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André DCA, Oliveira PF, Alves MG, Martins AD. Caloric Restriction and Sirtuins as New Players to Reshape Male Fertility. Metabolites 2025; 15:303. [PMID: 40422880 DOI: 10.3390/metabo15050303] [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: 03/11/2025] [Revised: 04/25/2025] [Accepted: 04/30/2025] [Indexed: 05/28/2025] Open
Abstract
Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown to be a promising contributor towards longevity and delaying the onset of age-related diseases. This diet consists of a reduction in caloric intake while maintaining essential energy and nutritional requirements to achieve optimal health while avoiding malnutrition. However, the effects of this nutritional regimen on male reproductive health have not yet been comprehensively studied. Nevertheless, such a complex process will certainly be regulated by a variety of metabolic sensors, likely sirtuins. Evidence has been gathered regarding this group of enzymes, and their ability to regulate processes such as chromatin condensation, the cell cycle, insulin signaling, and glucose and lipid metabolism, among many others. Concerning testicular function and male fertility, sirtuins can modulate certain metabolic processes through their interaction with the hypothalamic-pituitary-gonadal axis and mitochondrial dynamics, among many others, which remain largely unexplored. This review explores the impact of caloric restriction on male fertility, highlighting the emerging role of sirtuins as key regulators of male reproductive health through their influence on cellular metabolism.
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Affiliation(s)
- Diana C A André
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Pedro F Oliveira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Marco G Alves
- Institute of Biomedicine, Department of Medical Sciences (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ana D Martins
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
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2
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Peng B, Wang Y, Zhang H. Mitonuclear Communication in Stem Cell Function. Cell Prolif 2025; 58:e13796. [PMID: 39726221 PMCID: PMC12099226 DOI: 10.1111/cpr.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
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Affiliation(s)
- Baozhou Peng
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yaning Wang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Hongbo Zhang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
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3
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Heo YJ, Park J, Lee N, Choi SE, Jeon JY, Han SJ, Kim DJ, Lee KW, Kim HJ. Empagliflozin Alleviates Hepatic Steatosis and Oxidative Stress via the NRF1 Pathway in High-Fat Diet-Induced Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci 2025; 26:4054. [PMID: 40362294 PMCID: PMC12071685 DOI: 10.3390/ijms26094054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
Empagliflozin (EMPA)-a sodium-glucose cotransporter type 2 inhibitor-reduces endoplasmic reticulum (ER) stress, oxidative stress, and inflammation during metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the direct effects of EMPA on hepatic lipid metabolism and oxidative stress are unclear. Through the current study, we seek to explore the effects of EMPA on oxidative stress and related mechanisms in MASLD. To this end, MASLD was induced in C57BL/6J mice using a high-fat diet (HFD); nuclear respiratory factor 1 (NRF1) was downregulated via viral transduction (AAV8-shNrf1). Glucose homeostasis and liver histology were assessed, and oxidative stress and inflammation were measured. HFD-fed mice-derived liver tissue samples exhibited more lipid droplets, higher triglyceride levels, and elevated oxidative and ER stress than chow diet (CD)-fed mice. EMPA attenuated HFD-induced liver oxidative and ER stress. Additionally, the HFD significantly decreased NRF1 and Sirtuin (SIRT)7 expression compared with CD, which was rescued by EMPA treatment. However, these results did not affect insulin resistance or lipid synthesis-related changes upon EMPA treatment in the Nrf1-knockdown mice. Furthermore, EMPA alleviated HFD-induced hepatic steatosis and oxidative stress; however, these effects were lost in Nrf1-knockdown mice. Collectively, the results of this study suggest that EMPA ameliorates MASLD by reducing steatosis and attenuating oxidative stress via NRF1.
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Affiliation(s)
- Yu Jung Heo
- Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Jieun Park
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Sung-E Choi
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (J.P.); (N.L.); (S.-E.C.); (J.Y.J.); (S.J.H.); (D.J.K.); (K.W.L.)
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Barthez M, Xue B, Zheng J, Wang Y, Song Z, Mu WC, Wang CL, Guo J, Yang F, Ma Y, Wei X, Ye C, Sims N, Martinez-Sobrido L, Perlman S, Chen D. SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19. Cell Rep 2025; 44:115562. [PMID: 40220296 PMCID: PMC12074670 DOI: 10.1016/j.celrep.2025.115562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/11/2024] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.
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Affiliation(s)
- Marine Barthez
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Biyun Xue
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA
| | - Jian Zheng
- Department of Microbiology and Immunology, Center for Predictive Medicine, University of Louisville, Louisville, KY, USA
| | - Yifei Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Zehan Song
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Wei-Chieh Mu
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Chih-Ling Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jiayue Guo
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Fanghan Yang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yuze Ma
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Xuetong Wei
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Chengjin Ye
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Nicholas Sims
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | | | - Stanley Perlman
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
| | - Danica Chen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
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Yu T, Ding C, Peng J, Liang G, Tang Y, Zhao J, Li Z. SIRT7-mediated NRF2 deacetylation promotes antioxidant response and protects against chemodrug-induced liver injury. Cell Death Dis 2025; 16:232. [PMID: 40169535 PMCID: PMC11961749 DOI: 10.1038/s41419-025-07549-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 04/03/2025]
Abstract
NRF2 has been recognized as a central hub that neutralizes ROS and restores intracellular redox balance. In addition to KEAP1 mediated ubiquitin-proteasome degradation, post-translational modifications of NRF2 are critical for regulating its nuclear translocation and activation but precise mechanisms underly this regulation remain elusive. In this study, we found that SIRT7 was sufficient and essential for NRF2 nuclear localization and activation. Knockdown of SIRT7 significantly impaired intercellular ROS homeostasis and increased apoptosis in response to oxidative stress including chemodrug treatment. SIRT7 interacted with NRF2 and induced its deacetylation, by which inhibited binding of NRF2 to KEAP1, enhanced NRF2 protein stability and promoted its nuclear translocation. SIRT7 induced NRF2 deacetylation at K443 and K518 sites. Lysine-arginine mutations of these sites (2KR NRF2) significantly reduced KEAP1/NRF2 binding, increased NRF2 nuclear translocation and target gene expression, decreased intercellular ROS level, whereas lysine-glutamine (2KQ) mutant showed similar subcellular localization and functions with WT. Knockdown SIRT7 in hepatocyte exacerbated Oxaliplatin (Oxa) induced hepatic injury and inflammation. While AAV8-NRF2-mediated hepatic NRF2 overexpression or NRF2 agonist significantly prevented Oxa-induced elevation of ALT levels, sinusoidal dilatation and inflammation in SIRT7HKO mice. Our data thus uncovered previously unidentified role of SIRT7 in modulating NRF2 nuclear localization and activation via deacetylation. Activating SIRT7 might offer protection against chemodrug-induced liver injury.
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Affiliation(s)
- Tingzi Yu
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China
| | - Cong Ding
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China
| | - Jinying Peng
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China
| | - Gaoshuang Liang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China
| | - Yongyi Tang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China
| | - Jinqiu Zhao
- Department of infectious disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- Department of Cancer center, University of Hawaii at Manoa, Honolulu, HI, USA.
| | - Zhuan Li
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, and Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, Hunan, China.
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Zhang J, Liu C, Luo W, Sun B. Role of SIRT7 in Prostate Cancer Progression: New Insight Into Potential Therapeutic Target. Cancer Med 2025; 14:e70786. [PMID: 40165597 PMCID: PMC11959159 DOI: 10.1002/cam4.70786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/20/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025] Open
Abstract
Prostate cancer (PCa) is the second most common cancer in men worldwide, and understanding its molecular mechanisms is crucial for developing effective treatment strategies. SIRT7, a NAD+-dependent histone deacetylase, has emerged as a key regulator in PCa progression due to its roles in chromatin remodeling, DNA repair, and transcriptional regulation. Analysis of 492 PCa samples from The Cancer Genome Atlas (TCGA) via cBioPortal revealed that high SIRT7 expression is associated with poor prognosis in PCa patients. Mechanistically, SIRT7 deacetylates histone H3 at lysine 18 (H3K18Ac), a marker associated with aggressive tumors, suppressing tumor suppressor genes and promoting cancer cell proliferation and survival. Epithelial-mesenchymal transition (EMT) is a cellular biological process in which epithelial cells undergo specific molecular and morphological changes to transform into cells with characteristics of mesenchymal cells. SIRT7 also regulates EMT, and inhibiting SIRT7 in PCa cell lines reduces cell migration and invasion, highlighting its potential as a therapeutic target. In summary, the clinical significance of SIRT7 expression in PCa requires further research to elucidate its mechanisms. Developing specific inhibitors targeting SIRT7's deacetylase activity is a promising therapeutic strategy. SIRT7 plays a crucial role in regulating biological processes such as cell proliferation, cell cycle, and apoptosis in PCa through its epigenetic control of gene expression and maintenance of genomic stability. Therefore, SIRT7 may be a potential therapeutic target for PCa, and its expression could have prognostic value for PCa patients, providing important guidance for clinical monitoring and diagnosis by physicians.
