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Huang P, Qin D, Qin Y, Tao S, Liu G. SIRT3/6/7: promising therapeutic targets for pulmonary fibrosis. Front Cell Dev Biol 2025; 13:1557384. [PMID: 40241794 PMCID: PMC12000143 DOI: 10.3389/fcell.2025.1557384] [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: 01/08/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
Pulmonary fibrosis is a chronic progressive fibrosing interstitial lung disease of unknown cause, characterized by excessive deposition of extracellular matrix, leading to irreversible decline in lung function and ultimately death due to respiratory failure and multiple complications. The Sirtuin family is a group of nicotinamide adenine dinucleotide (NAD+) -dependent histone deacetylases, including SIRT1 to SIRT7. They are involved in various biological processes such as protein synthesis, metabolism, cell stress, inflammation, aging and fibrosis through deacetylation. This article reviews the complex molecular mechanisms of the poorly studied SIRT3, SIRT6, and SIRT7 subtypes in lung fibrosis and the latest research progress in targeting them to treat lung fibrosis.
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Affiliation(s)
- Pingping Huang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Dan Qin
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yanling Qin
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Sha Tao
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guangnan Liu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Liao S, Chen D, Long H, Jiang S, Fan J, Li S, Qi Y, Xue L, Ding Y, Chen Y. Hydrogen sulfide attenuates oxidative stress-induced cellular senescence via the Sirt3/SOD2 signaling pathway in chronic obstructive pulmonary disease. Chin Med J (Engl) 2025:00029330-990000000-01470. [PMID: 40082252 DOI: 10.1097/cm9.0000000000003452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Senescence significantly participates in shaping the pathobiological process underlying chronic obstructive pulmonary disease (COPD). Currently, the mechanisms underlying the anti-aging effects within COPD of hydrogen sulfide (H2S) are not fully illustrated. METHODS Immunohistochemistry (IHC) staining was performed on human lung tissue to detect the expression levels of sirtuin 3 (Sirt3), cyclin-dependent kinase 4 inhibitor (P16), and cystathionin gamma lyase (CTH). An animal model including wild-type (WT) and Sirt3 knockout (KO) mice was established by exposing them to cigarette smoking (CS) for 24 weeks, with or without intraperitoneal injection of sodium hydrosulfide (NaHS, 50 µmol∙L-1∙kg-1) 30 min prior to CS exposure. Lung function was assessed. The expression levels of P16, cyclin-dependent kinase inhibitor 1 (P21), Sirt3, manganese superoxide dismutase (SOD2), manganese acetylated superoxide dismutase (ac-SOD2), interleukin-6 (IL-6), IL-8, malondialdehyde (MDA), and glutathione (GSH), as well as the activity of SOD2 and Sirt3, were evaluated. Human bronchial epithelial BEAS-2B cells were subjected to diverse cigarette smoking extract (CSE) concentrations for 48 h with or without sodium hydrosulfide (NaHS). Subsequently, the levels of total intracellular reactive oxygen species (T-ROS), mitochondrial reactive oxygen species (mitoROS), mitochondrial membrane potential (MMP), senescence-associated β-galactosidase (SA-β-gal) staining positive cells, and related marker proteins and cytokines were assessed. Furthermore, the Sirt3-specific inhibitor 3-TYP and small interfering RNAs (siRNAs) of Sirt3 were used to examine the mechanisms whereby H2S inhibits oxidative stress and senescence in COPD. RESULTS IHC showed a significant reduction of CTH and Sirt3 protein levels in the lung tissue of COPD with smoking patients and smokers without COPD compared to non-smokers. Furthermore, the expression of the aging marker protein P16 was notably elevated in the COPD with smoking group compared to the smokers without COPD and non-smoker groups. Furthermore, our results demonstrated that exposure to CS resulted in imbalanced oxidative and cellular senescence, including elevated mitoROS, T-ROS, MDA, and ac-SOD2, along with increased proportions of SA-β-gal staining positive cells and the increased expression levels of IL-6, IL-8, P21, and P16, as well as decreased GSH levels, SOD2 and Sirt3 activities, and Sirt3 expression, which ultimately contribute to emphysema development and impaired lung function. However, pretreatment with NaHS effectively reversed these detrimental effects. Nevertheless, the protective effect of NaHS was alleviated in Sirt3 KO mice and in cellular models treated with Sirt3 siRNA and 3-TYP. CONCLUSION Our study indicates that H2S inhibits oxidative stress and cellular senescence by modulating the Sirt3/SOD2 signaling pathway, therefore attenuating the emphysema and impaired lung function induced by CS.
