Werner H, Laron Z. Insulin-like growth factors and aging: lessons from Laron syndrome. Front Endocrinol (Lausanne) 2023; 14:1291812. [PMID: 37941907 PMCID: PMC10628706 DOI: 10.3389/fendo.2023.1291812] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023] Open
Abstract
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Zvi Laron
- Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva, Israel
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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Carpi S, Quarta S, Doccini S, Saviano A, Marigliano N, Polini B, Massaro M, Carluccio MA, Calabriso N, Wabitsch M, Santorelli FM, Cecchini M, Maione F, Nieri P, Scoditti E. Tanshinone IIA and Cryptotanshinone Counteract Inflammation by Regulating Gene and miRNA Expression in Human SGBS Adipocytes. Biomolecules 2023; 13:1029. [PMID: 37509065 PMCID: PMC10377153 DOI: 10.3390/biom13071029] [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: 05/11/2023] [Revised: 06/14/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Inflammation of the adipose tissue contributes to the onset and progression of several chronic obesity-related diseases. The two most important lipophilic diterpenoid compounds found in the root of Salvia milthorrhiza Bunge (also called Danshen), tanshinone IIA (TIIA) and cryptotanshinone (CRY), have many favorable pharmacological effects. However, their roles in obesity-associated adipocyte inflammation and related sub-networks have not been fully elucidated. In the present study, we investigated the gene, miRNAs and protein expression profile of prototypical obesity-associated dysfunction markers in inflamed human adipocytes treated with TIIA and CRY. The results showed that TIIA and CRY prevented tumor necrosis factor (TNF)-α induced inflammatory response in adipocytes, by counter-regulating the pattern of secreted cytokines/chemokines associated with adipocyte inflammation (CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, IL-6, IL-8, MIF and PAI-1/Serpin E1) via the modulation of gene expression (as demonstrated for CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, and IL-8), as well as related miRNA expression (miR-126-3p, miR-223-3p, miR-124-3p, miR-155-5p, and miR-132-3p), and by attenuating monocyte recruitment. This is the first demonstration of a beneficial effect by TIIA and CRY on adipocyte dysfunction associated with obesity development and complications, offering a new outlook for the prevention and/or treatment of metabolic diseases.
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Affiliation(s)
- Sara Carpi
- Science of Health Department, Magna Græcia University, 88100 Catanzaro, Italy
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, 56100 Pisa, Italy
- Department of Pharmacy, University of Pisa, 56100 Pisa, Italy
| | - Stefano Quarta
- Department of Biological and Environmental Sciences and Technologies (DISTEBA), University of Salento, 73100 Lecce, Italy
| | - Stefano Doccini
- IRCCS Fondazione Stella Maris, Calambrone, 56128 Pisa, Italy
| | - Anella Saviano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Noemi Marigliano
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Beatrice Polini
- Department of Pharmacy, University of Pisa, 56100 Pisa, Italy
- Department of Pathology, University of Pisa, 56100 Pisa, Italy
| | - Marika Massaro
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | | | - Nadia Calabriso
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | - Martin Wabitsch
- Division of Pediatric Endocrinology, Diabetes and Obesity, Department of Pediatrics and Adolescent Medicine, University of Ulm, 89075 Ulm, Germany
| | | | - Marco Cecchini
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, 56100 Pisa, Italy
| | - Francesco Maione
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Paola Nieri
- Department of Pharmacy, University of Pisa, 56100 Pisa, Italy
| | - Egeria Scoditti
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
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14
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Elkhawaga SY, Ismail A, Elsakka EGE, Doghish AS, Elkady MA, El-Mahdy HA. miRNAs as cornerstones in adipogenesis and obesity. Life Sci 2023; 315:121382. [PMID: 36639051 DOI: 10.1016/j.lfs.2023.121382] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/06/2023] [Accepted: 01/07/2023] [Indexed: 01/12/2023]
Abstract
In recent decades, obesity has extensively emerged to the level of pandemics. It's significantly associated with serious co-morbidities that could decrease life quality and even life expectancy. Obesity has several determinants, such as age, sex, endocrine, and genetic factors. The miRNAs have emerged as genetic factors affecting obesity. The miRNAs are small noncoding nucleic acids that can modify gene expression and hence, control biological processes. The miRNAs can greatly affect many biological processes in obesity, such as adipogenesis, lipid metabolism, and homeostasis. As a result, the entry of miRNAs in obesity therapeutic approaches has been strongly advised as miRNAs mimics, inhibitors, and stimulators. Hence, this review aims to point out a summarized and updated overview of miRNAs and their roles in obesity and its included processes, such as adipogenesis and lipid metabolism. Besides, we also review recent applications of miRNAs as a treatment approach for obesity.
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Affiliation(s)
- Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
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15
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Mohseni R, Teimouri M, Safaei M, Arab Sadeghabadi Z. AMP-activated protein kinase is a key regulator of obesity-associated factors. Cell Biochem Funct 2023; 41:20-32. [PMID: 36468539 DOI: 10.1002/cbf.3767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/29/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022]
Abstract
An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.
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Affiliation(s)
- Roohollah Mohseni
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Maryam Teimouri
- Department of Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohsen Safaei
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Arab Sadeghabadi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
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16
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The Role of microRNAs in Inflammation. Int J Mol Sci 2022; 23:ijms232415479. [PMID: 36555120 PMCID: PMC9779565 DOI: 10.3390/ijms232415479] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a biological response of the immune system to various insults, such as pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-inflammatory factors and their direction towards inflammation often leads to the development and progression of various inflammation-associated diseases. The role of small non-coding RNAs (small ncRNAs) in inflammation has gained much attention in the past two decades for their regulation of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene regulation often turns out to be an important factor in controlling aberrant inflammatory reactions in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation.
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17
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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18
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Concistrè A, Petramala L, Circosta F, Romagnoli P, Soldini M, Bucci M, De Cesare D, Cavallaro G, De Toma G, Cipollone F, Letizia C. Analysis of the miRNA expression from the adipose tissue surrounding the adrenal neoplasia. Front Cardiovasc Med 2022; 9:930959. [PMID: 35966515 PMCID: PMC9366211 DOI: 10.3389/fcvm.2022.930959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/01/2022] [Indexed: 12/04/2022] Open
Abstract
Background Primary aldosteronism (PA) is characterized by several metabolic changes such as insulin resistance, metabolic syndrome, and adipose tissue (AT) inflammation. Mi(cro)RNAs (miRNAs) are a class of non-coding small RNA molecules known to be critical regulators in several cellular processes associated with AT dysfunction. The aim of this study was to evaluate the expression of some miRNAs in visceral and subcutaneous AT in patients undergoing adrenalectomy for aldosterone-secreting adrenal adenoma (APA) compared to the samples of AT obtained in patients undergoing adrenalectomy for non-functioning adrenal mass (NFA). Methods The quantitative expression of selected miRNA using real-time PCR was analyzed in surrounding adrenal neoplasia, peri-renal, and subcutaneous AT samples of 16 patients with adrenalectomy (11 patients with APA and 5 patients with NFA). Results Real-time PCR cycles for miRNA-132, miRNA-143, and miRNA-221 in fat surrounding adrenal neoplasia and in peri-adrenal AT were significantly higher in APA than in patients with NFA. Unlike patients with NFA, miRNA-132, miRNA-143, miRNA-221, and miRNA-26b were less expressed in surrounding adrenal neoplasia AT compared to subcutaneous AT in patients with APA. Conclusion This study, conducted on tissue expression of miRNAs, highlights the possible pathophysiological role of some miRNAs in determining the metabolic alterations in patients with PA.
