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Karmakar A, Augustine ABHR, Thummer RP. Genes as Genome Stabilizers in Pluripotent Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40095244 DOI: 10.1007/5584_2025_853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Pluripotent stem cells, comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are characterized by their self-renewal capacity and the ability to differentiate into cells of all three germ layers of an adult animal. Out of the two, iPSCs are generated through the reprogramming of somatic cells by inducing a pluripotency-specific transcriptional program. This process requires a resetting of the somatic cell genome to a pluripotent cell-specific genome, resulting in cellular stress at genomic, epigenetic, and transcriptional levels. Notably, in contrast to the predominant compact and inactive organization of chromatin in somatic cells, the chromatin in ESCs and iPSCs is open. Furthermore, maintaining a pluripotent state needs a plethora of changes in the genetic landscape of the cells. Here, we attempt to elucidate how certain genes safeguard genomic stability in ESCs and iPSCs, aiding in the complex cellular mechanisms that regulate self-renewal, pluripotency, and somatic reprogramming.
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Affiliation(s)
- Asmita Karmakar
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Allan Blessing Harison Raj Augustine
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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2
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Tang Y, Sun L, Li S, Luo L, Liu H, Chen Z, Li G. miR-9-5p regulates Sirt1 involved in testicular development and spermatogenesis in mouse. Theriogenology 2024; 230:61-71. [PMID: 39270444 DOI: 10.1016/j.theriogenology.2024.09.007] [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: 01/02/2023] [Revised: 08/16/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
Testicular development and spermatogenesis are critical for male reproduction, with histone (de)acetylation playing a key role in chromatin remodeling within germ cells. Sirt1, a key histone deacetylase, is implicated in chromatin remodeling, but its expression pattern and specific role in testicular development and spermatogenesis need further study. This study comprehensively analyzed Sirt1 expression in adult and juvenile mouse testicular tissues and across various male germ cells, utilizing RT-qPCR, Western blot, immunofluorescence, and cell transfection. GO and KEGG enrichment analyses were performed to elucidate the biological functions and pathways associated with Sirt1 and its related genes. Multiple miRNA databases were utilized to predict miRNAs targeting Sirt1, and their expression levels were validated using RT-qPCR. Lentiviral transfection was used to knockdown candidate miRNAs to assess their functional roles. The results revealed a significant downregulation of Sirt1 expression in adult mouse testicular tissues compared to juvenile tissues, with pronounced variation across diverse male germ cells. Sirt1 was highly expressed in spermatogonia and mature sperm, but comparatively lower in spermatocytes and spermatids. GO and KEGG enrichment analyses highlighted Sirt1's role in key biological processes, including chromatin organization, regulation of cell proliferation, and energy homeostasis, as well as its association with signaling pathways like cellular senescence, the FoxO signaling pathway, and the AMPK signaling pathway. Bioinformatic analysis and subsequent RT-qPCR validation identified miR-9-5p as a miRNA targeting Sirt1. The expression of miR-9-5p was significantly higher in adult mouse testicular tissues compared to juvenile tissues, inversely correlating with Sirt1 levels. Moreover, the knockdown of miR-9-5p led to a notable increase in Sirt1 mRNA and protein expression. In conclusion, Sirt1 is a key player in mouse testicular development and spermatogenesis. The discovery that miR-9-5p negatively regulates Sirt1 suggests a critical regulatory axis that may govern these processes, providing novel insights into male fertility and potential targets for therapeutic intervention.
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Affiliation(s)
- Yulian Tang
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Lishuang Sun
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Shu Li
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Lvjing Luo
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Huiting Liu
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Zhengyu Chen
- Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Genliang Li
- Youjiang Medical University for Nationalities, Baise, 533000, China.
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Gong X, Yang SY, Wang ZY, Tang M. The role of hypoxic microenvironment in autoimmune diseases. Front Immunol 2024; 15:1435306. [PMID: 39575238 PMCID: PMC11578973 DOI: 10.3389/fimmu.2024.1435306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.
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Affiliation(s)
- Xun Gong
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Su-Yin Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen-Yu Wang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
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Zhu F, Yang M, Wang D, Jiang Y, Jia C, Fu Y, Yu A, Liu H, Wang M, Wang T, Liu H, Li J. Spatial distribution of maternal factors in pig mature oocytes. Anim Biotechnol 2024; 35:2394692. [PMID: 39185998 DOI: 10.1080/10495398.2024.2394692] [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: 04/08/2024] [Accepted: 08/15/2024] [Indexed: 08/27/2024]
Abstract
It is known that asymmetrical maternal transcripts play an important role in the cell fate of the early embryo, but few studies are available in mammal oocytes especially in pig. To investigate the spatial factors in pig oocytes, the oriented bisection was established for collecting karyoplasts (NSOs) and cytoplasts (SSOs) with more than 95% efficiency. Subsequently, RNA-Seq and LC-MS/MS analysis were performed on NSOs and SSOs. Although no differentially expressed genes (DEGs) could be detected between NSOs and SSOs, 89 of the differentially expressed proteins (DEPs) were detected, that 58 proteins higher expressed but 31 proteins lower expressed in NSOs compared with SSOs. These DEPs mainly participated in the 'cell cycle' and 'ribosome' pathway, while the up-regulated DEPs were mainly GO in 'spindle' and 'positive regulation of translation', and the down-regulated DEPs were in 'cytosolic small ribosomal subunit' and 'mRNA binding'. The up-regulated DEP SIRT5 which are related to the regulation of gene expression, epigenetic were further detected and revealed. A spatial asymmetry of maternal factors at the protein level was firstly detected in pig mature oocytes.