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Affiliation(s)
- Jiale Zhang
- Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina
- Guangzhou LaboratoryGuangzhouChina
| | - Chenxin Liu
- Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina
- Guangzhou LaboratoryGuangzhouChina
| | - Wenting Luo
- Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina
- Guangzhou LaboratoryGuangzhouChina
| | - Baoqing Sun
- Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina
- Guangzhou LaboratoryGuangzhouChina
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Hu Z, Chen Y, Lei J, Wang K, Pan Z, Zhang L, Xu X, Li W, Zhang L, Qin X, Liu R, Chu Y, Wang C, Yu H. SIRT7 regulates T-cell antitumor immunity through modulation BCAA and fatty acid metabolism. Cell Death Differ 2025:10.1038/s41418-025-01490-y. [PMID: 40140560 DOI: 10.1038/s41418-025-01490-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025] Open
Abstract
SIRT7, one of the least studied members of the Sirtuins family, is an NAD+-dependent lysine deacetylase and desuccinylase. While previous studies using affinity enrichment and quantitative proteomics identified numerous lysine-deacetylated substrates of SIRT7, its lysine-desuccinylated substrates remain underexplored, limiting our understanding of its role in cellular homeostasis. Here, we demonstrated that SIRT7 is predominantly expressed in immune tissues, especially in adaptive immune cells, including T cells. Through proteomics, lysine succinylome, and acetylome analysis of spleen from wild-type (WT) and Sirt7-/- mice, we identified significant succinylation of proteins involved in the branched-chain amino acid (BCAA) catabolism pathway in Sirt7-/- mice. We further found that SIRT7 partially localizes to mitochondria, interacting with key enzymes of the BCAA catabolism pathway and promoting their desuccinylation. Sirt7 deficiency leads to enhanced BCAA catabolism, accumulation of acyl-CoA, and increased fatty acid (FA) synthesis. As T cells rely heavily on amino acid metabolism for activation, differentiation, and function, we investigated the impact of SIRT7 using a T cell-specific Sirt7 knockout mouse model (Sirt7fl/flCd4-Cre). Our results show that SIRT7 is crucial for T cell proliferation, activation, and antitumor function. Sirt7 deficiency in T cells results in the accumulation of BCAA metabolites and FAs, reduced cytotoxic cytokines secretion such as IFN-γ, and T cell exhaustion. Reducing BCAA levels with BT2, a BCKDK inhibitor, or BCAA-free treatment alleviated these effects, while FA treatment exacerbates them. Overall, our findings identify SIRT7 as a critical regulator linking BCAA and FA metabolism to T cell antitumor immunity, providing new insights into its potential as a therapeutic target.
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Affiliation(s)
- Zuojian Hu
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yingji Chen
- State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China
| | - Jielin Lei
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Ke Wang
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Ziyue Pan
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Lei Zhang
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China
| | - Xiayun Xu
- State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China
| | - Wenhui Li
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianjun Zhang
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ronghua Liu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chenji Wang
- State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China
| | - Hongxiu Yu
- Institute of Biomedicine Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, China.
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Fiorentino F, Fabbrizi E, Mai A, Rotili D. Activation and inhibition of sirtuins: From bench to bedside. Med Res Rev 2025; 45:484-560. [PMID: 39215785 PMCID: PMC11796339 DOI: 10.1002/med.22076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Antonello Mai
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
- Pasteur Institute, Cenci‐Bolognetti FoundationSapienza University of RomeRomeItaly
| | - Dante Rotili
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
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Lu X, Zhang Y, Xue J, Evert M, Calvisi D, Chen X, Wang X. MAD2L1 supports MYC-driven liver carcinogenesis in mice and predicts poor prognosis in human hepatocarcinoma. Toxicol Sci 2025; 203:41-51. [PMID: 39316419 DOI: 10.1093/toxsci/kfae126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
Mitotic arrest-deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint implicated in cancer cell proliferation and tumorigenesis. The functional role of MAD2L1 in hepatocellular carcinoma (HCC) has not been adequately investigated, especially in vivo. In the current manuscript, we sought to address the function of MAD2L1 in hepatocarcinogenesis. We found that MAD2L1 expression is upregulated in human HCCs, where its expression is associated with higher aggressive tumor grade, elevated proliferative activity, and poor prognosis. In human HCC cell lines, MAD2L1 knockdown led to decreased cell growth. Moreover, RNA-seq results demonstrated that MAD2L1 silencing induces the expression of genes associated with cell cycle, DNA replication, and various cancer-related pathways, supporting the critical role of MAD2L1 during HCC growth and differentiation. In a c-MYC-induced mouse HCC model, we revealed an increased expression of Mad2l1. Furthermore, Mad2l1 CRIPSR-mediated silencing prevented c-MYC-driven mouse liver development. Altogether, our study suggests that MAD2L1 plays a crucial role in hepatocarcinogenesis, and that its suppression could be a promising therapeutic strategy for treating human HCC. MAD2L1 plays a critical role in liver cancer development, silencing MAD2L1 reduced cell growth in vitro and inhibited c-MYC-driven liver cancer development in vivo. MAD2L1 suppression might be a promising therapeutic approach for treating human liver cancer.
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Affiliation(s)
- Xinjun Lu
- Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Ya Zhang
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
| | - Jiahao Xue
- Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Diego Calvisi
- Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
| | - Xin Chen
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
| | - Xue Wang
- Cancer Biology Program, University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, HA 96813, United States
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10
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Qu Q, Chen Y, Wang Y, Wang W, Long S, Yang HY, Wu J, Li M, Tian X, Wei X, Liu YH, Xu S, Xiong J, Yang C, Wu Z, Huang X, Xie C, Wu Y, Xu Z, Zhang C, Zhang B, Feng JW, Chen J, Feng Y, Fang H, Lin L, Xie ZK, Sun B, Tian H, Yu Y, Piao HL, Xie XS, Deng X, Zhang CS, Lin SC. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature 2024:10.1038/s41586-024-08348-2. [PMID: 39695235 DOI: 10.1038/s41586-024-08348-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 11/05/2024] [Indexed: 12/20/2024]
Abstract
Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins that co-immunoprecipitated with sirtuin 1 (SIRT1) identified TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, as a LCA receptor. In detail, LCA-bound TULP3 allosterically activates sirtuins, which then deacetylate the V1E1 subunit of v-ATPase on residues K52, K99 and K191. Muscle-specific expression of a V1E1 mutant (3KR), which mimics the deacetylated state, strongly activates AMPK and rejuvenates muscles in aged mice. In nematodes and flies, LCA depends on the TULP3 homologues tub-1 and ktub, respectively, to activate AMPK and extend lifespan and healthspan. Our study demonstrates that activation of the TULP3-sirtuin-v-ATPase-AMPK pathway by LCA reproduces the benefits of calorie restriction.
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Affiliation(s)
- Qi Qu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yan Chen
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yu Wang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Weiche Wang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Shating Long
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Heng-Ye Yang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jianfeng Wu
- Laboratory Animal Research Centre, Xiamen University, Xiamen, China
| | - Mengqi Li
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiao Tian
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiaoyan Wei
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yan-Hui Liu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Shengrong Xu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jinye Xiong
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Chunyan Yang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zhenhua Wu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xi Huang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Changchuan Xie
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yaying Wu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zheni Xu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Cixiong Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Baoding Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jin-Wei Feng
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Junjie Chen
- Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yuanji Feng
- State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
| | - Huapan Fang
- State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
| | - Liyun Lin
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Z K Xie
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Beibei Sun
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Huayu Tian
- State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
| | - Yong Yu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Hai-Long Piao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Xiao-Song Xie
- McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xianming Deng
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
| | - Chen-Song Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
| | - Sheng-Cai Lin
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
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11
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Fu Z, Wang W, Gao Y. Understanding the impact of ER stress on lung physiology. Front Cell Dev Biol 2024; 12:1466997. [PMID: 39744015 PMCID: PMC11688383 DOI: 10.3389/fcell.2024.1466997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/22/2024] [Indexed: 01/04/2025] Open
Abstract
Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.