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Affiliation(s)
- Antonio Concistrè
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Luigi Petramala
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome, Italy
| | - Francesco Circosta
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Priscilla Romagnoli
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Maurizio Soldini
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Marco Bucci
- Department of Medicine and Aging Sciences, University “Gabriele d'Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Domenico De Cesare
- Department of Medicine and Aging Sciences, University “Gabriele d'Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Giuseppe Cavallaro
- Department of Surgery “Pietro Valdoni, ” “Sapienza” University of Rome, Rome, Italy
| | - Giorgio De Toma
- Department of Surgery “Pietro Valdoni, ” “Sapienza” University of Rome, Rome, Italy
| | - Francesco Cipollone
- Department of Medicine and Aging Sciences, University “Gabriele d'Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Claudio Letizia
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, “Sapienza” University of Rome, Rome, Italy
- *Correspondence: Claudio Letizia
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19
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Reily-Bell M, Bahn A, Katare R. Reactive Oxygen Species-Mediated Diabetic Heart Disease: Mechanisms and Therapies. Antioxid Redox Signal 2022; 36:608-630. [PMID: 34011169 DOI: 10.1089/ars.2021.0098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Significance: Diabetic heart disease (DHD) is the primary cause of mortality in people with diabetes. A significant contributor to the development of DHD is the disruption of redox balance due to reactive oxygen species (ROS) overproduction resulting from sustained high glucose levels. Therapies specifically focusing on the suppression of ROS will hugely benefit patients with DHD. Recent Advances: In addition to the gold standard pharmacological therapies, the recent development of gene therapy provides an exciting avenue for developing new therapeutics to treat ROS-mediated DHD. In particular, microRNAs (miRNAs) are gaining interest due to their crucial role in several physiological and pathological processes, including DHD. Critical Issues: miRNAs have many targets and differential function depending on the environment. Therefore, a proper understanding of the function of miRNAs in specific cell types and cell states is required for the successful application of this technology. In the present review, we first provide an overview of the role of ROS in contributing to DHD and the currently available treatments. We then discuss the newer gene therapies with a specific focus on the role of miRNAs as the causative factors and therapeutic targets to combat ROS-mediated DHD. Future Directions: The future of miRNA therapeutics in tackling ROS-mediated DHD is dependent on a complete understanding of how miRNAs behave in different cells and environments. Future research should also aim to develop conditional miRNA therapeutic platforms capable of switching on and off in response to disruptions in the redox state. Antioxid. Redox Signal. 36, 608-630.
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Affiliation(s)
- Matthew Reily-Bell
- Department of Physiology-HeartOtago, University of Otago, Dunedin, New Zealand
| | - Andrew Bahn
- Department of Physiology-HeartOtago, University of Otago, Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology-HeartOtago, University of Otago, Dunedin, New Zealand
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20
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Xie K, Yan Z, Wang W, Luo R, Gao X, Wang P, Yang Q, Huang X, Zhang J, Yang J, Gun S. ssc-microRNA-132 targets DACH1 to exert anti-inflammatory and anti-apoptotic effects in Clostridium perfringens beta2 toxin-treated porcine intestinal epithelial cells. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 127:104270. [PMID: 34582881 DOI: 10.1016/j.dci.2021.104270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 06/13/2023]
Abstract
Clostridium perfringens (C. perfringens) type C (CPC) is one of the chief pathogens that causes diarrhea in piglets, and C. perfringens beta2 (CPB2) toxin is the main virulence factor of CPC. Our previous research demonstrated that ssc-microR-132 was differentially expressed in ileal tissues of CPC-mediated diarrheic piglets and healthy piglets, which implied a potential role of ssc-microR-132 in this process. Here, we found that ssc-microR-132 was notably down-regulated in CPB2-exposed intestinal porcine epithelial cells (IPEC-J2), which was consistent with the ileal tissue expression. Moreover, ssc-microR-132 upregulation alleviated CPB2-induced inflammatory damage and apoptosis in IPEC-J2, whereas ssc-microR-132 knockdown presented the opposite effects. Furthermore, the dual-luciferase reporter assay indicated that ssc-microR-132 directly targeted Dachshund homolog 1 (DACH1). Moreover, DACH1 overexpression intensified CPB2-induced inflammatory injury and apoptosis in IPEC-J2. Remarkably, the introduction of DACH1 weakened the anti-inflammatory and anti-apoptotic effects of ssc-microR-132 in CPB2-exposed IPEC-J2. Overall, the results reveal that ssc-microR-132 targeted DACH1 to alleviate CPB2-mediated inflammation and apoptosis in IPEC-J2.
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Affiliation(s)
- Kaihui Xie
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Zunqiang Yan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Wei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Ruirui Luo
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Juanli Zhang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Jiaojiao Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, 730070, China; Gansu Research Center for Swine Production Engineering and Technology, Lanzhou, Gansu, 730070, China.
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21
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microRNAs in Human Adipose Tissue Physiology and Dysfunction. Cells 2021; 10:cells10123342. [PMID: 34943849 PMCID: PMC8699244 DOI: 10.3390/cells10123342] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/20/2021] [Accepted: 11/26/2021] [Indexed: 12/11/2022] Open
Abstract
In recent years, there has been a large amount of evidence on the role of microRNA (miRNA) in regulating adipose tissue physiology. Indeed, miRNAs control critical steps in adipocyte differentiation, proliferation and browning, as well as lipolysis, lipogenesis and adipokine secretion. Overnutrition leads to a significant change in the adipocyte miRNOME, resulting in adipose tissue dysfunction. Moreover, via secreted mediators, dysfunctional adipocytes may impair the function of other organs and tissues. However, given their potential to control cell and whole-body energy expenditure, miRNAs also represent critical therapeutic targets for treating obesity and related metabolic complications. This review attempts to integrate present concepts on the role miRNAs play in adipose tissue physiology and obesity-related dysfunction and data from pre-clinical and clinical studies on the diagnostic or therapeutic potential of miRNA in obesity and its related complications.
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22
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De Geest B, Mishra M. Role of Oxidative Stress in Heart Failure: Insights from Gene Transfer Studies. Biomedicines 2021; 9:biomedicines9111645. [PMID: 34829874 PMCID: PMC8615706 DOI: 10.3390/biomedicines9111645] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/06/2021] [Accepted: 11/07/2021] [Indexed: 12/14/2022] Open
Abstract
Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure.