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Affiliation(s)
- Sha Liao
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Dian Chen
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Huanyu Long
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Simin Jiang
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jing Fan
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Shurun Li
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yongfen Qi
- Department of Pathogenic Biology, Peking University School of Basic Medicine, Beijing 100191, China
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Yanling Ding
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yahong Chen
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
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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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Trinh D, Al Halabi L, Brar H, Kametani M, Nash JE. The role of SIRT3 in homeostasis and cellular health. Front Cell Neurosci 2024; 18:1434459. [PMID: 39157755 PMCID: PMC11327144 DOI: 10.3389/fncel.2024.1434459] [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: 05/17/2024] [Accepted: 06/25/2024] [Indexed: 08/20/2024] Open
Abstract
Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.
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Affiliation(s)
- Dennison Trinh
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Lina Al Halabi
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Harsimar Brar
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Marie Kametani
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Joanne E. Nash
- Department of Biological Sciences, University of Toronto Scarborough Graduate Department of Cells Systems Biology, University of Toronto Cross-Appointment with Department of Psychology, University of Toronto Scarborough Scientist – KITE, Toronto, ON, Canada
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Zhang X, Huang C, Hou Y, Jiang S, Zhang Y, Wang S, Chen J, Lai J, Wu L, Duan H, He S, Liu X, Yu S, Cai Y. Research progress on the role and mechanism of Sirtuin family in doxorubicin cardiotoxicity. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155673. [PMID: 38677274 DOI: 10.1016/j.phymed.2024.155673] [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: 12/23/2023] [Revised: 04/16/2024] [Accepted: 04/21/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Doxorubicin (DOX) is a widely utilized anthracycline chemotherapy drug in cancer treatment, yet its efficacy is hindered by both short-term and long-term cardiotoxicity. Although oxidative stress, inflammation and mitochondrial dysfunction are established factors in DOX-induced cardiotoxicity, the precise molecular pathways remain elusive. Further exploration of the pathogenesis and identification of novel molecular targets are imperative. Recent studies have implicated the Sirtuins family in various physiological and pathological processes, suggesting their potential in ameliorating DOX-induced cardiotoxicity. Moreover, research on Sirtuins has discovered small-molecule compounds or medicinal plants with regulatory effects, representing a notable advancement in preventing and treating DOX-induced cardiac injury. PURPOSE In this review, we delve into the pathogenesis of DOX-induced cardiotoxicity and explore the therapeutic effects of Sirtuins in mitigating this condition, along with the associated molecular mechanisms. Furthermore, we delineate the roles and mechanisms of small-molecule regulators of Sirtuins in the prevention and treatment of DOX-induced cardiotoxicity. STUDY-DESIGN/METHODS Data for this review were sourced from various scientific databases (such as Web of Science, PubMed and Science Direct) up to March 2024. Search terms included "Sirtuins," "DOX-induced cardiotoxicity," "DOX," "Sirtuins regulators," "histone deacetylation," among others, as well as several combinations thereof. RESULTS Members of the Sirtuins family regulate both the onset and progression of DOX-induced cardiotoxicity through anti-inflammatory, antioxidative stress and anti-apoptotic mechanisms, as well as by maintaining mitochondrial stability. Moreover, natural plant-derived active compounds such as Resveratrol (RES), curcumin, berberine, along with synthetic small-molecule compounds like EX527, modulate the expression and activity of Sirtuins. CONCLUSION The therapeutic role of the Sirtuins family in mitigating DOX-induced cardiotoxicity represents a potential molecular target. However, further research is urgently needed to elucidate the relevant molecular mechanisms and to assess the safety and biological activity of Sirtuins regulators. This review offers an in-depth understanding of the therapeutic role of the Sirtuins family in mitigating DOX-induced cardiotoxicity, providing a preliminary basis for the clinical application of Sirtuins regulators in this condition.