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Affiliation(s)
- Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Wang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuan Gao
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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12
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Kamal S, Babar S, Ali W, Rehman K, Hussain A, Akash MSH. Sirtuin insights: bridging the gap between cellular processes and therapeutic applications. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9315-9344. [PMID: 38976046 DOI: 10.1007/s00210-024-03263-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024]
Abstract
The greatest challenges that organisms face today are effective responses or detection of life-threatening environmental changes due to an obvious semblance of stress and metabolic fluctuations. These are associated with different pathological conditions among which cancer is most important. Sirtuins (SIRTs; NAD+-dependent enzymes) are versatile enzymes with diverse substrate preferences, cellular locations, crucial for cellular processes and pathological conditions. This article describes in detail the distinct roles of SIRT isoforms, unveiling their potential as either cancer promoters or suppressors and also explores how both natural and synthetic compounds influence the SIRT function, indicating promise for therapeutic applications. We also discussed the inhibitors/activators tailored to specific SIRTs, holding potential for diseases lacking effective treatments. It may uncover the lesser-studied SIRT isoforms (e.g., SIRT6, SIRT7) and their unique functions. This article also offers a comprehensive overview of SIRTs, linking them to a spectrum of diseases and highlighting their potential for targeted therapies, combination approaches, disease management, and personalized medicine. We aim to contribute to a transformative era in healthcare and innovative treatments by unraveling the intricate functions of SIRTs.
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Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Sharon Babar
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Waqas Ali
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Amjad Hussain
- Institute of Chemistry, University of Okara, Okara, Punjab, Pakistan
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13
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Li H, Yuan Z, Wu J, Lu J, Wang Y, Zhang L. Unraveling the multifaceted role of SIRT7 and its therapeutic potential in human diseases. Int J Biol Macromol 2024; 279:135210. [PMID: 39218192 DOI: 10.1016/j.ijbiomac.2024.135210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Sirtuins, as NAD+-dependent deacetylases, are widely found in eubacteria, archaea, and eukaryotes, and they play key roles in regulating cellular functions. Among these, SIRT7 stands out as a member discovered relatively late and studied less extensively. It is localized within the nucleus and displays enzymatic activity as an NAD+-dependent deacetylase, targeting a diverse array of acyl groups. The role of SIRT7 in important cellular processes like gene transcription, cellular metabolism, cellular stress responses, and DNA damage repair has been documented in a number of studies conducted recently. These studies have also highlighted SIRT7's strong correlation with human diseases like aging, cancer, neurological disorders, and cardiovascular diseases. In addition, a variety of inhibitors against SIRT7 have been reported, indicating that targeting SIRT7 may be a promising strategy for inhibiting tumor growth. The purpose of this review is to thoroughly look into the structure and function of SIRT7 and to explore its potential value in clinical applications, offering an essential reference for research in related domains.
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Affiliation(s)
- Han Li
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Ziyue Yuan
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Junhao Wu
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinjia Lu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Yibei Wang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
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14
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Cao C, Liu W, Guo X, Weng S, Chen Y, Luo Y, Wang S, Zhu B, Liu Y, Peng D. Identification and validation of efferocytosis-related biomarkers for the diagnosis of metabolic dysfunction-associated steatohepatitis based on bioinformatics analysis and machine learning. Front Immunol 2024; 15:1460431. [PMID: 39497821 PMCID: PMC11532026 DOI: 10.3389/fimmu.2024.1460431] [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: 07/06/2024] [Accepted: 10/02/2024] [Indexed: 11/07/2024] Open
Abstract
Background Metabolic dysfunction-associated steatohepatitis (MASH) is a highly prevalent liver disease globally, with a significant risk of progressing to cirrhosis and even liver cancer. Efferocytosis, a process implicated in a broad spectrum of chronic inflammatory disorders, has been reported to be associated with the pathogenesis of MASH; however, its precise role remains obscure. Thus, we aimed to identify and validate efferocytosis linked signatures for detection of MASH. Methods We retrieved gene expression patterns of MASH from the GEO database and then focused on assessing the differential expression of efferocytosis-related genes (EFRGs) between MASH and control groups. This analysis was followed by a series of in-depth investigations, including protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis, to uncover the molecular interactions and pathways at play. To screen for biomarkers for diagnosis, we applied machine learning algorithm to identify hub genes and constructed a clinical predictive model. Additionally, we conducted immune infiltration and single-cell transcriptome analyses in both MASH and control samples, providing insights into the immune cell landscape and cellular heterogeneity in these conditions. Results This research pinpointed 39 genes exhibiting a robust correlation with efferocytosis in MASH. Among these, five potential diagnostic biomarkers-TREM2, TIMD4, STAB1, C1QC, and DYNLT1-were screened using two distinct machine learning models. Subsequent external validation and animal experimentation validated the upregulation of TREM2 and downregulation of TIMD4 in MASH samples. Notably, both TREM2 and TIMD4 demonstrated area under the curve (AUC) values exceeding 0.9, underscoring their significant potential in facilitating the diagnosis of MASH. Conclusion Our study comprehensively elucidated the relationship between MASH and efferocytosis, constructing a favorable diagnostic model. Furthermore, we identified potential therapeutic targets for MASH treatment and offered novel insights into unraveling the underlying mechanisms of this disease.
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Affiliation(s)
- Chenghui Cao
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Wenwu Liu
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xin Guo
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuwei Weng
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Chen
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yonghong Luo
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuai Wang
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Botao Zhu
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yuxuan Liu
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Daoquan Peng
- Department of Cardiology, Research Institute of Blood Lipids and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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15
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Song Z, Park SH, Mu WC, Feng Y, Wang CL, Wang Y, Barthez M, Maruichi A, Guo J, Yang F, Lin AW, Heydari K, Chini CCS, Chini EN, Jang C, Chen D. An NAD +-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging. NATURE AGING 2024; 4:1384-1393. [PMID: 39044033 PMCID: PMC11565225 DOI: 10.1038/s43587-024-00670-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 06/18/2024] [Indexed: 07/25/2024]
Abstract
How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
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Affiliation(s)
- Zehan Song
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- Metabolic Biology Graduate Program, University of California, Berkeley, CA, USA
| | - Sang Hee Park
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Wei-Chieh Mu
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- Endocrinology Graduate Program, University of California, Berkeley, CA, USA
| | - Yufan Feng
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Chih-Ling Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Yifei Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- Metabolic Biology Graduate Program, University of California, Berkeley, CA, USA
| | - Marine Barthez
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Ayane Maruichi
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- Endocrinology Graduate Program, University of California, Berkeley, CA, USA
| | - Jiayue Guo
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Fanghan Yang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- Endocrinology Graduate Program, University of California, Berkeley, CA, USA
| | - Anita Wong Lin
- Cancer Research Laboratory, University of California, Berkeley, CA, USA
| | - Kartoosh Heydari
- Cancer Research Laboratory, University of California, Berkeley, CA, USA
| | - Claudia C S Chini
- Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL, USA
| | - Eduardo N Chini
- Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Danica Chen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
- Metabolic Biology Graduate Program, University of California, Berkeley, CA, USA.
- Endocrinology Graduate Program, University of California, Berkeley, CA, USA.
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16
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Li X, Li Y, Hao Q, Jin J, Wang Y. Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses. Front Immunol 2024; 15:1448535. [PMID: 39372420 PMCID: PMC11449768 DOI: 10.3389/fimmu.2024.1448535] [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: 06/13/2024] [Accepted: 09/03/2024] [Indexed: 10/08/2024] Open
Abstract
Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1-7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells.
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Affiliation(s)
- Xiaoqing Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, China
| | - Yunjia Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, China
| | - Quan Hao
- China Spallation Neutron Source, Dongguan, Guangdong, China
| | - Jing Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, China
| | - Yi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, Anhui, China
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Wang Y, Barthez M, Chen D. Mitochondrial regulation in stem cells. Trends Cell Biol 2024; 34:685-694. [PMID: 37919163 PMCID: PMC11193947 DOI: 10.1016/j.tcb.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/30/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023]
Abstract
Stem cells persist throughout the lifespan to repair and regenerate tissues due to their unique ability to self-renew and differentiate. Here we reflect on the recent discoveries in stem cells that highlight a mitochondrial metabolic checkpoint at the restriction point of the stem cell cycle. Mitochondrial activation supports stem cell proliferation and differentiation by providing energy supply and metabolites as signaling molecules. Concomitant mitochondrial stress can lead to loss of stem cell self-renewal and requires the surveillance of various mitochondrial quality control mechanisms. During aging, a mitochondrial protective program mediated by several sirtuins becomes dysregulated and can be targeted to reverse stem cell aging and tissue degeneration, giving hope for targeting the mitochondrial metabolic checkpoint for treating tissue degenerative diseases.