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Affiliation(s)
- Bart De Geest
- Centre for Molecular and Vascular Biology, Catholic University of Leuven, 3000 Leuven, Belgium
- Correspondence: ; Tel.: +32-16-372-059
| | - Mudit Mishra
- Department of Cardiothoracic Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
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23
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MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression. Int J Mol Sci 2021; 22:ijms222111861. [PMID: 34769292 PMCID: PMC8584665 DOI: 10.3390/ijms222111861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
The growth hormone (GH)–insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH–IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.
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24
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Zia A, Sahebdel F, Farkhondeh T, Ashrafizadeh M, Zarrabi A, Hushmandi K, Samarghandian S. A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases. Int J Biol Macromol 2021; 188:52-61. [PMID: 34364937 DOI: 10.1016/j.ijbiomac.2021.08.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/15/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023]
Abstract
Sirtuin-1 (SIRT1) as a NAD + -dependent Class III protein deacetylase, involves in longevity and various cellular physiological processes. SIRT1 via deacetylating transcription factors regulates cell growth, inflammation, metabolism, hypoxic responses, cell survival, senescence, and aging. MicroRNAs (miRNAs) are short non-coding RNAs that modulate the expression of target genes in a post-transcriptional manner. Recent investigations have exhibited that miRNAs have an important role in regulating cell growth, development, stress responses, tumor formation and suppression, cell death, and aging. In the present review, we summarize recent findings about the roles of miRNAs in regulating SIRT1 and SIRT1-associated signaling cascade and downstream effects, like apoptosis and aging. Here we introduce and discuss how activity and expression of SIRT1 are modulated by miRNAs and further review the therapeutic potential of targeting miRNAs for age-associated diseases that involve SIRT1 dysfunction. Although at its infancy, research on the roles of miRNAs in aging and their function through modulating SIRT1 may provide new insights in deciphering the key molecular pathways related to aging and age-associated disorders.
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Affiliation(s)
- Aliabbas Zia
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Faezeh Sahebdel
- Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran; Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Faculty of Veterinary Medicine, Department of Food Hygiene and Quality Control, Division of epidemiology, University of Tehran, Tehran, Iran
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Momen-Heravi F, Catalano D, Talis A, Szabo G, Bala S. Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:155-167. [PMID: 34458001 PMCID: PMC8368790 DOI: 10.1016/j.omtn.2021.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.
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Affiliation(s)
- Fatemeh Momen-Heravi
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Austin Talis
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
- KASA BIO, 10405 Old Alabama Road Connector, Suite 201, Alpharetta, GA 30022, USA
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26
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Eikelis N, Dixon JB, Lambert EA, Hanin G, Tzur Y, Greenberg DS, Soreq H, Marques FZ, Fahey MT, Head GA, Schlaich MP, Lambert GW. MicroRNA-132 may be associated with blood pressure and liver steatosis-preliminary observations in obese individuals. J Hum Hypertens 2021; 36:911-916. [PMID: 34453104 DOI: 10.1038/s41371-021-00597-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/08/2021] [Accepted: 08/18/2021] [Indexed: 11/09/2022]
Abstract
Recent findings in experimental models have shown that the microRNA miR-132 (mir-132) is an important regulator of liver homeostasis and lipid metabolism. We aimed to assess miR-132 expression in liver and fat tissues of obese individuals and examine its association with blood pressure (BP) and hepatic steatosis. We examined obese individuals undergoing bariatric surgery for weight loss (n = 19). Clinical and demographic information was obtained. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and subcutaneous and visceral fat biopsies obtained during bariatric surgery. Liver biopsies were read by a single liver pathologist and graded for steatosis, inflammation and fibrosis. Participants (aged 39 ± 8.1 years) had a body mass index (BMI) of 42 ± 4.5 kg/m2 and presented with 2.2 ± 1.2 metabolic abnormalities. Supine BP was 127 ± 16/74 ± 11 mmHg. Hepatic and visceral fat expression of miR-132 were correlated (r = 0.59, P = 0.033). There was no correlation between subcutaneous and visceral expression of miR-132 (r = -0.31, P = 0.20). Hepatic and visceral fat miR-132 expression were associated with BMI (r = 0.62 and r = 0.68, P = 0.049 respectively) and degree of liver steatosis (r = 0.60 and r = 0.55, P < 0.05, respectively). Subcutaneous fat miRNA-132 expression was correlated to office systolic BP (r = 0.46, P < 0.05), several aspects of 24 h BP (24 h systolic BP: r = 0.52; day systolic BP: r = 0.59, P < 0.05 for all), plasma triglycerides (r = 0.51, P < 0.01) and liver enzymes (ALT: r = -0.52; AST: r = -0.48, P < 0.05 for all). We found an association between miR-132 and markers of cardiovascular and metabolic disease. Reduction of miR-132 may be a target for the regulation of liver lipid homeostasis and control of obesity-related blood pressure.
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Affiliation(s)
- Nina Eikelis
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
| | - John B Dixon
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
| | - Elisabeth A Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
| | - Geula Hanin
- Department of Genetics, University of Cambridge, Cambridge, UK.,The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yonat Tzur
- The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - David S Greenberg
- The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hermona Soreq
- The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Francine Z Marques
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, Melbourne, VIC, Australia
| | - Michael T Fahey
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Geoffrey A Head
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology, Monash University, Melbourne, VIC, Australia
| | - Markus P Schlaich
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Dobney Hypertension Centre, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia
| | - Gavin W Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia. .,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.
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27
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Zhang M, Bian Z. Alzheimer's Disease and microRNA-132: A Widespread Pathological Factor and Potential Therapeutic Target. Front Neurosci 2021; 15:687973. [PMID: 34108863 PMCID: PMC8180577 DOI: 10.3389/fnins.2021.687973] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/30/2021] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly and is the most common type of dementia. AD is mostly gradual onset, and involves slow, progressive mental decline, accompanied by personality changes; the incidence of AD gradually increases with age. The etiology of AD is unknown, although it is currently believed to be related to abnormal deposition of amyloid β-protein (Aβ) in the brain, hyperphosphorylation of microtubule-associated protein tau, and the release of various cytokines, complements, activators and chemokines by cells. MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs that regulate gene expression at the post-transcriptional level, and manipulate the functions of intracellular proteins and physiological processes. Emerging studies have shown that miRNA plays an important role in regulating AD-related genes. MiR-132 is known as "NeurimmiR" due to its involvement in numerous neurophysiological and pathological processes. Accumulating pre-clinical results suggest that miR-132 may be involved in the progression of Aβ and tau pathology. Moreover, clinical studies have indicated that decreased circulating miR-132 levels could be used a potential diagnostic biomarker in AD. Here, we review the pathogenic role of miR-132 activity in AD, and the potential of targeting miR-132 for developing future therapeutic strategies.