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Affiliation(s)
- Fuquan Zhu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Meng Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Dayu Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yuan Jiang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Chao Jia
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yanfeng Fu
- Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Aochen Yu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Huijun Liu
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang Province, China
| | - Meixia Wang
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang Province, China
| | - Tingzhang Wang
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Zhejiang Institute of Microbiology, Hangzhou, Zhejiang Province, China
| | - Honglin Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Juan Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
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Tan D, Huang Z, Zhao Z, Chen X, Liu J, Wang D, Deng Z, Li W. Single‑cell sequencing, genetics, and epigenetics reveal mesenchymal stem cell senescence in osteoarthritis (Review). Int J Mol Med 2024; 53:2. [PMID: 37937669 PMCID: PMC10688769 DOI: 10.3892/ijmm.2023.5326] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 10/04/2023] [Indexed: 11/09/2023] Open
Abstract
Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage degeneration, secondary bone hyperplasia, inadequate extracellular matrix synthesis and degeneration of articular cartilage. Mesenchymal stem cells (MSCs) can self‑renew and undergo multidirectional differentiation; they can differentiate into chondrocytes. Aging MSCs have a weakened ability to differentiate, and release various pro‑inflammatory cytokines, which may contribute to OA progression; the other mechanism contributing to OA is epigenetic regulation (for instance, DNA methylation, histone modification and regulation of non‑coding RNA). Owing to the self‑renewal and differentiation ability of MSCs, various MSC‑based exogenous cell therapies have been developed to treat OA. The efficacy of MSC‑based therapy is mainly attributed to cytokines, growth factors and the paracrine effect of exosomes. Recently, extensive studies have been conducted on MSC‑derived exosomes. Exosomes from MSCs can deliver a variety of DNA, RNA, proteins and lipids, thereby facilitating MSC migration and cartilage repair. Therefore, MSC‑derived exosomes are considered a promising therapy for OA. The present review summarized the association between MSC aging and OA in terms of genetics and epigenetics, and characteristics of MSC‑derived exosomes, and the mechanism to alleviate OA cartilage damage.
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Affiliation(s)
- Dunyong Tan
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Zeqi Huang
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Zhe Zhao
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Xiaoqiang Chen
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Jianquan Liu
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Daping Wang
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Zhiqin Deng
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
| | - Wencui Li
- Hand and Foot Surgery Department, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, Guangdong 518000, P.R. China
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Maiese K. Mitochondria, Mitophagy, Mitoptosis, and Programmed Cell Death: Implications from Aging to Cancer. Curr Neurovasc Res 2024; 21:1-5. [PMID: 38251666 DOI: 10.2174/1567202621999240118155618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
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Amato I, Meurant S, Renard P. The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate. Int J Mol Sci 2023; 24:12181. [PMID: 37569553 PMCID: PMC10418455 DOI: 10.3390/ijms241512181] [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: 06/30/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
The study of the mechanisms underlying stem cell differentiation is under intensive research and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has strengthened the interest in the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission, and mitophagy processes as well as emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.
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Affiliation(s)
- Ilario Amato
- Ressearch Unit in Cell Biology (URBC), Namur Research Institute for Life Sciences (Narilis), University of Namur (UNamur), 5000 Namur, Belgium; (I.A.); (S.M.)
| | - Sébastien Meurant
- Ressearch Unit in Cell Biology (URBC), Namur Research Institute for Life Sciences (Narilis), University of Namur (UNamur), 5000 Namur, Belgium; (I.A.); (S.M.)
| | - Patricia Renard
- Ressearch Unit in Cell Biology (URBC), Namur Research Institute for Life Sciences (Narilis), University of Namur (UNamur), 5000 Namur, Belgium; (I.A.); (S.M.)
- Mass Spectrometry Platform (MaSUN), Namur Research Institute for Life Sciences (Narilis), University of Namur (UNamur), 5000 Namur, Belgium
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Mormone E, Iorio EL, Abate L, Rodolfo C. Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming. Front Neurosci 2023; 17:1073689. [PMID: 36816109 PMCID: PMC9929468 DOI: 10.3389/fnins.2023.1073689] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/13/2023] [Indexed: 02/04/2023] Open
Abstract
Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation's steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency's reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD+-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere's chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.
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Affiliation(s)
- Elisabetta Mormone
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy,*Correspondence: Elisabetta Mormone, ;
| | | | - Lucrezia Abate
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carlo Rodolfo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy,Department of Paediatric Onco-Haematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy,Carlo Rodolfo,
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Al-Azab M, Safi M, Idiiatullina E, Al-Shaebi F, Zaky MY. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting. Cell Mol Biol Lett 2022; 27:69. [PMID: 35986247 PMCID: PMC9388978 DOI: 10.1186/s11658-022-00366-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.