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Affiliation(s)
- Yifei Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Marine Barthez
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Danica Chen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
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18
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Ding Z, Zhang J, Choudhury M. A High-Fat and High-Fructose Diet Exacerbates Liver Dysfunction by Regulating Sirtuins in a Murine Model. Life (Basel) 2024; 14:729. [PMID: 38929712 PMCID: PMC11205069 DOI: 10.3390/life14060729] [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: 05/10/2024] [Revised: 05/31/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet's abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression.
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Affiliation(s)
| | | | - Mahua Choudhury
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX 77843-1114, USA
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19
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Tian C, Huang R, Xiang M. SIRT1: Harnessing multiple pathways to hinder NAFLD. Pharmacol Res 2024; 203:107155. [PMID: 38527697 DOI: 10.1016/j.phrs.2024.107155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/04/2024] [Accepted: 03/21/2024] [Indexed: 03/27/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. It is the primary cause of chronic liver disorders, with a high prevalence but no approved treatment. Therefore, it is indispensable to find a trustworthy therapy for NAFLD. Recently, mounting evidence illustrates that Sirtuin 1 (SIRT1) is strongly associated with NAFLD. SIRT1 activation or overexpression attenuate NAFLD, while SIRT1 deficiency aggravates NAFLD. Besides, an array of therapeutic agents, including natural compounds, synthetic compounds, traditional Chinese medicine formula, and stem cell transplantation, alleviates NALFD via SIRT1 activation or upregulation. Mechanically, SIRT1 alleviates NAFLD by reestablishing autophagy, enhancing mitochondrial function, suppressing oxidative stress, and coordinating lipid metabolism, as well as reducing hepatocyte apoptosis and inflammation. In this review, we introduced the structure and function of SIRT1 briefly, and summarized the effect of SIRT1 on NAFLD and its mechanism, along with the application of SIRT1 agonists in treating NAFLD.
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Affiliation(s)
- Cheng Tian
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rongrong Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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20
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Meng B, Xu M, Chen Z, You J, Zhou R, Guan J, Zhou L. SIRT7 sustains tumor development and radioresistance by repressing endoplasmic reticulum stress-induced apoptosis in cutaneous melanoma. Cell Signal 2024; 116:111058. [PMID: 38244711 DOI: 10.1016/j.cellsig.2024.111058] [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: 08/24/2023] [Revised: 11/23/2023] [Accepted: 01/15/2024] [Indexed: 01/22/2024]
Abstract
Cutaneous melanoma is one of the most malignant human tumors and possesses strong resistance to radiotherapy. However, the mechanisms contribute to such radioresistance of melanoma is unclear. In this study, SIRT7 is identified to be higher-expressed in melanoma and positively correlated with melanoma staging. Under ionizing radiation (IR)-treatment condition, loss of SIRT7 compromised the survivability of melanoma cells showed by decreased proliferation, colony formation, migration, but enhancing apoptosis. Transcriptomic sequencing analysis indicated the apoptosis induced after SIRT7 knockdown is tightly related with the induction of endoplasmic reticulum stress (ER stress) by IR treatment. Loss of SIRT7 enhanced EIF2α acetylation and activated its phosphorylation to induce the expression of ER stress proteins including DDIT3, XBP1 and GRP78, among which DDIT3 is responsible for apoptosis induction. SIRT7 depletion enriched ER stress-activated transcription factor ATF4 at the promoter region of DDIT3 gene to transactivate its expression and induces apoptotic cascade in both mock- and IR-treatment conditions. Consistently, SIRT7 is highly upregulated in radioresistant melanoma cell strain and still modulates the ER-stress responsive genes to maintain the homeostasis of melanoma. Collectively, SIRT7 negatively regulates ER stress-activated apoptosis to enhance the survivability of melanoma cells in both non-IR- and IR-treatment conditions. Our study highlights the role of SIRT7 in repressing ER stress and the following apoptosis to sustain tumor development and mediate radioresistance in melanoma, which may suggest a novel intervention target for melanoma therapy.
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Affiliation(s)
- Bingyao Meng
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China; Guangzhou Nansha District Center for Disease Prevention and Control, Guangzhou, China
| | - Minna Xu
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zihan Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jia You
- Guangzhou KingMed Diagnostics, Guangzhou, China
| | - Rui Zhou
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jian Guan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Liang Zhou
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
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21
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Bai Y, Morita K, Kokaji T, Hatano A, Ohno S, Egami R, Pan Y, Li D, Yugi K, Uematsu S, Inoue H, Inaba Y, Suzuki Y, Matsumoto M, Takahashi M, Izumi Y, Bamba T, Hirayama A, Soga T, Kuroda S. Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity. iScience 2024; 27:109121. [PMID: 38524370 PMCID: PMC10960062 DOI: 10.1016/j.isci.2024.109121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/03/2023] [Accepted: 01/31/2024] [Indexed: 03/26/2024] Open
Abstract
Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.
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Affiliation(s)
- Yunfan Bai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Keigo Morita
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Toshiya Kokaji
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Data Science Center, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, Japan
| | - Atsushi Hatano
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Satoshi Ohno
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
- Department of AI Systems Medicine, M&D Data Science Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Riku Egami
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Yifei Pan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Dongzi Li
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Katsuyuki Yugi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
- Institute for Advanced Biosciences, Keio University, Fujisawa 252-8520, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Saori Uematsu
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan
| | - Yuka Inaba
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Masaki Matsumoto
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Masatomo Takahashi
- Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Takeshi Bamba
- Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
| | - Shinya Kuroda
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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22
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Ianni A, Kumari P, Tarighi S, Braun T, Vaquero A. SIRT7: a novel molecular target for personalized cancer treatment? Oncogene 2024; 43:993-1006. [PMID: 38383727 PMCID: PMC10978493 DOI: 10.1038/s41388-024-02976-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
The Sirtuin family of NAD+-dependent enzymes assumes a pivotal role in orchestrating adaptive responses to environmental fluctuations and stress stimuli, operating at both genomic and metabolic levels. Within this family, SIRT7 emerges as a versatile player in tumorigenesis, displaying both pro-tumorigenic and tumor-suppressive functions in a context-dependent manner. While other sirtuins, such as SIRT1 and SIRT6, exhibit a similar dual role in cancer, SIRT7 stands out due to distinctive attributes that sharply distinguish it from other family members. Among these are a unique key role in regulation of nucleolar functions, a close functional relationship with RNA metabolism and processing -exceptional among sirtuins- and a complex multienzymatic nature, which provides a diverse range of molecular targets. This review offers a comprehensive overview of the current understanding of the role of SIRT7 in various malignancies, placing particular emphasis on the intricate molecular mechanisms employed by SIRT7 to either stimulate or counteract tumorigenesis. Additionally, it delves into the unique features of SIRT7, discussing their potential and specific implications in tumor initiation and progression, underscoring the promising avenue of targeting SIRT7 for the development of innovative anti-cancer therapies.
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Affiliation(s)
- Alessandro Ianni
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles, Badalona, Barcelona, Catalonia, 08916, Spain.
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
| | - Poonam Kumari
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
| | - Shahriar Tarighi
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
| | - Thomas Braun
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
| | - Alejandro Vaquero
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles, Badalona, Barcelona, Catalonia, 08916, Spain.
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23
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Tran K, Gilbert M, Vazquez BN, Ianni A, Garcia BA, Vaquero A, Berger S. SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.05.578810. [PMID: 38370824 PMCID: PMC10871251 DOI: 10.1101/2024.02.05.578810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Sirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally and translationally and via localization within the cell. While Sirtiun proteins are implicated with aging, how their levels are regulated during aging across cell types and eliciting tissue specific age-related cellular changes is unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance of SIRT7 loss, we performed proteomics analysis and identified a new SIRT7 interactor, the HMG box protein NUCKS1. We found that the NUCKS1 transcription factor is recruited onto chromatin during senescence and this is mediated by SIRT7 loss. Further, depletion of NUCKS1 delayed senescence upon DNA damage leading to reduction of inflammatory gene expression. Examination of NUCKS1 transcriptional regulation during senescence revealed gene targets of transcription factors NFKB1, RELA, and CEBPβ. Consistently, in both Sirt7 KO mouse liver and in naturally aged livers, Nucks1 was recruited to chromatin. Further, Nucks1 was bound at promoters and enhancers of age-related genes, including transcription factor Rela, and, moreover, these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, and show that loss of SIRT7 during senescence and liver aging promotes NUCKS1 chromatin binding to regulate metabolic and inflammatory genes.