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Affiliation(s)
- Meng Zhang
- Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhigang Bian
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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Abu-Izneid T, AlHajri N, Ibrahim AM, Javed MN, Salem KM, Pottoo FH, Kamal MA. Micro-RNAs in the regulation of immune response against SARS CoV-2 and other viral infections. J Adv Res 2021; 30:133-145. [PMID: 33282419 PMCID: PMC7708232 DOI: 10.1016/j.jare.2020.11.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 11/24/2020] [Accepted: 11/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Micro-RNAs (miRNAS) are non-coding, small RNAs that have essential roles in different biological processes through silencing genes, they consist of 18-24 nucleotide length RNA molecules. Recently, miRNAs have been viewed as important modulators of viral infections they can function as suppressors of gene expression by targeting cellular or viral RNAs during infection. AIM OF REVIEW We describe the biological roles and effects of miRNAs on SARS-CoV-2 life-cycle and pathogenicity, and we discuss the modulation of the immune system with micro-RNAs which would serve as a new foundation for the treatment of SARS-CoV-2 and other viral infections. KEY SCIENTIFIC CONCEPTS OF REVIEW miRNAs are the key players that regulate the expression of the gene in the post-transcriptional phase and have important effects on viral infections, thus are potential targets in the development of novel therapeutics for the treatment of viral infections. Besides, micro-RNAs (miRNAs) modulation of immune-pathogenesis responses to viral infection is one of the most-known indirect effects, which leads to suppressing of the interferon (IFN-α/β) signalling cascade or upregulation of the IFN-α/β production another IFN-stimulated gene (ISGs) that inhibit replication of the virus. These virus-mediated alterations in miRNA levels lead to an environment that might either enhance or inhibit virus replication.
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Affiliation(s)
- Tareq Abu-Izneid
- Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Noora AlHajri
- Department of Epidemiology and Population Health, College of Medicine, Khalifa University, United Arab Emirates
| | - Abdallah Mohammad Ibrahim
- Fundamentals of Nursing Department, College of Nursing, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
| | - Md. Noushad Javed
- Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New-Delhi, India
| | - Khairi Mustafa Salem
- Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
| | - Mohammad Amjad Kamal
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia
- Enzymoics, Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia
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Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity. Cells 2021; 10:cells10051004. [PMID: 33923175 PMCID: PMC8147115 DOI: 10.3390/cells10051004] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/20/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.
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30
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Wang Y, Soneson C, Malinowska AL, Laski A, Ghosh S, Kanitz A, Gebert LFR, Robinson MD, Hall J. MiR-CLIP reveals iso-miR selective regulation in the miR-124 targetome. Nucleic Acids Res 2021; 49:25-37. [PMID: 33300035 PMCID: PMC7797034 DOI: 10.1093/nar/gkaa1117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 10/04/2020] [Accepted: 12/07/2020] [Indexed: 12/15/2022] Open
Abstract
Many microRNAs regulate gene expression via atypical mechanisms, which are difficult to discern using native cross-linking methods. To ascertain the scope of non-canonical miRNA targeting, methods are needed that identify all targets of a given miRNA. We designed a new class of miR-CLIP probe, whereby psoralen is conjugated to the 3p arm of a pre-microRNA to capture targetomes of miR-124 and miR-132 in HEK293T cells. Processing of pre-miR-124 yields miR-124 and a 5′-extended isoform, iso-miR-124. Using miR-CLIP, we identified overlapping targetomes from both isoforms. From a set of 16 targets, 13 were differently inhibited at mRNA/protein levels by the isoforms. Moreover, delivery of pre-miR-124 into cells repressed these targets more strongly than individual treatments with miR-124 and iso-miR-124, suggesting that isomirs from one pre-miRNA may function synergistically. By mining the miR-CLIP targetome, we identified nine G-bulged target-sites that are regulated at the protein level by miR-124 but not isomiR-124. Using structural data, we propose a model involving AGO2 helix-7 that suggests why only miR-124 can engage these sites. In summary, access to the miR-124 targetome via miR-CLIP revealed for the first time how heterogeneous processing of miRNAs combined with non-canonical targeting mechanisms expand the regulatory range of a miRNA.
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Affiliation(s)
- Yuluan Wang
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
| | - Charlotte Soneson
- Department of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, 8057, Zurich, Switzerland
| | - Anna L Malinowska
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
| | - Artur Laski
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
| | - Souvik Ghosh
- Biozentrum, University of Basel, 4056 Basel, Switzerland
| | | | - Luca F R Gebert
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Mark D Robinson
- Department of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, 8057, Zurich, Switzerland
| | - Jonathan Hall
- Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland
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31
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Al-Rawaf HA, Alghadir AH, Gabr SA. Molecular Changes in Circulating microRNAs' Expression and Oxidative Stress in Adults with Mild Cognitive Impairment: A Biochemical and Molecular Study. Clin Interv Aging 2021; 16:57-70. [PMID: 33447019 PMCID: PMC7802783 DOI: 10.2147/cia.s285689] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The release of miRNAs in tissue fluids significantly recommends its use as non-invasive diagnostic biomarkers for the progression and pathogenesis of mild cognitive impairment (MCI) in aged patients. OBJECTIVE The potential role of circulated miRNAs in the pathogenesis of MCI and its association with cellular oxidative stress, apoptosis, and circulated BDNF, Sirtuin 1 (SIRT1), and dipeptidyl peptidase-4 (DPP4) were evaluated in older adults with MCI. METHODS A total of 150 subjects aged 65.4±3.7 years were recruited in this study. The participants were classified into two groups: healthy normal (n=80) and MCI (n=70). Real-time PCR analysis was performed to estimate the relative expression of miRNAs; miR-124a, miR-483-5p, miR-142-3p, and miR-125b, and apoptotic-related genes Bax, Bcl-2, and caspase-3 in the sera of MCI and control subjects. In addition, oxidative stress parameters; MDA, NO, SOD, and CAT; as well as plasma DPP4 activity, BDNF, SIRT1 levels were colorimetrically estimated. RESULTS The levels of miR-124a and miR-483-5p significantly increased and miR-142-3p and miR-125b significantly reduced in the serum of MCI patients compared to controls. The expressed miRNAs significantly correlated with severe cognitive decline, measured by MMSE, MoCA, ADL, and memory scores. The expression of Bax, and caspase-3 apoptotic inducing genes significantly increased and Bcl-2 antiapoptotic gene significantly reduced in MCI subjects compared to controls. In addition, the plasma levels of MDA, NO, and DPP4 activity significantly increased, and the levels of SOD, CAT, BDNF, and SIRT1 significantly reduced in MCI subjects compared to controls. The expressed miRNAs correlated positively with NO, MDA, DPP4 activity, BDNF, and SIRT-1, and negatively with the levels of CAT, SOD, Bcl-2, Bax, and caspase-3 genes. CONCLUSION Circulating miR-124a, miR-483-5p, miR-142-3p, and miR-125b significantly associated with severe cognitive decline, cellular oxidative stress, and apoptosis in patients with MCI. Thus, it could be potential non-invasive biomarkers for the diagnosis of MCI with high diagnostic performance.