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Fluorofenidone Inhibits UUO/IRI-Induced Renal Fibrosis by Reducing Mitochondrial Damage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2453617. [PMID: 35355864 PMCID: PMC8958071 DOI: 10.1155/2022/2453617] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/21/2022] [Accepted: 02/01/2022] [Indexed: 12/11/2022]
Abstract
Objective Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism. Method Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF-β with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined. Results In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1α, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-β, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression. Conclusion We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.
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Bai L, Yang ZX, Ma PF, Liu JS, Wang DS, Yu HC. Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5. Free Radic Biol Med 2022; 182:11-22. [PMID: 35182732 DOI: 10.1016/j.freeradbiomed.2022.02.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 02/13/2022] [Accepted: 02/14/2022] [Indexed: 11/21/2022]
Abstract
Solute carrier family 25 member 20 (SLC25A51) is a newly identified mammalian mitochondrial NAD+ transporter. However, the clinicopathological and biological significance of SLC25A51 in human cancers, including hepatocellular carcinoma (HCC), remains unclear. The aim of this study was to define the role of SLC25A51 in HCC progression. Here we demonstrate that SLC25A51 is significantly overexpressed in human HCC specimens and cell lines, caused by, at least in partial, the decrease of miR-212-3p. SLC25A51 overexpression is positively correlated with the clinicopathological characteristics of vascular invasion and tumor diameter, as well as poor survival in patients with HCC. Knockdown of SLC25A51 attenuated, while overexpression of SLC25A51 enhanced the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistically, glucose metabolism reprogramming from oxidative phosphorylation to glycolysis by activation of mitochondrial sirtuin 5 (SIRT5) was found to contribute to the promotion of growth and metastasis by SLC25A51 in HCC cells. Together, these findings reveal important roles of SLC25A51 in HCC tumorigenesis and suggest SLC25A51 as a promising prognostic marker and therapeutic target for treating HCC.
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Affiliation(s)
- Lu Bai
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Zhao-Xu Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Peng-Fei Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jian-Shan Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - De-Sheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China.
| | - Heng-Chao Yu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China.
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Chen R, Huang H, Liang L, Zhang W, Zheng Y, Fu D, Lin S. Improving the repair mechanism and miRNA expression profile of tibial defect in rats based on silent information regulator 7 protein analysis of mesenchymal stem cells. Bioengineered 2022; 13:4674-4687. [PMID: 35139764 PMCID: PMC8973621 DOI: 10.1080/21655979.2022.2027066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
The aim of this study was to verify the role of Silent Information Regulator 7 (SIRT7) in improving the repair mechanism of bone marrow mesenchymal stem cells (BMMSCs) and the expression of microribonucleic acid (miRNA). Human BMMSCs were extracted from patients with femoral fractures, and the proliferation activity of human BMMSCs before and after knockout SIRT7 and the expression levels of bone-related genes and proteins were compared. Thirty-two 8-week-old male Sprague-Dawley (SD) rats were randomly divided into a blank group, a chitosan scaffold group, a control group, and a silence information regulator knockout group 7 (n = 8). In addition to the blank group, the chitosan scaffold, the green fluorescent protein (GFP) transfected stem cell composite chitosan scaffold, and the SIRT7 knockout stem cell composite chitosan scaffold were implanted in the other three groups, respectively. The X-rays and small animal in vivo three-dimensional tomography (Micro-CT) were adopted to quantitatively analyze the volume fraction, the number of trabeculae, and the connection density. Compared with the other three groups, the bone defect was formed more in the medullary mesenchymal stem cell knockout group, and the bone volume fraction, number of trabeculae and connection density were significantly increased (P < 0.05). MiR-98-5p can significantly promote the formation of bone molecules and bone structure in rats (P < 0.05). Human BMMSCs combined with chitosan scaffold can accelerate the repair of tibial defects. MiR-98-5p targeting and regulating bone formation gene (CKIP-1) could significantly improve the process of osteogenesis in rats.