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24
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Kim Y, Kang BE, Gariani K, Gariani J, Lee J, Kim HJ, Lee CW, Schoonjans K, Auwerx J, Ryu D. Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair. BMB Rep 2024; 57:98-103. [PMID: 38303560 PMCID: PMC10910089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/16/2023] [Accepted: 12/07/2023] [Indexed: 02/03/2024] Open
Abstract
The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor [BMB Reports 2024; 57(2): 98-103].
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Affiliation(s)
- Yuna Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
| | - Baeki E. Kang
- Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea, Gwangju 61005, Korea
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Geneva University Hospitals, Geneva 1205, Korea
| | - Joanna Gariani
- Department of Radiology, Hirslanden Grangettes Clinic, Geneva 1224, Switzerland, Gwangju 61005, Korea
| | - Junguee Lee
- Department of Pathology, Konyang University, Daejeon 35365, Korea, Gwangju 61005, Korea
| | - Hyun-Jin Kim
- Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea, Gwangju 61005, Korea
| | - Chang-Woo Lee
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland, Gwangju 61005, Korea
| | - Johan Auwerx
- Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Switzerland, Gwangju 61005, Korea
| | - Dongryeol Ryu
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
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25
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Raza U, Tang X, Liu Z, Liu B. SIRT7: the seventh key to unlocking the mystery of aging. Physiol Rev 2024; 104:253-280. [PMID: 37676263 PMCID: PMC11281815 DOI: 10.1152/physrev.00044.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 08/07/2023] [Accepted: 09/01/2023] [Indexed: 09/08/2023] Open
Abstract
Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to a variety of exogenous and endogenous stresses, which engender various counteractive responses at the cellular, tissue, organ, as well as organismal levels. The compromised cellular and tissue functions that occur because of genetic factors or prolonged stress (or even the stress response) may accelerate aging. Over the last two decades, the sirtuin (SIRT) family of lysine deacylases has emerged as a key regulator of longevity in a variety of organisms. SIRT7, the most recently identified member of the SIRTs, maintains physiological homeostasis and provides protection against aging by functioning as a watchdog of genomic integrity, a dynamic sensor and modulator of stresses. SIRT7 decline disrupts metabolic homeostasis, accelerates aging, and increases the risk of age-related pathologies including cardiovascular and neurodegenerative diseases, pulmonary and renal disorders, inflammatory diseases, and cancer, etc. Here, we present SIRT7 as the seventh key to unlock the mystery of aging, and its specific manipulation holds great potential to ensure healthiness and longevity.
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Affiliation(s)
- Umar Raza
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
| | - Xiaolong Tang
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Zuojun Liu
- School of Life Sciences, Hainan University, Haikou, China
| | - Baohua Liu
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
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26
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Yamagata K, Mizumoto T, Yoshizawa T. The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells 2023; 13:48. [PMID: 38201252 PMCID: PMC10778536 DOI: 10.3390/cells13010048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tomoya Mizumoto
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
| | - Tatsuya Yoshizawa
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
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27
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Bolding JE, Nielsen AL, Jensen I, Hansen TN, Ryberg LA, Jameson ST, Harris P, Peters GHJ, Denu JM, Rogers JM, Olsen CA. Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7. Angew Chem Int Ed Engl 2023; 62:e202314597. [PMID: 37873919 DOI: 10.1002/anie.202314597] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 10/25/2023]
Abstract
The sirtuins are NAD+ -dependent lysine deacylases, comprising seven isoforms (SIRT1-7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ϵ-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms, in part due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small-angle X-ray scattering, reveal SIRT7 to be a monomeric enzyme with a low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism-based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA-display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause an increase in the acetylation of H3 K18.
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Affiliation(s)
- Julie E Bolding
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
| | - Alexander L Nielsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
- Current address: Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
| | - Iben Jensen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
| | - Tobias N Hansen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
| | - Line A Ryberg
- Department of Chemistry, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark
- Current address: Department of Immunology and Microbiology, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Samuel T Jameson
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
| | - Pernille Harris
- Department of Chemistry, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark
- Current address: Department of Chemistry, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Günther H J Peters
- Department of Chemistry, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark
| | - John M Denu
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Joseph M Rogers
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
| | - Christian A Olsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
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28
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Liu F, Liao Z, Zhang Z. MYC in liver cancer: mechanisms and targeted therapy opportunities. Oncogene 2023; 42:3303-3318. [PMID: 37833558 DOI: 10.1038/s41388-023-02861-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023]
Abstract
MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.
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Affiliation(s)
- Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Scieszka D, Bolt AM, McCormick MA, Brigman JL, Campen MJ. Aging, longevity, and the role of environmental stressors: a focus on wildfire smoke and air quality. FRONTIERS IN TOXICOLOGY 2023; 5:1267667. [PMID: 37900096 PMCID: PMC10600394 DOI: 10.3389/ftox.2023.1267667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/25/2023] [Indexed: 10/31/2023] Open
Abstract
Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied. Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD + boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.
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Affiliation(s)
- David Scieszka
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Alicia M. Bolt
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Mark A. McCormick
- Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Jonathan L. Brigman
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Matthew J. Campen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
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Wu S, Jia S. Functional Diversity of SIRT7 Across Cellular Compartments: Insights and Perspectives. Cell Biochem Biophys 2023; 81:409-419. [PMID: 37581721 DOI: 10.1007/s12013-023-01162-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/05/2023] [Indexed: 08/16/2023]
Abstract
Posttranslational modifications (PTMs) play important roles in the regulation of protein function. Acetylation and deacetylation are among the most important PTMs. SIRT7 is a relatively understudied member of the sirtuin family, but recent studies have revealed that it plays a regulatory role in a variety of cellular activities, such as genome stabilization and repair, gene translation, ribosome production and other important processes. Here, we provide a list of the functions and mechanisms of SIRT7 in various organelles and show the important role of SIRT7 in maintaining normal cell function.
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Affiliation(s)
- Songtao Wu
- Zhejiang University School of Medicine, Hangzhou, China.
| | - Shengnan Jia
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
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Li R, Meng M, Chen Y, Pan T, Li Y, Deng Y, Zhang R, Tian R, Xu W, Zheng X, Gong F, Liu J, Tang H, Ding X, Tang Y, Annane D, Chen E, Qu H, Li L. ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury. Cell Death Dis 2023; 14:401. [PMID: 37414769 PMCID: PMC10325983 DOI: 10.1038/s41419-023-05932-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 06/16/2023] [Accepted: 06/26/2023] [Indexed: 07/08/2023]
Abstract
Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of vascular dysfunction is of the essence. ATP-citrate lyase (ACLY) directs glucose metabolic fluxes to de novo lipogenesis by generating acetyl-Co-enzyme A (acetyl-CoA), which facilitates transcriptional priming via protein acetylation. It is well illustrated that ACLY participates in promoting cancer metastasis and fatty liver diseases. Its biological functions in ECs during sepsis remain unclear. We found that plasma levels of ACLY were increased in septic patients and were positively correlated with interleukin (IL)-6, soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), and lactate levels. ACLY inhibition significantly ameliorated lipopolysaccharide challenge-induced EC proinflammatory response in vitro and organ injury in vivo. The metabolomic analysis revealed that ACLY blockade fostered ECs a quiescent status by reducing the levels of glycolytic and lipogenic metabolites. Mechanistically, ACLY promoted forkhead box O1 (FoxO1) and histone H3 acetylation, thereby increasing the transcription of c-Myc (MYC) to facilitate the expression of proinflammatory and gluco-lipogenic genes. Our findings revealed that ACLY promoted EC gluco-lipogenic metabolism and proinflammatory response through acetylation-mediated MYC transcription, suggesting ACLY as the potential therapeutic target for treating sepsis-associated EC dysfunction and organ injury.
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Affiliation(s)
- Ranran Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
| | - Mei Meng
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Tingting Pan
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Yinjiaozhi Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Yunxin Deng
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Ruyuan Zhang
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Rui Tian
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Wen Xu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xiangtao Zheng
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Fangchen Gong
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Jie Liu
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, P.R. China
| | - Haiting Tang
- Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xiaowei Ding
- Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Yaoqing Tang
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Djillali Annane
- General intensive care unit, Raymond Poincaré Hospital (APHP), Laboratory of Inflammation and Infection U1173, University of Versailles SQY/INSERM 104 bd Raymond Poincaré, 92380, Garches, France
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
| | - Hongping Qu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
| | - Lei Li
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
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Wang CL, Ohkubo R, Mu WC, Chen W, Fan JL, Song Z, Maruichi A, Sudmant PH, Pisco AO, Dubal DB, Ji N, Chen D. The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging. Cell Metab 2023; 35:996-1008.e7. [PMID: 37146607 PMCID: PMC10330239 DOI: 10.1016/j.cmet.2023.04.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 04/14/2022] [Accepted: 04/06/2023] [Indexed: 05/07/2023]
Abstract
Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.