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Affiliation(s)
- Hadeel A Al-Rawaf
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Sami A Gabr
- Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
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32
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Potter ML, Hill WD, Isales CM, Hamrick MW, Fulzele S. MicroRNAs are critical regulators of senescence and aging in mesenchymal stem cells. Bone 2021; 142:115679. [PMID: 33022453 PMCID: PMC7901145 DOI: 10.1016/j.bone.2020.115679] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 01/10/2023]
Abstract
MicroRNAs (miRNAs) have recently come under scrutiny for their role in various age-related diseases. Similarly, cellular senescence has been linked to disease and aging. MicroRNAs and senescence likely play an intertwined role in driving these pathologic states. In this review, we present the connection between these two drivers of age-related disease concerning mesenchymal stem cells (MSCs). First, we summarize key miRNAs that are differentially expressed in MSCs and other musculoskeletal lineage cells during senescence and aging. Additionally, we also reviewed miRNAs that are regulated via traditional senescence-associated secretory phenotype (SASP) cytokines in MSC. Lastly, we summarize miRNAs that have been found to target components of the cell cycle arrest pathways inherently activated in senescence. This review attempts to highlight potential miRNA targets for regenerative medicine applications in age-related musculoskeletal disease.
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Affiliation(s)
- Matthew L Potter
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America
| | - William D Hill
- Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, 29403, United States of America
| | - Carlos M Isales
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America
| | - Mark W Hamrick
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America
| | - Sadanand Fulzele
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America.
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33
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Niespolo C, Johnston JM, Deshmukh SR, Satam S, Shologu Z, Villacanas O, Sudbery IM, Wilson HL, Kiss-Toth E. Tribbles-1 Expression and Its Function to Control Inflammatory Cytokines, Including Interleukin-8 Levels are Regulated by miRNAs in Macrophages and Prostate Cancer Cells. Front Immunol 2020; 11:574046. [PMID: 33329538 PMCID: PMC7728618 DOI: 10.3389/fimmu.2020.574046] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/27/2020] [Indexed: 12/21/2022] Open
Abstract
The pseudokinase TRIB1 controls cell function in a range of contexts, by regulating MAP kinase activation and mediating protein degradation via the COP1 ubiquitin ligase. TRIB1 regulates polarization of macrophages and dysregulated Trib1 expression in murine models has been shown to alter atherosclerosis burden and adipose homeostasis. Recently, TRIB1 has also been implicated in the pathogenesis of prostate cancer, where it is often overexpressed, even in the absence of genetic amplification. Well described TRIB1 effectors include MAP kinases and C/EBP transcription factors, both in immune cells and in carcinogenesis. However, the mechanisms that regulate TRIB1 itself remain elusive. Here, we show that the long and conserved 3’untranslated region (3’UTR) of TRIB1 is targeted by miRNAs in macrophage and prostate cancer models. By using a systematic in silico analysis, we identified multiple “high confidence” miRNAs potentially binding to the 3’UTR of TRIB1 and report that miR-101-3p and miR-132-3p are direct regulators of TRIB1 expression and function. Binding of miR-101-3p and miR-132-3p to the 3’UTR of TRIB1 mRNA leads to an increased transcription and secretion of interleukin-8. Our data demonstrate that modulation of TRIB1 by miRNAs alters the inflammatory profile of both human macrophages and prostate cancer cells.
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Affiliation(s)
- Chiara Niespolo
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Jessica M Johnston
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Sumeet R Deshmukh
- Department of Molecular Biology and Biotechnology, Sheffield Institute for Nucleic Acids, University of Sheffield, Sheffield, United Kingdom
| | - Swapna Satam
- Institute for Diabetes and Cancer IDC, Helmholtz Center, Munich, Germany
| | - Ziyanda Shologu
- Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | | | - Ian M Sudbery
- Department of Molecular Biology and Biotechnology, Sheffield Institute for Nucleic Acids, University of Sheffield, Sheffield, United Kingdom
| | - Heather L Wilson
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Endre Kiss-Toth
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
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Meng T, Qin W, Liu B. SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication. Front Endocrinol (Lausanne) 2020; 11:568861. [PMID: 33304318 PMCID: PMC7701141 DOI: 10.3389/fendo.2020.568861] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/21/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications.
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Affiliation(s)
- Teng Meng
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University, Shenzhen, China
| | - Weifeng Qin
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
| | - Baohua Liu
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
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Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int J Mol Sci 2020; 21:ijms21218362. [PMID: 33171811 PMCID: PMC7664704 DOI: 10.3390/ijms21218362] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and 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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Ait-Aissa K, Nguyen QM, Gabani M, Kassan A, Kumar S, Choi SK, Gonzalez AA, Khataei T, Sahyoun AM, Chen C, Kassan M. MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy. Cardiovasc Diabetol 2020; 19:136. [PMID: 32907629 PMCID: PMC7488343 DOI: 10.1186/s12933-020-01107-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/28/2020] [Indexed: 01/17/2023] Open
Abstract
The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.
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Affiliation(s)
- Karima Ait-Aissa
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
| | - Quynh My Nguyen
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, USA
| | - Mohanad Gabani
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Adam Kassan
- Department of Pharmaceutical Sciences, School of Pharmacy, West Coast University, Los Angeles, USA
| | - Santosh Kumar
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Soo-Kyoung Choi
- Department of Physiology, College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Alexis A Gonzalez
- Instituto de Química, Pontificia, Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Tahsin Khataei
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Amal M Sahyoun
- Department of Food Science and Agriculture Chemistry, McGill University, Montreal, QC, Canada
| | - Cheng Chen
- Department of emergency and Critical Care, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Modar Kassan
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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Liu JH, Cao L, Zhang CH, Li C, Zhang ZH, Wu Q. Dihydroquercetin attenuates lipopolysaccharide-induced acute lung injury through modulating FOXO3-mediated NF-κB signaling via miR-132-3p. Pulm Pharmacol Ther 2020; 64:101934. [PMID: 32805387 DOI: 10.1016/j.pupt.2020.101934] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 07/15/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dihydroquercetin (DHQ) is a potent flavonoid which has been demonstrated to have multiple biological activities including anti-inflammation activity, antioxidant activity as well as anti-cancer activity etc. Recently, many studies have focused on the antioxidant activity of DHQ. However, the use of the anti-inflammation activity of DHQ in acute lung injury (ALI) has not been reported. METHODS Cell viability was examined by CCK-8 assay. The relative expression of miR-132-3p, FOXO3 were detected by qPCR. The levels of TNF-α, IL-6 and IL-1β were detected using enzyme-linked immunosorbent assay. The amount of apoptosis cells was detected by flow cytometry. The protein levels of Bcl-2, Bax, p-p65 and p-IκBα were measured by western blot. RESULTS We found that DHQ-induced the expression of miR-132-3p in LPS-induced ALI. Overexpression of miR-132-3p resulted in the inhibition of FOXO3 expression and then suppressed FOXO3-activated NF-κB pathway, attenuating LPS-induced inflammatory response and apoptosis. CONCLUSION We demonstrated FOXO3 to be a target of miR-132-3p, and DHQ could induce the expression of miR-132-3p, relieving LPS-induced ALI via miR-132-3p/FOXO3/NF-κB axis, providing a promising therapeutic target for ALI.