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Affiliation(s)
| | | | - Li Liang
- Orthopaedic Trauma, Maoming People's Hospital, Maoming City, China
| | - Weibin Zhang
- Orthopaedic Trauma, Maoming People's Hospital, Maoming City, China
| | - Yingjie Zheng
- Orthopaedic Trauma, Maoming People's Hospital, Maoming City, China
| | - Dehong Fu
- Orthopaedic Trauma, Maoming People's Hospital, Maoming City, China
| | - Shibang Lin
- Orthopaedic Trauma, Maoming People's Hospital, Maoming City, China
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13
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Hansen JM, Lucas SM, Ramos CD, Green EJ, Nuttall DJ, Clark DS, Marchant ED, Hancock CR, Piorczynski TB. Valproic acid promotes SOD2 acetylation: A potential mechanism of valproic acid-induced oxidative stress in developing systems. Free Radic Res 2021; 55:1130-1144. [PMID: 34895005 DOI: 10.1080/10715762.2021.2017913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Valproic acid (VPA) is an antiepileptic, bipolar and migraine medication, which is associated with embryonic dysmorphology, more specifically neural tube defects (NTDs), if taken while pregnant. One mechanism by which VPA may cause NTDs is through oxidative stress that cause disruption of cell signaling. However, mechanisms of VPA-induced oxidative stress are not fully understood. Since VPA is a deacetylase inhibitor, we propose that VPA promotes mitochondrial superoxide dismutase-2 (SOD2) acetylation, decreasing SOD2 activity and increasing oxidant levels. Using the pluripotent embryonal carcinoma cell line, P19, VPA effects were evaluated in undifferentiated and neurodifferentiated cells. VPA treatments increased oxidant levels, oxidized the glutathione (GSH)/glutathione disulfide (GSSG) redox couple, and decreased total SOD and SOD2 activity in undifferentiated P19 cells but not in differentiated P19 cells. VPA caused a specific increase in mitochondrial oxidants in undifferentiated P19 cells, VPA did not alter respirometry measurements. Immunoblot analyses demonstrated that VPA increased acetylation of SOD2 at lysine68 (AcK68 SOD2) in undifferentiated P19 cells but not in differentiated P19 cells. Pretreatments with the Nrf2 inducer, dithiol-3-thione (D3T), in undifferentiated P19 cells prevented increased oxidant levels, GSH/GSSG redox oxidation and restored total SOD and SOD2 activity, correlating with a decrease in AcK68 SOD2 levels. In embryos, VPA decreased total SOD and SOD2 activity and increased levels of AcK68 SOD2, and D3T pretreatments prevented VPA effects, increasing total SOD and SOD2 activity and lowering levels of AcK68 SOD2. These data demonstrate a potential, contributing oxidizing mechanism by which VPA incites teratogenesis in developing systems. Moreover, these data also suggest that Nrf2 interventions may serve as a means to protect developmental signaling and inhibit VPA-induced malformations.
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Affiliation(s)
| | | | | | | | | | | | - Erik D Marchant
- Department of Nutrition, Dietetics and Food Science, College of Life Sciences, Brigham Young University, Provo, Utah, USA
| | - Chad R Hancock
- Department of Nutrition, Dietetics and Food Science, College of Life Sciences, Brigham Young University, Provo, Utah, USA
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14
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Samoilova EM, Belopasov VV, Ekusheva EV, Zhang C, Troitskiy AV, Baklaushev VP. Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation. J Pers Med 2021; 11:1050. [PMID: 34834402 PMCID: PMC8620936 DOI: 10.3390/jpm11111050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
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Affiliation(s)
- Ekaterina M. Samoilova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | | | - Evgenia V. Ekusheva
- Academy of Postgraduate Education of the Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies, FMBA of Russia, 125371 Moscow, Russia;
| | - Chao Zhang
- Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China;
| | - Alexander V. Troitskiy
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | - Vladimir P. Baklaushev
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
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15
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Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism. J Pers Med 2021; 11:jpm11090905. [PMID: 34575682 PMCID: PMC8466012 DOI: 10.3390/jpm11090905] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 12/11/2022] Open
Abstract
Human-induced pluripotent stem cells (hiPSCs) offer numerous possibilities in science and medicine, particularly when combined with precise genome editing methods. hiPSCs are artificially generated equivalents of human embryonic stem cells (hESCs), which possess an unlimited ability to self-renew and the potential to differentiate into any cell type of the human body. Importantly, generating patient-specific hiPSCs enables personalized drug testing or autologous cell therapy upon differentiation into a desired cell line. However, to ensure the highest standard of hiPSC-based biomedical products, their safety and reliability need to be proved. One of the key factors influencing human pluripotent stem cell (hPSC) characteristics and function is oxygen concentration in their microenvironment. In recent years, emerging data have pointed toward the beneficial effect of low oxygen pressure (hypoxia) on both hiPSCs and hESCs. In this review, we examine the state-of-the-art research on the oxygen impact on hiPSC functions and activity with an emphasis on their niche, metabolic state, reprogramming efficiency, and differentiation potential. We also discuss the similarities and differences between PSCs and cancer stem cells (CSCs) with respect to the role of oxygen in both cell types.
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16
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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17
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18
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Di Emidio G, Falone S, Artini PG, Amicarelli F, D’Alessandro AM, Tatone C. Mitochondrial Sirtuins in Reproduction. Antioxidants (Basel) 2021; 10:antiox10071047. [PMID: 34209765 PMCID: PMC8300669 DOI: 10.3390/antiox10071047] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 12/21/2022] Open
Abstract
Mitochondria act as hubs of numerous metabolic pathways. Mitochondrial dysfunctions contribute to altering the redox balance and predispose to aging and metabolic alterations. The sirtuin family is composed of seven members and three of them, SIRT3-5, are housed in mitochondria. They catalyze NAD+-dependent deacylation and the ADP-ribosylation of mitochondrial proteins, thereby modulating gene expression and activities of enzymes involved in oxidative metabolism and stress responses. In this context, mitochondrial sirtuins (mtSIRTs) act in synergistic or antagonistic manners to protect from aging and aging-related metabolic abnormalities. In this review, we focus on the role of mtSIRTs in the biological competence of reproductive cells, organs, and embryos. Most studies are focused on SIRT3 in female reproduction, providing evidence that SIRT3 improves the competence of oocytes in humans and animal models. Moreover, SIRT3 protects oocytes, early embryos, and ovaries against stress conditions. The relationship between derangement of SIRT3 signaling and the imbalance of ROS and antioxidant defenses in testes has also been demonstrated. Very little is known about SIRT4 and SIRT5 functions in the reproductive system. The final goal of this work is to understand whether sirtuin-based signaling may be taken into account as potential targets for therapeutic applications in female and male infertility.