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Affiliation(s)
- Chih-Ling Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Rika Ohkubo
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Wei-Chieh Mu
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Wei Chen
- Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Jiang Lan Fan
- Joint Graduate Program in Bioengineering, University of California, San Francisco, and University of California, Berkeley, San Francisco, CA 94720, USA
| | - Zehan Song
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Ayane Maruichi
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Peter H Sudmant
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | | | - Dena B Dubal
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Na Ji
- Department of Physics, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Danica Chen
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
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Xu X, Zhang B, Wang Y, Shi S, Lv J, Fu Z, Gao X, Li Y, Wu H, Song Q. Renal fibrosis in type 2 cardiorenal syndrome: An update on mechanisms and therapeutic opportunities. Biomed Pharmacother 2023; 164:114901. [PMID: 37224755 DOI: 10.1016/j.biopha.2023.114901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/13/2023] [Accepted: 05/16/2023] [Indexed: 05/26/2023] Open
Abstract
Cardiorenal syndrome (CRS) is a state of coexisting heart failure and renal insufficiency in which acute or chronic dysfunction of the heart or kidney lead to acute or chronic dysfunction of the other organ.It was found that renal fibrosis is an important pathological process in the progression of type 2 CRS to end-stage renal disease, and progressive renal impairment accelerates the deterioration of cardiac function and significantly increases the hospitalization and mortality rates of patients. Previous studies have found that Hemodynamic Aiteration, RAAS Overactivation, SNS Dysfunction, Endothelial Dysfunction and Imbalance of natriuretic peptide system contribute to the development of renal disease in the decompensated phase of heart failure, but the exact mechanisms is not clear. Therefore, in this review, we focus on the molecular pathways involved in the development of renal fibrosis due to heart failure and identify the canonical and non-canonical TGF-β signaling pathways and hypoxia-sensing pathways, oxidative stress, endoplasmic reticulum stress, pro-inflammatory cytokines and chemokines as important triggers and regulators of fibrosis development, and summarize the therapeutic approaches for the above signaling pathways, including SB-525334 Sfrp1, DKK1, IMC, rosarostat, 4-PBA, etc. In addition, some potential natural drugs for this disease are also summarized, including SQD4S2, Wogonin, Astragaloside, etc.
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Affiliation(s)
- Xia Xu
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bingxuan Zhang
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajiao Wang
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Science, Beijing, China
| | - Shuqing Shi
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayu Lv
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhenyue Fu
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiya Gao
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Yumeng Li
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Huaqin Wu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qingqiao Song
- Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Cho W, Choi SW, Oh H, Baygutalp F, Abd El-Aty A, Jeong JH, Song JH, Shin YK, Jung TW. Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress. Biochem Biophys Res Commun 2023; 658:62-68. [PMID: 37023616 DOI: 10.1016/j.bbrc.2023.03.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 03/25/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).
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SIRT7 affects autophagy and activation of hepatic stellate cells by regulating the acetylation level of high mobility group protein 1. Immunobiology 2023; 228:152323. [PMID: 36753789 DOI: 10.1016/j.imbio.2022.152323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/16/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Preventing the progression of hepatic fibrosis is an important strategy to improve the prognosis of liver disease. The purpose of this study was to investigate the role of sirtuin7 (SIRT7) and high mobility group box 1 (HMGB1) acetylation in the occurrence and development of hepatic fibrosis. MATERIALS AND METHODS Hepatic fibrosis mice model was induced by CCl4. TGF-β1 was used to activated quiescent hepatic stellate cell (qHSC) into activated HSC (aHSC). Hematoxylin-eosin evaluated hepatic fibrosis in vivo, and the distribution of α-smooth muscle actin (α-SMA) or HMGB1 was detected by immunohistochemistry or immunofluorescence. The expressions of SIRT7, autophagy related proteins, and HSC activation-related proteins were detected by Western blot. Immunoprecipitation detected the acetylation level of HMGB1. Lysine mutants of HMGB1 were constructed in vitro to explore the acetylation sites of HMGB1. RESULTS Hepatocyte autophagy and activation levels were enhanced in CCl4 group or aHSC group, and the acetylation level of HMGB1 was increased. Nuclear transfer of HMGB1 occurred in aHSC, and HMGB1was mainly distributed in cytoplasm. The expression of SIRT7 in CCl4 group or aHSC group was most significantly decreased, and knockdown of SIRT7 leads to increased levels of HSCs autophagy and activation. Overexpression of SIRT7 or interference of HMGB1 alone in aHSC can reduce the level of autophagy and activation of aHSC. However, continued overexpression of SIRT7 in shHMGB1-aHSC could not reduce the autophagy and activation levels of aHSC. Among the 11 Flag-HMGB1 mutants, the acetylation level of K86R-Flag-HMGB1 was the lowest. The acetylation level of K86R-Flag-HMGB1 did not change due to SIRT7 downregulation. CONCLUSION This study proved that SIRT7 can directly target the K86R site of HMGB1 and participate in regulating the expression and distribution of HMGB1, thus affecting the autophagy and activation level of HSCs.
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Huang CJ, Choo KB. Circular RNA- and microRNA-Mediated Post-Transcriptional Regulation of Preadipocyte Differentiation in Adipogenesis: From Expression Profiling to Signaling Pathway. Int J Mol Sci 2023; 24:ijms24054549. [PMID: 36901978 PMCID: PMC10002489 DOI: 10.3390/ijms24054549] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Adipogenesis is an indispensable cellular process that involves preadipocyte differentiation into mature adipocyte. Dysregulated adipogenesis contributes to obesity, diabetes, vascular conditions and cancer-associated cachexia. This review aims to elucidate the mechanistic details on how circular RNA (circRNA) and microRNA (miRNA) modulate post-transcriptional expression of targeted mRNA and the impacted downstream signaling and biochemical pathways in adipogenesis. Twelve adipocyte circRNA profiling and comparative datasets from seven species are analyzed using bioinformatics tools and interrogations of public circRNA databases. Twenty-three circRNAs are identified in the literature that are common to two or more of the adipose tissue datasets in different species; these are novel circRNAs that have not been reported in the literature in relation to adipogenesis. Four complete circRNA-miRNA-mediated modulatory pathways are constructed via integration of experimentally validated circRNA-miRNA-mRNA interactions and the downstream signaling and biochemical pathways involved in preadipocyte differentiation via the PPARγ/C/EBPα gateway. Despite the diverse mode of modulation, bioinformatics analysis shows that the circRNA-miRNA-mRNA interacting seed sequences are conserved across species, supporting mandatory regulatory functions in adipogenesis. Understanding the diverse modes of post-transcriptional regulation of adipogenesis may contribute to the development of novel diagnostic and therapeutic strategies for adipogenesis-associated diseases and in improving meat quality in the livestock industries.
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Affiliation(s)
- Chiu-Jung Huang
- Department of Animal Science & Graduate Institute of Biotechnology, School of Agriculture, Chinese Culture University, 11114 Taipei, Taiwan
- Correspondence: (C.-J.H.); (K.B.C.)
| | - Kong Bung Choo
- Department of Preclinical Sciences, M Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, 43000 Selangor, Malaysia
- Correspondence: (C.-J.H.); (K.B.C.)
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Quan X, Xin Y, Wang HL, Sun Y, Chen C, Zhang J. Implications of altered sirtuins in metabolic regulation and oral cancer. PeerJ 2023; 11:e14752. [PMID: 36815979 PMCID: PMC9936870 DOI: 10.7717/peerj.14752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/27/2022] [Indexed: 02/16/2023] Open
Abstract
Sirtuins (SIRTs 1-7) are a group of histone deacetylase enzymes with a wide range of enzyme activities that target a range of cellular proteins in the nucleus, cytoplasm, and mitochondria for posttranslational modifications by acetylation (SIRT1, 2, 3, and 5) or ADP ribosylation (SIRT4, 6, and 7). A variety of cellular functions, including mitochondrial functions and functions in energy homeostasis, metabolism, cancer, longevity and ageing, are regulated by sirtuins. Compromised sirtuin functions and/or alterations in the expression levels of sirtuins may lead to several pathological conditions and contribute significantly to alterations in metabolic phenotypes as well as oral carcinogenesis. Here, we describe the basic characteristics of seven mammalian sirtuins. This review also emphasizes the key molecular mechanisms of sirtuins in metabolic regulation and discusses the possible relationships of sirtuins with oral cancers. This review will provide novel insight into new therapeutic approaches targeting sirtuins that may potentially lead to effective strategies for combating oral malignancies.