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Affiliation(s)
- Jian-Hua Liu
- Department of Respiratory and Critical Care Medicine, Haihe Clinical College of Tianjin Medical University, Tianjin, 300350, PR China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, PR China
| | - Liang Cao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, PR China
| | - Chang-Hong Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, PR China
| | - Chen Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, PR China
| | - Zhi-Hua Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, PR China
| | - Qi Wu
- Department of Respiratory and Critical Care Medicine, Haihe Clinical College of Tianjin Medical University, Tianjin, 300350, PR China.
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Rostamtabar M, Esmaeilzadeh S, Tourani M, Rahmani A, Baee M, Shirafkan F, Saleki K, Mirzababayi SS, Ebrahimpour S, Nouri HR. Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome. J Cell Physiol 2020; 236:824-838. [PMID: 32617971 DOI: 10.1002/jcp.29912] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/28/2020] [Accepted: 06/15/2020] [Indexed: 12/29/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive-aged women. Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne. Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists. In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics. Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell. Therefore, the PCOS can be related to a low-grade inflammation state and inflammatory markers. Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways. In the present review, we discuss the pathophysiological roles of chronic low-grade inflammation mediators including inflammasome-related cytokines, interleukin-1β (IL-1β), and IL-18 in PCOS development.
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Affiliation(s)
- Maryam Rostamtabar
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Sedigheh Esmaeilzadeh
- Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Mehdi Tourani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Abolfazl Rahmani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Masoud Baee
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Fatemeh Shirafkan
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | - Soheil Ebrahimpour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Hamid Reza Nouri
- Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran.,Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Menikdiwela KR, Ramalingam L, Abbas MM, Bensmail H, Scoggin S, Kalupahana NS, Palat A, Gunaratne P, Moustaid-Moussa N. Role of microRNA 690 in Mediating Angiotensin II Effects on Inflammation and Endoplasmic Reticulum Stress. Cells 2020; 9:cells9061327. [PMID: 32466437 PMCID: PMC7348980 DOI: 10.3390/cells9061327] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/15/2020] [Accepted: 05/22/2020] [Indexed: 12/27/2022] Open
Abstract
Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.
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Affiliation(s)
- Kalhara R. Menikdiwela
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.R.M.); (L.R.); (S.S.); (N.S.K.)
| | - Latha Ramalingam
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.R.M.); (L.R.); (S.S.); (N.S.K.)
| | - Mostafa M. Abbas
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar; (M.M.A.); (H.B.)
- Department of Imaging Science and Innovation, Geisinger Health System, Danville, PA 17822, USA
| | - Halima Bensmail
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha 34110, Qatar; (M.M.A.); (H.B.)
| | - Shane Scoggin
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.R.M.); (L.R.); (S.S.); (N.S.K.)
| | - Nishan S. Kalupahana
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.R.M.); (L.R.); (S.S.); (N.S.K.)
- Department of Physiology, University of Peradeniya, Peradeniya 20400, Sri Lanka
| | - Asha Palat
- Biology and Biochemistry, University of Houston, Houston, TX 77204, USA; (A.P.); (P.G.)
| | - Preethi Gunaratne
- Biology and Biochemistry, University of Houston, Houston, TX 77204, USA; (A.P.); (P.G.)
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA; (K.R.M.); (L.R.); (S.S.); (N.S.K.)
- Correspondence: ; Tel.: +806-834-7946
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Intracranial Self-Stimulation Modulates Levels of SIRT1 Protein and Neural Plasticity-Related microRNAs. Mol Neurobiol 2020; 57:2551-2562. [PMID: 32219698 DOI: 10.1007/s12035-020-01901-w] [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: 09/23/2019] [Accepted: 03/09/2020] [Indexed: 02/07/2023]
Abstract
Deep brain stimulation (DBS) of reward system brain areas, such as the medial forebrain bundle (MFB), by means of intracranial self-stimulation (ICSS), facilitates learning and memory in rodents. MFB-ICSS has been found capable of modifying different plasticity-related proteins, but its underlying molecular mechanisms require further elucidation. MicroRNAs (miRNAs) and the longevity-associated SIRT1 protein have emerged as important regulatory molecules implicated in neural plasticity. Thus, we aimed to analyze the effects of MFB-ICSS on miRNAs expression and SIRT1 protein levels in hippocampal subfields and serum. We used OpenArray to select miRNA candidates differentially expressed in the dentate gyrus (DG) of ICSS-treated (3 sessions, 45' session/day) and sham rats. We further analyzed the expression of these miRNAs, together with candidates selected after bibliographic screening (miR-132-3p, miR-134-5p, miR-146a-5p, miR-181c-5p) in DG, CA1, and CA3, as well as in serum, by qRT-PCR. We also assessed tissue and serum SIRT1 protein levels by Western Blot and ELISA, respectively. Expression of miR-132-3p, miR-181c-5p, miR-495-3p, and SIRT1 protein was upregulated in DG of ICSS rats (P < 0.05). None of the analyzed molecules was regulated in CA3, while miR-132-3p was also increased in CA1 (P = 0.011) and serum (P = 0.048). This work shows for the first time that a DBS procedure, specifically MFB-ICSS, modulates the levels of plasticity-related miRNAs and SIRT1 in specific hippocampal subfields. The mechanistic role of these molecules could be key to the improvement of memory by MFB-ICSS. Moreover, regarding the proposed clinical applicability of DBS, serum miR-132 is suggested as a potential treatment biomarker.