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Affiliation(s)
- Giovanna Di Emidio
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (S.F.); (F.A.); (A.M.D.); (C.T.)
- Correspondence: ; Tel.: +39-(0)-862-433-441
| | - Stefano Falone
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (S.F.); (F.A.); (A.M.D.); (C.T.)
| | - Paolo Giovanni Artini
- Department of Obstetrics and Gynecology “P. Fioretti”, University of Pisa, 56126 Pisa, Italy;
| | - Fernanda Amicarelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (S.F.); (F.A.); (A.M.D.); (C.T.)
| | - Anna Maria D’Alessandro
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (S.F.); (F.A.); (A.M.D.); (C.T.)
| | - Carla Tatone
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (S.F.); (F.A.); (A.M.D.); (C.T.)
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19
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Giallongo S, Rehakova D, Raffaele M, Lo Re O, Koutna I, Vinciguerra M. Redox and Epigenetics in Human Pluripotent Stem Cells Differentiation. Antioxid Redox Signal 2021; 34:335-349. [PMID: 32567336 DOI: 10.1089/ars.2019.7983] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Since their discovery, induced pluripotent stem cells (iPSCs) had generated considerable interest in the scientific community for their great potential in regenerative medicine, disease modeling, and cell-based therapeutic approach, due to their unique characteristics of self-renewal and pluripotency. Recent Advances: Technological advances in iPSC genome-wide epigenetic profiling led to the elucidation of the epigenetic control of cellular identity during nuclear reprogramming. Moreover, iPSC physiology and metabolism are tightly regulated by oxidation-reduction events that mainly occur during the respiratory chain. In theory, iPSC-derived differentiated cells would be ideal for stem cell transplantation as autologous cells from donors, as the risks of rejection are minimal. Critical Issues: However, iPSCs experience high oxidative stress that, in turn, confers a high risk of increased genomic instability, which is most often linked to DNA repair deficiencies. Genomic instability has to be assessed before iPSCs can be used in therapeutic designs. Future Directions: This review will particularly focus on the links between redox balance and epigenetic modifications-in particular based on the histone variant macroH2A1-that determine DNA damage response in iPSCs and derived differentiated cells, and that might be exploited to decrease the teratogenic potential on iPSC transplantation. Antioxid. Redox Signal. 34, 335-349.
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Affiliation(s)
- Sebastiano Giallongo
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Daniela Rehakova
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.,Faculty of Informatics, Centre for Biomedical Image Analysis, Masaryk University, Brno, Czech Republic
| | - Marco Raffaele
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic
| | - Oriana Lo Re
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic
| | - Irena Koutna
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.,Faculty of Informatics, Centre for Biomedical Image Analysis, Masaryk University, Brno, Czech Republic
| | - Manlio Vinciguerra
- International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.,Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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20
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Simulated Microgravity Suppresses Osteogenic Differentiation of Mesenchymal Stem Cells by Inhibiting Oxidative Phosphorylation. Int J Mol Sci 2020; 21:ijms21249747. [PMID: 33371243 PMCID: PMC7767150 DOI: 10.3390/ijms21249747] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 12/15/2022] Open
Abstract
Studies showed that energy metabolism plays a pivotal role in the differentiation of stem cells. Previous studies revealed that simulated microgravity (SMG) inhibits osteogenic differentiation of mesenchymal stem cells (MSCs). However, the underlying relationship between osteogenesis and energy metabolism under SMG conditions is not fully understood. In the present study, we investigated mitochondrial oxidative phosphorylation (OXPHOS) by assessing the level of peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α), mitochondrial DNA (mtDNA) copy number, mitochondrial mass and oxygen consumption rate (OCR) during osteogenesis of MSCs under SMG conditions. We found that SMG inhibited osteogenic differentiation and OXPHOS of MSCs. Moreover, the expression of sirtuin 1 (Sirt1), an important energy sensor, significantly decreased. After upregulating the expression of Sirt1 using resveratrol, an activator of Sirt1, SMG-inhibited OXPHOS and osteogenic differentiation of MSCs were recovered. Taken together, our results suggest that SMG suppresses osteogenic differentiation of MSCs by inhibiting OXPHOS, indicating that OXPHOS might serve as a potential therapeutic target for repairing bone loss under microgravity conditions.
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21
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Xia C, Tao Y, Li M, Che T, Qu J. Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Exp Ther Med 2020; 20:2923-2940. [PMID: 32855658 PMCID: PMC7444376 DOI: 10.3892/etm.2020.9073] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 04/24/2020] [Indexed: 12/16/2022] Open
Abstract
Cells primarily rely on proteins to perform the majority of their physiological functions, and the function of proteins is regulated by post-translational modifications (PTMs). The acetylation of proteins is a dynamic and highly specific PTM, which has an important influence on the functions of proteins, such as gene transcription and signal transduction. The acetylation of proteins is primarily dependent on lysine acetyltransferases and lysine deacetylases. In recent years, due to the widespread use of mass spectrometry and the emergence of new technologies, such as protein chips, studies on protein acetylation have been further developed. Compared with histone acetylation, acetylation of non-histone proteins has gradually become the focus of research due to its important regulatory mechanisms and wide range of applications. The discovery of specific protein acetylation sites using bioinformatic tools can greatly aid the understanding of the underlying mechanisms of protein acetylation involved in related physiological and pathological processes.
