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      MiR-182/Sestrin2 affects the function of asthmatic airway smooth muscle cells by the AMPK/mTOR pathway

      research-article
      , , , , , , , , , , Ph.D.
      Journal of Translational Internal Medicine
      De Gruyter
      asthma, ASMCs, Sestrin2, miR-182, AMPK/mTOR pathway

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          Abstract

          Background and Objectives

          Asthma is a chronic inflammatory airway disease and brings heavy economic and spiritual burdens to patients’ families and the society. Airway smooth muscle cells (ASMCs) afect the development of asthma by secreting cytokines, growth factors, and prostates. The stress-inducing protein, Sestrin2, plays a vital role in antioxidant defense. The aim of this study is to investigate the role of Sestrin2 in asthma and its corresponding molecular mechanism.

          Materials and Methods

          Airway remodeling was induced by construction of asthma rat model. Primary ASMCs were isolated through combining tissue block adherence and enzymatic digestion and identified by immunofluorescence staining. Gene expression was measured by quantitative real-time PCR (qPCR) and western blot (WB) experiments. Cell viability, proliferation, migration, and calcium flow of ASMCs were measured by Cell Counting Kit-8 (CCK-8), 5-ethynyl-deoxyuridine (EdU), Transwell, and Fluo-3AM, respectively. The binding of miR-182 and Sestrin2 3′-untranslated region (3′-UTR) was measured by luciferase reporter system and RNA-binding protein immunoprecipitation (RIP) analysis.

          Results

          Sestrin2 expression was upregulated in asthma rat model and cell model. Overexpression of Sestrin2 enhanced the growth, migration, and calcium flow, and inversely, repression of Sestrin2 was reduced in ASMCs from the asthma group. MiR-182, one of the microRNAs (miRNAs) that possesses the potential to regulate Sestrin2, was downregulated in ASMCs from the asthma group. Further experiments revealed that Sestrin2 was inhibited by miR-182 and that overexpression of Sestrin2 reversed the miR-182–induced inhibition of the cellular progression of ASMCs from the asthma group. This study further investigated the downstream signaling pathway of Sestrin2 and found that increased expression of Sestrin2 activated 5′-adenosine monophosphate-activated protein kinase (AMPK), leading to the inactivation of mammalian target of rapamycin (mTOR) and thus promoting the growth, migration, and calcium flow of ASMCs from the asthma group.

          Conclusion

          This study investigated the role of Sestrin2 for the first time and further dissected the regulatory factor of Sestrin2, ultimately elucidating the downstream signaling pathway of Sestrin2 in asthma, providing a novel pathway, and improving the understanding of the development and progression of asthma.

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          Most cited references28

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          A Brief Review on the Mechanisms of miRNA Regulation

          MicroRNAs (miRNAs) are a class of short, endogenously-initiated non-coding RNAs that post-transcriptionally control gene expression via either translational repression or mRNA degradation. It is becoming evident that miRNAs are playing significant roles in regulatory mechanisms operating in various organisms, including developmental timing and host-pathogen interactions as well as cell differentiation, proliferation, apoptosis and tumorigenesis. Likewise, as a regulatory element, miRNA itself is coordinatively modulated by multifarious effectors when carrying out basic functions, such as SNP, miRNA editing, methylation and circadian clock. This mini-review summarized the current understanding of interactions between miRNAs and their targets, including recent advancements in deciphering the regulatory mechanisms that control the biogenesis and functionality of miRNAs in various cellular processes.
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            Global strategy for asthma management and prevention: GINA executive summary.

            Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.
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              Asthma: definitions and pathophysiology.

              James Mims (2015)
              Asthma is a common condition due to chronic inflammation of the lower respiratory tract. Chronic lower airway inflammation is known to be more common in individuals that also have inflammatory disorders of the upper airway. The scientific understanding of asthma continues to improve and it is important for providers who treat upper or lower airway inflammation to be familiar with asthma's definition and pathophysiology.
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                Author and article information

                Contributors
                Journal
                J Transl Int Med
                J Transl Int Med
                jtim
                jtim
                Journal of Translational Internal Medicine
                De Gruyter
                2450-131X
                2224-4018
                24 August 2021
                September 2023
                : 11
                : 3
                : 282-293
                Affiliations
                Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital , Zhengzhou 450003, Henan Province, China
                Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital , Zhengzhou 450003, Henan Province, China
                Department of Respiratory and Critical Care Medicine, Henan University of Traditional Chinese Medicine, Henan Provincial People’s Hospital , Zhengzhou 450046, Henan Province, China
                Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital , Zhengzhou 450003, Henan Province, China
                Author notes
                Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, No.7 Weiwu Road, Zhengzhou 450003, Henan Province, China

                #These two authors contributed equally to this work.

                Article
                jtim-2021-0033
                10.2478/jtim-2021-0033
                10476473
                37662894
                a3117a39-88e0-4ca6-a6ea-b4b4c2dff10e
                © 2023 Yali Xiao, He Zhu, Jiahui Lei, Jing Xie, Ke Wu, Wenbo Gu, Jinxin Ma, Dongxue wei, Zhenhui Shu, Limin Zhao, published by De Gruyter on behalf of Scholar Media Publishing

                This work is licensed under the Creative Commons Attribution 4.0 International License.

                History
                Page count
                Pages: 12
                Funding
                This work was supported by the special research project of traditional Chinese medicine in Henan Province (20-21ZY1068) and the National Natural Science Foundation of China (U2004120).
                Categories
                Original Article

                asthma,asmcs,sestrin2,mir-182,ampk/mtor pathway
                asthma, asmcs, sestrin2, mir-182, ampk/mtor pathway

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