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Vaknine S, Soreq H. Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors. Neuropharmacology 2020; 168:108020. [PMID: 32143069 DOI: 10.1016/j.neuropharm.2020.108020] [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: 11/10/2019] [Revised: 02/09/2020] [Accepted: 02/25/2020] [Indexed: 12/31/2022]
Abstract
Acetylcholinesterase (AChE) inhibitors modulate acetylcholine hydrolysis and hence play a key role in determining the cholinergic tone and in implementing its impact on the cholinergic blockade of inflammatory processes. Such inhibitors may include rapidly acting small molecule AChE-blocking drugs and poisonous anti-AChE insecticides or war agent inhibitors which penetrate both body and brain. Notably, traumatized patients may be hyper-sensitized to anti-AChEs due to their impaired cholinergic tone, higher levels of circulation pro-inflammatory cytokines and exacerbated peripheral inflammatory responses. Those largely depend on the innate-immune system yet reach the brain via vagus pathways and/or disrupted blood-brain-barrier. Other regulators of the neuro-inflammatory cascade are AChE-targeted microRNAs (miRs) and synthetic chemically protected oligonucleotide blockers thereof, whose size prevents direct brain penetrance. Nevertheless, these larger molecules may exert parallel albeit slower inflammatory regulating effects on brain and body tissues. Additionally, oligonucleotide aptamers interacting with innate immune Toll-Like Receptors (TLRs) may control inflammation through diverse routes and in different rates. Such aptamers may compete with the action of both small molecule inhibitors and AChE-inhibiting miRs in peripheral tissues including muscle and intestine. However, rapid adaptation processes, visualized in neuromuscular junctions enable murine survival under otherwise lethal anti-cholinesterase exposure; and both miR inhibitors and TLR-modulating aptamers may exert body-brain signals protecting experimental mice from acute inflammation. The complex variety of AChE inhibiting molecules identifies diverse body-brain communication pathways which may rapidly induce long-lasting central reactions to peripheral stressful and inflammatory insults in both mice and men. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
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Affiliation(s)
- Shani Vaknine
- The Edmond and Lily Safra Center of Brain Science, The Life Sciences Institute, The Hebrew University of Jerusalem, 9190401, Israel
| | - Hermona Soreq
- The Edmond and Lily Safra Center of Brain Science, The Life Sciences Institute, The Hebrew University of Jerusalem, 9190401, Israel.
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Majidinia M, Mir SM, Mirza-Aghazadeh-Attari M, Asghari R, Kafil HS, Safa A, Mahmoodpoor A, Yousefi B. MicroRNAs, DNA damage response and ageing. Biogerontology 2020; 21:275-291. [PMID: 32067137 DOI: 10.1007/s10522-020-09862-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/08/2020] [Indexed: 02/07/2023]
Abstract
Ageing is a multifactorial and integrated gradual deterioration affecting the most of biological process of cells. MiRNAs are differentially expressed in the cellular senescence and play important role in regulating of genes expression involved in features of ageing. The perception of miRNAs functions in ageing regulation can be useful in clarifying the mechanisms underlying ageing and designing of therapeutic strategies. The preservation of genomic integrity through DNA damage response (DDR) is related to the process of cellular senescence. The recent studies have shown that miRNAs has directly regulated the expression of numerous proteins in DDR pathways. In this review study, DDR pathways, miRNA biogenesis and functions, current finding on DDR regulations, molecular biology of ageing and the role of miRNAs in these processes have been studied. Finally, a brief explanation about the therapeutic function of miRNAs in ageing regarding its regulation of DDR has been provided.
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Affiliation(s)
- Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Seyed Mostafa Mir
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | - Roghaieh Asghari
- Anesthesiology Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Stem Cell Center Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Safa
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam. .,Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain.
| | - Ata Mahmoodpoor
- Anesthesiology Research Team, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Yousefi
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Center Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Chandan K, Gupta M, Sarwat M. Role of Host and Pathogen-Derived MicroRNAs in Immune Regulation During Infectious and Inflammatory Diseases. Front Immunol 2020; 10:3081. [PMID: 32038627 PMCID: PMC6992578 DOI: 10.3389/fimmu.2019.03081] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/17/2019] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs, miRs) are short, endogenously initiated, non-coding RNAs that bind to target mRNAs, leading to the degradation or translational suppression of respective mRNAs. They have been reported as key players in physiological processes like differentiation, cellular proliferation, development, and apoptosis. They have gained importance as gene expression regulators in the immune system. They control antibody production and release various inflammatory mediators. Abnormal expression and functioning of miRNA in the immune system is linked to various diseases like inflammatory disorders, allergic diseases, cancers etc. As compared to the average human genome, miRNA targets the genes of immune system quite differently. miRNA appeared to regulate the responses related to both acquired and innate immunity of the humans. Several miRNAs importantly regulate the transcription and even, dysregulation of inflammation-related mediators. Many miRNAs are either upregulated or downregulated in various inflammatory and infectious diseases. Hence, modifying or targeting the expression of miRNAs might serve as a novel strategy for the diagnosis, prevention, and treatment of various inflammatory and infectious conditions.
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Affiliation(s)
| | | | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida, India
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45
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Shoeibi S. Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis. Acta Physiol (Oxf) 2020; 228:e13353. [PMID: 31344321 DOI: 10.1111/apha.13353] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are a group of small single strand and noncoding RNAs that regulate several physiological and molecular signalling pathways. Alterations of miRNA expression profiles may be involved with pathophysiological processes underlying the development of atherosclerosis and cardiovascular diseases, including changes in the functions of the endothelial cells and vascular smooth muscle cells, such as cell proliferation, migration and inflammation, which are involved in angiogenesis, macrophage function and foam cell formation. Thus, miRNAs can be considered to have a crucial role in the progression, modulation and regulation of every stage of atherosclerosis. Such potential biomarkers will enable us to predict therapeutic response and prognosis of cardiovascular diseases and adopt effective preclinical and clinical treatment strategies. In the present review article, the current data regarding the role of miRNAs in atherosclerosis were summarized and the potential miRNAs as prognostic, diagnostic and theranostic biomarkers in preclinical and clinical studies were further discussed. The highlights of this review are expected to present opportunities for future research of clinical therapeutic approaches in vascular diseases resulting from atherosclerosis with an emphasis on miRNAs.
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Affiliation(s)
- Sara Shoeibi
- Atherosclerosis Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
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46
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Gholami M, Larijani B, Zahedi Z, Mahmoudian F, Bahrami S, Omran SP, Saadatian Z, Hasani-Ranjbar S, Taslimi R, Bastami M, Amoli MM. Inflammation related miRNAs as an important player between obesity and cancers. J Diabetes Metab Disord 2019; 18:675-692. [PMID: 31890692 PMCID: PMC6915181 DOI: 10.1007/s40200-019-00459-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/23/2019] [Indexed: 12/13/2022]
Abstract
The growing trend in addition to their burden, prevalence, and death has made obesity and cancer two of the most concerning diseases worldwide. Obesity is an important risk factor for common types of cancers where the risk of some cancers is directly related to the obesity. Various inflammatory mechanisms and increased level of pro-inflammatory cytokines have been investigated in many previous studies, which play key roles in the pathophysiology and development of both of these conditions. On the other hand, in the recent years, many studies have individually focused on the biomarker's role and therapeutic targeting of microRNAs (miRNAs) in different types of cancers and obesity including newly discovered small noncoding RNAs (sncRNAs) which regulate gene expression and RNA silencing. This study is a comprehensive review of the main inflammation related miRNAs in obesity/obesity related traits. For the first time, the main roles of miRNAs in obesity related cancers have been discussed in response to the question raised in the following hypothesis; do the main inflammatory miRNAs link obesity with obesity-related cancers regarding their role as biomarkers? Graphical abstractConceptual design of inflammatory miRNAs which provide link between obesity and cancers.