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Affiliation(s)
- Can Xia
- Department of Cell Biology, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yu Tao
- Department of Cell Biology, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Mingshan Li
- Department of Cell Biology, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Tuanjie Che
- Laboratory of Precision Medicine and Translational Medicine, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou Science and Technology Town Hospital, Suzhou, Jiangsu 215153, P.R. China
| | - Jing Qu
- Department of Cell Biology, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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22
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Withaferin A Exerts Preventive Effect on Liver Fibrosis through Oxidative Stress Inhibition in a Sirtuin 3-Dependent Manner. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2452848. [PMID: 33029279 PMCID: PMC7532400 DOI: 10.1155/2020/2452848] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/14/2020] [Accepted: 09/05/2020] [Indexed: 12/11/2022]
Abstract
Sirtuin 3 (SIRT3) is a deacetylase involved in the development of many inflammation-related diseases including liver fibrosis. Withaferin A (WFA) is a bioactive constituent derived from the Withania somnifera plant, which has extensive pharmacological activities; however, little is known about the regulatory role of SIRT3 in the WFA-induced antifibrogenic effect. The current study is aimed at investigating the role of SIRT3 in WFA-induced antioxidant effects in liver fibrosis. Our study verified that WFA attenuated platelet-derived growth factor BB- (PDGF-BB-) induced liver fibrosis and promoted PDGF-BB-induced SIRT3 activity and expression in JS1 cells. SIRT3 silencing attenuated the antifibrogenic and antioxidant effects of WFA in activated JS1 cells. Moreover, WFA inhibited carbon tetrachloride- (CCl4-) induced liver injury, collagen deposition, and fibrosis; increased the SIRT3 expression; and suppressed the CCl4-induced oxidative stress in fibrotic livers of C57/BL6 mice. Furthermore, the antifibrogenic and antioxidant effects of WFA could be available in CCl4-induced WT (129S1/SvImJ) mice but were unavailable in CCl4-induced SIRT3 knockout (KO) mice. Our study suggested that WFA inhibited liver fibrosis through the inhibition of oxidative stress in a SIRT3-dependent manner. WFA could be a potential compound for the treatment of liver fibrosis.
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23
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Lai X, Li Q, Wu F, Lin J, Chen J, Zheng H, Guo L. Epithelial-Mesenchymal Transition and Metabolic Switching in Cancer: Lessons From Somatic Cell Reprogramming. Front Cell Dev Biol 2020; 8:760. [PMID: 32850862 PMCID: PMC7423833 DOI: 10.3389/fcell.2020.00760] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) and its critical roles during cancer progression have long been recognized and extensively reviewed. Recent studies on the generation of induced pluripotent stem cells (iPSCs) have established the connections among EMT, energy metabolism, DNA methylation, and histone modification. Since energy metabolism, DNA methylation, and histone modification are important for cancer development and there are common characteristics between cancer cells and stem cells, it is reasonable to identify mechanisms that have been established during both reprogramming and cancer progression. In the current review, we start from a brief review on EMT and related processes during cancer progression, and then switch to the EMT during somatic cell reprogramming. We summarize the connection between EMT and metabolic switch during reprogramming, and further review the involvements of DNA methylation and cell proliferation. The connections between EMT and mesenchymal-epithelial transition (MET) and cellular aspects including DNA methylation, histone modification and energy metabolism may provide potential new targets for cancer diagnosis and treatment.
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Affiliation(s)
- Xiaowei Lai
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Qian Li
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Fang Wu
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Jiechun Lin
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Jiekai Chen
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Hui Zheng
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
| | - Lin Guo
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
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24
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Du L, Liu X, Ren Y, Li J, Li P, Jiao Q, Meng P, Wang F, Wang Y, Wang YS, Wang C. Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells. Theranostics 2020; 10:9458-9476. [PMID: 32863939 PMCID: PMC7449925 DOI: 10.7150/thno.44688] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022] Open
Abstract
Rationale: It has been proposed that cancer stem/progenitor cells (or tumor-initiating cells, TICs) account for breast cancer initiation and progression. Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class-III histone deacetylases and mediate various basic biological processes, including metabolic homeostasis. However, interplay and cross-regulation among the sirtuin family are not fully understood. As one of the least studied sirtuin family members, the mitochondrial sirtuin SIRT4 is a tumor suppressor gene in various cancers. However, its role in cancer stemness, as well as initiation and progression of breast cancer, remains unknown. Methods: The expression of SIRT4 in breast cancer was analyzed using the TCGA breast cancer database and 3 GSEA data. Normal breast epithelial cells MCF10A and breast cancer cell lines MCF-7, MDA-MB-231, BT549, MDA-MB-468 were used to establish SIRT4 gene knockdown and corresponding overexpression cells. Identified MTT cytotoxicity assays, cell invasion and motility assay, sorting of SP, confocal immunofluorescence microscopy, mouse mammary stem cell analysis, glutamine and glucose production, clonogenic and sphere-formation assay, mass spectrometric metabolomics analysis and ChIP-seq to further explore SIRT4 biological role in breast cancer. Results: We elucidated a novel role for SIRT4 in the negative regulation of mammary gland development and stemness, which is related to the mammary tumorigenesis. We also uncovered an inverse correlation between SIRT4 and SIRT1. Most importantly, SIRT4 negatively regulates SIRT1 expression via repressing glutamine metabolism. Besides, we identified H4K16ac and BRCA1 as new prime targets of SIRT4 in breast cancer. Conclusions: These results demonstrate that SIRT4 exerts its tumor-suppressive activity via modulating SIRT1 expression in breast cancer and provide a novel cross-talk between mitochondrial and nuclear sirtuins.