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Affiliation(s)
- Xu Quan
- Department of Stomatology, Shanghai General Hospital, Shanghai, China
| | - Ying Xin
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Pathology, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - He-Ling Wang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
| | - Yingjie Sun
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Chanchan Chen
- Department of Stomatology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, China
| | - Jiangying Zhang
- Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
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NAD +-Consuming Enzymes in Stem Cell Homeostasis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:4985726. [PMID: 36819783 PMCID: PMC9931471 DOI: 10.1155/2023/4985726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/27/2022] [Accepted: 01/06/2023] [Indexed: 02/10/2023]
Abstract
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme used in redox reactions, energy metabolism, and mitochondrial biogenesis. NAD+ is also required as a cofactor by nonredox NAD+-dependent enzymes. Hundreds of enzymes that consume NAD+ have been identified. The NAD+-consuming enzymes are involved in a variety of cellular processes such as signal transduction, DNA repair, cellular senescence, and stem cell (SC) homeostasis. In this review, we discussed how different types of NAD+-consuming enzymes regulate SC functions and summarized current research on the roles of the NAD+ consumers in SC homeostasis. We hope to provide a more global and integrative insight to the mechanism and intervention of SC homeostasis via the regulation of the NAD+-consuming enzymes.
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Ajoolabady A, Kaplowitz N, Lebeaupin C, Kroemer G, Kaufman RJ, Malhi H, Ren J. Endoplasmic reticulum stress in liver diseases. Hepatology 2023; 77:619-639. [PMID: 35524448 PMCID: PMC9637239 DOI: 10.1002/hep.32562] [Citation(s) in RCA: 168] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 02/02/2023]
Abstract
The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis ("adaptive UPR"), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained ("maladaptive UPR"). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.
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Affiliation(s)
- Amir Ajoolabady
- Department of Cardiology, Shanghai Institute for Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
| | - Neil Kaplowitz
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Cynthia Lebeaupin
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Randal J. Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jun Ren
- Department of Cardiology, Shanghai Institute for Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab 2023; 35:12-35. [PMID: 36599298 DOI: 10.1016/j.cmet.2022.11.001] [Citation(s) in RCA: 230] [Impact Index Per Article: 115.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/11/2022] [Accepted: 11/07/2022] [Indexed: 01/05/2023]
Abstract
Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
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Affiliation(s)
- Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - David Roiz-Valle
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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Abstract
Sirtuins are identified as NAD+-dependent class III histone deacetylases (HDAC) and are involved in a variety of cellular activities, including energy metabolism, DNA repair, epigenetics, gene expression, cell proliferation, differentiation, and survival. Using genetically modified model organisms, sirtuins are proved to be one of the most conserved aging-regulatory and longevity-promoting genes/pathways among species. Of the seven sirtuins, SIRT7 is the only sirtuin that localizes in the nucleolus. SIRT7 senses endogenous and environmental stress to maintain physiological homeostasis. Sirt7 deficient and transgenic mice provide a useful tool to understand the mechanisms of aging and related pathologies. In this chapter, we summarized the most widely applied methods to understand the physiopathological function of SIRT7 in mice.
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Affiliation(s)
- Shimin Sun
- Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China
| | - Xiaojiao Xia
- Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China
| | - Ming Wang
- Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China
| | - Baohua Liu
- Shenzhen Key Laboratory of Systemic Aging and Intervention (SKL-SAI), School of Basic Medical Sciences, Shenzhen University, Shenzhen, China.
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Ohkubo R, Mu WC, Wang CL, Song Z, Barthez M, Wang Y, Mitchener N, Abdullayev R, Lee YR, Ma Y, Curtin M, Srinivasan S, Zhang X, Yang F, Sudmant PH, Pisco AO, Neff N, Haynes CM, Chen D. The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease. Cell Rep 2022; 41:111803. [PMID: 36516757 PMCID: PMC9825120 DOI: 10.1016/j.celrep.2022.111803] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 10/14/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.
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Affiliation(s)
- Rika Ohkubo
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Wei-Chieh Mu
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Chih-Ling Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Zehan Song
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Marine Barthez
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yifei Wang
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Nathaniel Mitchener
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Rasul Abdullayev
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yeong Rim Lee
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yuze Ma
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Megan Curtin
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Suraj Srinivasan
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Xingjia Zhang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Fanghan Yang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Peter H Sudmant
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | | | - Norma Neff
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Cole M Haynes
- Department of Molecular, Cell and Cancer Biology, UMass-Chan Medical School, Worcester, MA 01605, USA
| | - Danica Chen
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
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Xu Z, Wu FW, Niu X, Lu XP, Li YR, Zhang ST, Ou JZ, Wang XM. Integrated strategy of RNA-sequencing and network pharmacology for exploring the protective mechanism of Shen-Shi-Jiang-Zhuo formula in rat with non-alcoholic fatty liver disease. PHARMACEUTICAL BIOLOGY 2022; 60:1819-1838. [PMID: 36124995 PMCID: PMC9518293 DOI: 10.1080/13880209.2022.2106250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 07/08/2022] [Accepted: 07/22/2022] [Indexed: 06/15/2023]
Abstract
CONTEXT Shen-Shi-Jiang-Zhuo formula (SSJZF) exhibits a definite curative effect in the clinical treatment of non-alcoholic fatty liver disease (NAFLD). OBJECTIVE To explore the therapeutic effect and mechanism of SSJZF on NAFLD. MATERIALS AND METHODS Sprague Dawley rats were randomly divided into control, NAFLD, positive drug (12 mg/kg/day), SSJZF high-dose (200 mg/kg/day), SSJZF middle-dose (100 mg/kg/day), and SSJZF low-dose (50 mg/kg/day) groups. After daily intragastric administration of NAFLD rats for 8 weeks, lipid metabolism and hepatic fibrosis were evaluated by biochemical indices and histopathology. Then we uncovered the main active compounds and mechanism of SSJZF against NAFLD by integrating RNA-sequencing and network pharmacology, and PI3K/AKT pathway activity was verified by western blot. RESULTS High dose SSJZF had the best inhibitory effect on hepatic lipid accumulation and fibrosis in rats with NAFLD, which significantly down-regulated total triglycerides (58%), cholesterol (62%), aspartate aminotransferase (57%), alanine aminotransferase (41%) andγ-glutamyl transpeptidase (36%), as well as the expression of ACC (5.3-fold), FAS (12.1-fold), SREBP1C (2.3-fold), and CD36 (4.4-fold), and significantly reduced collagen deposition (67%). Then we identified 23 compounds of SSJZF that acted on 25 key therapeutic targets of NAFLD by integrating RNA-sequencing and network pharmacology. Finally, we also confirmed that high dose SSJZF increased p-PI3K/PI3K (1.6-fold) and p-AKT/AKT (1.6-fold) in NAFLD rats. DISCUSSION AND CONCLUSION We found for first time that SSJZF improved NAFLD in rats by activating the PI3K/Akt pathway. These findings provide scientific support for SSJZF in the clinical treatment of NAFLD and contribute to the development of new NAFLD drugs.
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Affiliation(s)
- Zheng Xu
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fan-Wei Wu
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xuan Niu
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xiao-Peng Lu
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yan-Rong Li
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shu-Ting Zhang
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Guangdong Agriculture and Reclamation Central Hospital, Zhanjiang, Guangdong
| | - Jun-Zhao Ou
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue-Mei Wang
- Liu Pai Chinese Medical Center, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, China
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Hou T, Tian Y, Cao Z, Zhang J, Feng T, Tao W, Sun H, Wen H, Lu X, Zhu Q, Li M, Lu X, Liu B, Zhao Y, Yang Y, Zhu WG. Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation. Mol Cell 2022; 82:4099-4115.e9. [PMID: 36208627 DOI: 10.1016/j.molcel.2022.09.018] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/08/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022]
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Nucleolus and Nucleolar Stress: From Cell Fate Decision to Disease Development. Cells 2022; 11:cells11193017. [PMID: 36230979 PMCID: PMC9563748 DOI: 10.3390/cells11193017] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/30/2022] Open
Abstract
Besides the canonical function in ribosome biogenesis, there have been significant recent advances towards the fascinating roles of the nucleolus in stress response, cell destiny decision and disease progression. Nucleolar stress, an emerging concept describing aberrant nucleolar structure and function as a result of impaired rRNA synthesis and ribosome biogenesis under stress conditions, has been linked to a variety of signaling transductions, including but not limited to Mdm2-p53, NF-κB and HIF-1α pathways. Studies have uncovered that nucleolus is a stress sensor and signaling hub when cells encounter various stress conditions, such as nutrient deprivation, DNA damage and oxidative and thermal stress. Consequently, nucleolar stress plays a pivotal role in the determination of cell fate, such as apoptosis, senescence, autophagy and differentiation, in response to stress-induced damage. Nucleolar homeostasis has been involved in the pathogenesis of various chronic diseases, particularly tumorigenesis, neurodegenerative diseases and metabolic disorders. Mechanistic insights have revealed the indispensable role of nucleolus-initiated signaling in the progression of these diseases. Accordingly, the intervention of nucleolar stress may pave the path for developing novel therapies against these diseases. In this review, we systemically summarize recent findings linking the nucleolus to stress responses, signaling transduction and cell-fate decision, set the spotlight on the mechanisms by which nucleolar stress drives disease progression, and highlight the merit of the intervening nucleolus in disease treatment.