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Affiliation(s)
- Morteza Gholami
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zhila Zahedi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mahmoudian
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Bahrami
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sima Parvizi Omran
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 5th floor, Shariati Hospital, North Kargar Ave, Tehran, Iran
| | - Zahra Saadatian
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Hasani-Ranjbar
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Taslimi
- Department of Gastroenterology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa M. Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 5th floor, Shariati Hospital, North Kargar Ave, Tehran, Iran
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MiR-124 suppression in the prefrontal cortex reduces depression-like behavior in mice. Biosci Rep 2019; 39:BSR20190186. [PMID: 31431514 PMCID: PMC6744582 DOI: 10.1042/bsr20190186] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/30/2019] [Accepted: 08/19/2019] [Indexed: 02/04/2023] Open
Abstract
Depression is a potentially life-threatening mental disorder with unknown etiology. Several microRNAs (miRNAs) have been shown to play critical roles in the etiology of depression. Here, we aim to elucidate the anti-depressive behavior of miR-124 suppression in prefrontal cortex (PFC). Quantitative real-time PCR (RT-PCR) was used to evaluate the expression of miR-124 and SIRT1 in the PFC of a chronic unpredictable mild stress (CUMS) model. The PFC of C57BL/6J mice was bilaterally injected with lentiviral vectors (LV) for ectopic expression of SIRT1, miR-124, or miR-124 inhibitor (si-miR-124). The anti-depressive behavior was observed after injection of LV-SIRT1 or LV-si-miR-124 into the PFC, using behavior tests including latency to feed, food and water intake, sucrose preference test, and forced swimming test. MiR-124 overexpression and inhibition resulted in upregulation and down-regulation of SIRT1 and cyclic AMP responsive element binding protein 1 (CREB1), respectively. MiR-124 overexpression exacerbated depression-like behaviors and decreased SIRT1. Further, dual-luciferase assay confirmed that SIRT1 was a target of miR-124. Taken together, a potential molecular regulation of miR-124 on SIRT1 is revealed by our study and miR-124 suppression in PFC is a potential strategy to reduce depression-like behavior.
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Landrier JF, Derghal A, Mounien L. MicroRNAs in Obesity and Related Metabolic Disorders. Cells 2019; 8:cells8080859. [PMID: 31404962 PMCID: PMC6721826 DOI: 10.3390/cells8080859] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 12/14/2022] Open
Abstract
Metabolic disorders are characterized by the inability to properly use and/or store energy. The burdens of metabolic disease, such as obesity or diabetes, are believed to arise through a complex interplay between genetics and epigenetics predisposition, environment and nutrition. Therefore, understanding the molecular mechanisms for the onset of metabolic disease will provide new insights for prevention and treatment. There is growing concern about the dysregulation of micro-RNAs (miRNAs) in metabolic diseases. MiRNAs are short non-coding RNA molecules that post-transcriptionally repress the expression of genes by binding to untranslated regions and coding sequences of the target mRNAs. This review aims to provide recent data about the potential involvement of miRNAs in metabolic diseases, particularly obesity and type 2 diabetes.
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Affiliation(s)
| | - Adel Derghal
- Aix Marseille Univ, INSERM, INRA, C2VN, 13005 Marseille, France
| | - Lourdes Mounien
- Aix Marseille Univ, INSERM, INRA, C2VN, 13005 Marseille, France.
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SIRT1 Modulates the Sensitivity of Prostate Cancer Cells to Vesicular Stomatitis Virus Oncolysis. J Virol 2019; 93:JVI.00626-19. [PMID: 31092575 DOI: 10.1128/jvi.00626-19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 05/06/2019] [Indexed: 12/21/2022] Open
Abstract
Oncolytic virotherapy represents a promising experimental anticancer strategy, based on the use of genetically modified viruses to selectively infect and kill cancer cells. Vesicular stomatitis virus (VSV) is a prototypic oncolytic virus (OV) that induces cancer cell death through activation of the apoptotic pathway, although intrinsic resistance to oncolysis is found in some cell lines and many primary tumors, as a consequence of residual innate immunity to the virus. In the effort to improve OV therapeutic efficacy, we previously demonstrated that different agents, including histone deacetylase inhibitors (HDIs), functioned as reversible chemical switches to dampen the innate antiviral response and improve the susceptibility of resistant cancer cells to VSV infection. In the present study, we demonstrated that the NAD+-dependent histone deacetylase SIRT1 (silent mating type information regulation 2 homolog 1) plays a key role in the permissivity of prostate cancer PC-3 cells to VSVΔM51 replication and oncolysis. HDI-mediated enhancement of VSVΔM51 infection and cancer cell killing directly correlated with a decrease of SIRT1 expression. Furthermore, pharmacological inhibition as well as silencing of SIRT1 by small interfering RNA (siRNA) was sufficient to sensitize PC-3 cells to VSVΔM51 infection, resulting in augmentation of virus replication and spread. Mechanistically, HDIs such as suberoylanilide hydroxamic acid (SAHA; Vorinostat) and resminostat upregulated the microRNA miR-34a that regulated the level of SIRT1. Taken together, our findings identify SIRT1 as a viral restriction factor that limits VSVΔM51 infection and oncolysis in prostate cancer cells.IMPORTANCE The use of nonpathogenic viruses to target and kill cancer cells is a promising strategy in cancer therapy. However, many types of human cancer are resistant to the oncolytic (cancer-killing) effects of virotherapy. In this study, we identify a host cellular protein, SIRT1, that contributes to the sensitivity of prostate cancer cells to infection by a prototypical oncolytic virus. Knockout of SIRT1 activity increases the sensitivity of prostate cancer cells to virus-mediated killing. At the molecular level, SIRT1 is controlled by a small microRNA termed miR-34a. Altogether, SIRT1 and/or miR-34a levels may serve as predictors of response to oncolytic-virus therapy.
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Abstract
Perivascular adipose tissue (PVAT) refers to the local aggregate of adipose tissue surrounding the vascular tree, exhibiting phenotypes from white to brown and beige adipocytes. Although PVAT has long been regarded as simply a structural unit providing mechanical support to vasculature, it is now gaining reputation as an integral endocrine/paracrine component, in addition to the well-established modulator endothelium, in regulating vascular tone. Since the discovery of anti-contractile effect of PVAT in 1991, the use of multiple rodent models of reduced amounts of PVAT has revealed its regulatory role in vascular remodeling and cardiovascular implications, including atherosclerosis. PVAT does not only release PVAT-derived relaxing factors (PVRFs) to activate multiple subsets of endothelial and vascular smooth muscle potassium channels and anti-inflammatory signals in the vasculature, but it does also provide an interface for neuron-adipocyte interactions in the vascular wall to regulate arterial vascular tone. In this review, we outline our current understanding towards PVAT and attempt to provide hints about future studies that can sharpen the therapeutic potential of PVAT against cardiovascular diseases and their complications.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Hamidah Abu Bakar
- Health Sciences Department, Universiti Selangor, 40000, Shah Alam, Selangor, Malaysia
| | - Maik Gollasch
- Experimental and Clinical Research Center (ECRC)-a joint cooperation between the Charité-University Medicine Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany.
- Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Yu Huang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
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