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Affiliation(s)
- Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Qinlian Jiao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
- International Biotechnology R&D Center, Shandong University School of Ocean, 180 Wenhua Xi Road, Weihai, Shandong 264209, China
| | - Peng Meng
- The Medical Department of IVD Division, 3D Medicines, Inc., Pujiang Hi‑tech Park, Shanghai 201114, China
| | - Fang Wang
- Institute of basic medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Yuli Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Yun-shan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, China
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Roles of Mitochondrial Sirtuins in Mitochondrial Function, Redox Homeostasis, Insulin Resistance and Type 2 Diabetes. Int J Mol Sci 2020; 21:ijms21155266. [PMID: 32722262 PMCID: PMC7432223 DOI: 10.3390/ijms21155266] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/19/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Mitochondria are the metabolic hubs that process a number of reactions including tricarboxylic acid cycle, β-oxidation of fatty acids and part of the urea cycle and pyrimidine nucleotide biosynthesis. Mitochondrial dysfunction impairs redox homeostasis and metabolic adaptation, leading to aging and metabolic disorders like insulin resistance and type 2 diabetes. SIRT3, SIRT4 and SIRT5 belong to the sirtuin family proteins and are located at mitochondria and also known as mitochondrial sirtuins. They catalyze NAD+-dependent deacylation (deacetylation, demalonylation and desuccinylation) and ADP-ribosylation and modulate the function of mitochondrial targets to regulate the metabolic status in mammalian cells. Emerging evidence has revealed that mitochondrial sirtuins coordinate the regulation of gene expression and activities of a wide spectrum of enzymes to orchestrate oxidative metabolism and stress responses. Mitochondrial sirtuins act in synergistic or antagonistic manners to promote respiratory function, antioxidant defense, insulin response and adipogenesis to protect individuals from aging and aging-related metabolic abnormalities. In this review, we focus on the molecular mechanisms by which mitochondrial sirtuins regulate oxidative metabolism and antioxidant defense and discuss the roles of their deficiency in the impairment of mitochondrial function and pathogenesis of insulin resistance and type 2 diabetes.
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Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells. Cancers (Basel) 2020; 12:cancers12030663. [PMID: 32178477 PMCID: PMC7139964 DOI: 10.3390/cancers12030663] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/07/2020] [Accepted: 03/09/2020] [Indexed: 12/18/2022] Open
Abstract
Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.
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Chen C, Zhou M, Ge Y, Wang X. SIRT1 and aging related signaling pathways. Mech Ageing Dev 2020; 187:111215. [PMID: 32084459 DOI: 10.1016/j.mad.2020.111215] [Citation(s) in RCA: 380] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/30/2020] [Accepted: 02/17/2020] [Indexed: 12/30/2022]
Abstract
Aging is a biological phenomenon in which the structure and function of organisms declining with the increasing of age. It has become a major risk factor of human diseases, including diabetes, cancers, cardiovascular diseases and neurodegenerative diseases. Silencing information regulator 2 related enzyme 1(sirtuin1, SIRT1) is an NAD+-dependent deacetylase, which has been reported to be involved in the regulation of cellular senescence and aging. The expression of SIRT1 is diminished with aging in mice. By contrast, increased expression of SIRT1 is sufficient to extend lifespan in yeast, caenorhabditis elegans and mice. In this review, the relationship between SIRT1 and aging and various signaling networks associated with aging, including NF-κB, AMPK, mTOR, P53, PGC1α, and FoxOs will be discussed. Meanwhile, the potential therapeutic strategies of targeting SIRT1 to anti-aging are also addressed.
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Affiliation(s)
- Cui Chen
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Min Zhou
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Yuchen Ge
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Xiaobo Wang
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan, 671000, China.