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ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response. J Lipid Res 2022; 63:100279. [PMID: 36100091 PMCID: PMC9579414 DOI: 10.1016/j.jlr.2022.100279] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/20/2022] Open
Abstract
The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells.
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Li X, Liu J, Lu L, Huang T, Hou W, Wang F, Yu L, Wu F, Qi J, Chen X, Meng Z, Zhu M. Sirt7 associates with ELK1 to participate in hyperglycemia memory and diabetic nephropathy via modulation of DAPK3 expression and endothelial inflammation. Transl Res 2022; 247:99-116. [PMID: 35470010 DOI: 10.1016/j.trsl.2022.04.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/01/2022] [Accepted: 04/18/2022] [Indexed: 02/08/2023]
Abstract
Diabetic nephropathy (DN) is one of the most serious complications of advanced diabetes, and increases patient mortality. Recently, epigenetics-mediated hyperglycemic memory in pathological process of DN has received attention. The purpose of this study was to determine the underlying mechanism by which sirt7 modulates hyperglycemic memory in DN. In glomerular endothelial cells (GECs) cultured in high glucose and glomeruli of DN patients and rats, an increase in p65 phosphorylation and endothelial adhesion molecule levels persisted after glucose normalization but was reversed by glucose normalization associated with death-associated protein kinase-3 (DAPK3) knockout or DAPK3 inhibitor. High glucose-mediated decrease in sirt7, the deacetylase modulating H3K18-acetylation (H3K18ac), was sustained after normoglycemia. Sirt7 overexpression accompanied by glucose normalization suppressed DAPK3 expression and inflammation in GECs. Moreover, sh-sirt7-induced inflammation was inhibited by si-DAPK3. Furthermore, sirt7 and H3K18ac were located at the DAPK3 promoter region. ELK1 was found to combine with sirt7. si-ELK1 supplemented with normoglycemia inhibited high glucose-induced DAPK3 expression and inflammation in GECs. ELK1 overexpression-mediated inflammation was inhibited by si-DAPK3. In addition, ELK1 and sirt7 were located at the same promoter region of DAPK3. ELK1 overexpression enhanced DAPK3 promoter activity, which disappeared after specific binding site mutation. In vivo, sirt7 overexpression decreased inflammation and improved renal function during insulin treatment of DN rats, whereas insulin alone did not work. Our data demonstrated high glucose-mediated mutual inhibition between sirt7 and ELK1 induced DAPK3 transcription and inflammation despite normoglycemia in GECs, thus forming a vicious cycle and participating in the occurrence of hyperglycemic memory in DN.
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Affiliation(s)
- Xue Li
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing Liu
- Department of Anaesthesiology, Huzhou Maternal & Child Health Care Hospital, Huzhou, Zhejiang, China
| | - Lihong Lu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ting Huang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenting Hou
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fei Wang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lang Yu
- Department of Anaesthesiology, Huzhou Central Hospital, Affiliated Central Hospital of HuZhou University, No.1558 Sanhuan North Road, Huzhou, Zhejiang, China
| | - Fengfeng Wu
- Department of Orthopedics and Rehabilitation, Huzhou Central Hospital, Affiliated Central Hospital of HuZhou University, No.1558 Sanhuan North Road, Huzhou, Zhejiang, China
| | - Jie Qi
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangyuan Chen
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhipeng Meng
- Department of Anaesthesiology, Huzhou Central Hospital, Affiliated Central Hospital of HuZhou University, No.1558 Sanhuan North Road, Huzhou, Zhejiang, China.
| | - Minmin Zhu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Cheng W, Li M, Zhang L, Zhou C, Yu S, Peng X, Zhang W, Zhang W. New roles of N6-methyladenosine methylation system regulating the occurrence of non-alcoholic fatty liver disease with N6-methyladenosine-modified MYC. Front Pharmacol 2022; 13:973116. [PMID: 36120320 PMCID: PMC9471244 DOI: 10.3389/fphar.2022.973116] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/28/2022] [Indexed: 12/04/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a major chronic disease in contemporary society, affected by N6-methyladenosine (m6A) RNA methylation, one of the most common RNA modifications. Compared with healthy control, m6A RNA methyltransferase 3 (METTL3) and METTL14 increased, while Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) decreased significantly in NAFLD, and the m6A demethylases fat mass and obesity-associated protein (FTO) elevated. Meanwhile, the m6A binding proteins, YT521-B homology (YTH) domain-containing 1 (YTHDC1), YTHDC2, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), and HNRNPA2B1 were decreased, while eukaryotic translation initiation factor 3 subunit H (EIF3H) was increased significantly. All these changes of m6A regulators had significant differences between healthy control and NAFLD, but no differences between the NAFL and NASH group. The expression level of RBM15, HNRNPC, and HNRNPA2B1 were related to body fat index. RBM15, YTHDC2, HNRNPC, HNRNPA2B1, and EIF3H were related to steatosis. Also, KIAA1429 and YTH domain family 1 (YTHDF1) were related to lobular inflammation. Taken together, m6A regulators were involved in the occurrence of NAFLD. More importantly, abnormal MYC was determined as a key link to m6A regulation of NAFLD. The higher MYC mRNA level was accompanied by higher HDL cholesterol and unsaturated fatty acid proportions, as well as lower fat mass, glucose, and transaminase. Taken together, dysregulation of m6A methylation caused steatosis and fibrosis, affecting the occurrence of NAFLD, and MYC might be its potential target.
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Affiliation(s)
- Wenli Cheng
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Min Li
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Luyun Zhang
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Cheng Zhou
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Susu Yu
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Xinyue Peng
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Wenji Zhang
- Guangdong Provincial Engineering and Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Crops Research Institute, Guangdong Academy of Agricultural Science, Guangzhou, China
- *Correspondence: Wenji Zhang, ; Wenjuan Zhang,
| | - Wenjuan Zhang
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Wenji Zhang, ; Wenjuan Zhang,
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Mizutani H, Sato Y, Yamazaki M, Yoshizawa T, Ando Y, Ueda M, Yamagata K. SIRT7 Deficiency Protects against Aβ 42-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells. Int J Mol Sci 2022; 23:ijms23169027. [PMID: 36012298 PMCID: PMC9408927 DOI: 10.3390/ijms23169027] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/11/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ42, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD. However, the involvement of SIRT7 in AD pathogenesis is not known. Here, we demonstrate that SIRT7 mRNA expression is increased in the cortex, entorhinal cortex, and prefrontal cortex of AD patients. We also found that Aβ42 treatment rapidly increased NADPH oxidase 4 (NOX4) expression at the post-transcriptional level, and induced reactive oxygen species (ROS) production and apoptosis in neuronal SH-SY5Y cells. In contrast, SIRT7 knockdown inhibited Aβ42-induced ROS production and apoptosis by suppressing the upregulation of NOX4. Collectively, these findings suggest that the inhibition of SIRT7 may play a beneficial role in AD pathogenesis through the regulation of ROS production.
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Affiliation(s)
- Hironori Mizutani
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan
| | - Yoshifumi Sato
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Correspondence: (Y.S.); (K.Y.); Tel.: +81-96-373-5068 (Y.S. & K.Y.); Fax: +81-96-364-6940 (Y.S. & K.Y.)
| | - Masaya Yamazaki
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tatsuya Yoshizawa
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yukio Ando
- Department of Amyloidosis Research, Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch Sasebo, Nagasaki 859-3298, Japan
| | - Mitsuharu Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan
| | - Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Correspondence: (Y.S.); (K.Y.); Tel.: +81-96-373-5068 (Y.S. & K.Y.); Fax: +81-96-364-6940 (Y.S. & K.Y.)
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