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Sergi C, Shen F, Liu SM. Insulin/IGF-1R, SIRT1, and FOXOs Pathways-An Intriguing Interaction Platform for Bone and Osteosarcoma. Front Endocrinol (Lausanne) 2019; 10:93. [PMID: 30881341 PMCID: PMC6405434 DOI: 10.3389/fendo.2019.00093] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 02/01/2019] [Indexed: 12/25/2022] Open
Abstract
Aging is a substantial risk factor for the development of osteoarthritis (OA) and, probably, an essential substrate for the development of neoplastic disease of the bone, such as osteosarcoma, which is the most common malignant mesenchymal primary bone tumor. Genetic studies have established that the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) signal transduction pathway is involved across species, including nematodes, fruit flies, and mammals. SIRT1, a phylogenetically-conserved family of deacetylases, seems to play pleiotropic effects in epithelial malignancies of the liver and interact with the IGF-1/PI3K/AKT signal transduction pathway. Some of the most critical processes in degenerative conditions may indeed include the insulin/IGF1R and SIRT1 signaling pathways as well as some specific transcription factors. The Forkhead box O (FOXO) transcription factors (FOXOs) control diverse cellular functions, such as metabolism, longevity, and cell death. FOXOs play a critical role in the IGF-1/PI3K/AKT signal transduction pathway. FOXOs can indeed be modulated to reduce age-related diseases. FOXOs have advantageous inhibitory effects on fibroblast and myofibroblast activation, which are accompanied by a subsequent excessive production of extracellular matrix. FOXOs can block or decrease the fibrosis levels in numerous organs. Previously, we observed a correlation between nuclear FOXO3 and high caspase-8 expression, which induces cellular apoptosis in response to harmful external stimuli. In this perspective, we emphasize the current advances and interactions involving the insulin/IGF1R, SIRT1, and FOXOs pathways in the bone and osteosarcoma for a better understanding of the mechanisms potentially underpinning tissue degeneration and tumorigenesis.
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Affiliation(s)
- Consolato Sergi
- Department of Orthopedics, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
- Department of Pediatrics, Stollery Children's Hospital, Edmonton, AB, Canada
| | - Fan Shen
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
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Wu YT, Chi KT, Lan YW, Chan JC, Ma YS, Wei YH. Depletion of Sirt3 leads to the impairment of adipogenic differentiation and insulin resistance via interfering mitochondrial function of adipose-derived human mesenchymal stem cells. Free Radic Res 2018; 52:1398-1415. [PMID: 29898623 DOI: 10.1080/10715762.2018.1489130] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Upregulation of mitochondrial function and oxidative metabolism is a hallmark in the differentiation of stem cells. However, the mechanism underlying the metabolic reprogramming and upregulation of mitochondrial function during the differentiation of human mesenchymal stem cells (hMSCs) is largely unclear. Sirt3 has emerged as a sensor in regulating mitochondrial function and antioxidant defence system in cellular response to energy demand or environmental stimuli, but its roles in stem cell differentiation have not been fully understood. In this study, we used adipose-derived hMSCs (ad-hMSCs) to investigate the role of Sirt3 in adipogenic differentiation and in the function of mature adipocytes. We showed that at the early stage of adipogenic differentiation, Sirt3 upregulation is essential for the activation of biogenesis and bioenergetic function of mitochondria. In addition, we found that induction of Forkhead Box O 3a (FoxO3a), an upstream factor that regulates MnSOD gene transcription, is involved in the upregulation of antioxidant enzymes at the early stage of adipogenic differentiation. Silencing of Sirt3 by shRNA decreased the protein level of FoxO3a and subsequently downregulated a number of FoxO3a-mediated antioxidant enzymes and increased oxidative stress in ad-hMSCs after adipogenic induction. Importantly, depletion of Sirt3 compromised the ability of ad-hMSCs to undergo adipogenic differentiation and led to adipocyte dysfunction and insulin resistance. These findings suggest that Sirt3-mediated protein deacetylation plays an important role in regulating oxidative metabolism and antioxidant defence in stem cell differentiation, and that Sirt3 deficiency may be related to insulin resistance.
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Affiliation(s)
- Yu-Ting Wu
- a Center for Mitochondrial Medicine and Free Radical Research , Changhua Christian Hospital , Changhua City , Taiwan.,b Institute of Biochemistry and Molecular Biology , National Yang-Ming University , Taipei , Taiwan
| | - Kun-Ting Chi
- b Institute of Biochemistry and Molecular Biology , National Yang-Ming University , Taipei , Taiwan
| | - Yueh-Wen Lan
- b Institute of Biochemistry and Molecular Biology , National Yang-Ming University , Taipei , Taiwan
| | - Jui-Chi Chan
- b Institute of Biochemistry and Molecular Biology , National Yang-Ming University , Taipei , Taiwan
| | - Yi-Shing Ma
- a Center for Mitochondrial Medicine and Free Radical Research , Changhua Christian Hospital , Changhua City , Taiwan
| | - Yau-Huei Wei
- a Center for Mitochondrial Medicine and Free Radical Research , Changhua Christian Hospital , Changhua City , Taiwan.,b Institute of Biochemistry and Molecular Biology , National Yang-Ming University , Taipei , Taiwan.,c Institute of Biomedical Sciences , Mackay Medical College , New Taipei City , Taiwan
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Maiese K. Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer's Disease. Curr Neurovasc Res 2018; 15:367-371. [PMID: 30484407 PMCID: PMC6538488 DOI: 10.2174/1567202616666181128120003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/14/2018] [Accepted: 10/20/2018] [Indexed: 02/07/2023]
Abstract
The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world's population and life expectancy will increase well over eighty years of age. Accompanied by the aging of the global population is a significant rise in Non-Communicable Diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer's Disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, Aβ toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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