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Affiliation(s)
- Xuan Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Chaoming Huang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Yanhong Hou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Shisheng Jiang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Yu Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Shulin Wang
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou, Qingyuan 511500, China
| | - Jiamin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Jianmei Lai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Lifeng Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Huiying Duan
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Shuwen He
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xinyi Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Shanshan Yu
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Yi Cai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
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6
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Kim JE, Jo MJ, Bae SY, Ahn SY, Ko GJ, Kwon YJ. Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity. Sci Rep 2024; 14:10143. [PMID: 38698042 PMCID: PMC11065982 DOI: 10.1038/s41598-024-60453-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 04/23/2024] [Indexed: 05/05/2024] Open
Abstract
Sirtuin3 (SIRT3), a mitochondrial deacetylase, has been shown to be involved in various kidney diseases. In this study, we aimed to clarify the role of SIRT3 in cyclosporine-induced nephrotoxicity and the associated mitochondrial dysfunction. Madin-Darby canine kidney (MDCK) cells were transfected with Flag-tagged SIRT3 for SIRT3 overexpression or SIRT3 siRNA for the inhibition of SIRT3. Subsequently, the cells were treated with cyclosporine A (CsA) or vehicle. Wild-type and SIRT3 knockout (KO) mice were randomly assigned to receive cyclosporine A or olive oil. Furthermore, SIRT3 activator, honokiol, was treated alongside CsA to wild type mice. Our results revealed that CsA treatment inhibited mitochondrial SIRT3 expression in MDCK cells. Inhibition of SIRT3 through siRNA transfection exacerbated apoptosis, impaired the expression of the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK-PGC1α) pathway, and worsened mitochondrial dysfunction induced by CsA treatment. Conversely, overexpression of SIRT3 through Flag-tagged SIRT3 transfection ameliorated apoptosis, increased the expression of mitochondrial superoxide dismutase 2, and restored the mitochondrial regulator pathway, AMPK-PGC1α. In SIRT3 KO mice, CsA treatment led to aggravated kidney dysfunction, increased kidney tubular injury, and accumulation of oxidative end products indicative of oxidative stress injury. Meanwhile, SIRT3 activation in vivo significantly mitigated these adverse effects, improving kidney function, reducing oxidative stress markers, and enhancing mitochondrial health following CsA treatment. Overall, our findings suggest that SIRT3 plays a protective role in alleviating mitochondrial dysfunction caused by CsA through the activation of the AMPK-PGC1α pathway, thereby preventing further kidney injury.
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Affiliation(s)
- Ji Eun Kim
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea
| | - Min Jee Jo
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea
| | - So Yeon Bae
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea
| | - Shin Young Ahn
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Gang Jee Ko
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Young Joo Kwon
- Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea.
- Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
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7
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Wei Z, Yang B, Wang H, Lv S, Chen H, Liu D. Caloric restriction, Sirtuins, and cardiovascular diseases. Chin Med J (Engl) 2024; 137:921-935. [PMID: 38527930 PMCID: PMC11046024 DOI: 10.1097/cm9.0000000000003056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Indexed: 03/27/2024] Open
Abstract
ABSTRACT Caloric restriction (CR) is a well-established dietary intervention known to extend healthy lifespan and exert positive effects on aging-related diseases, including cardiovascular conditions. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylases, have emerged as key regulators of cellular metabolism, stress responses, and the aging process, serving as energy status sensors in response to CR. However, the mechanism through which CR regulates Sirtuin function to ameliorate cardiovascular disease remains unclear. This review not only provided an overview of recent research investigating the interplay between Sirtuins and CR, specifically focusing on their potential implications for cardiovascular health, but also provided a comprehensive summary of the benefits of CR for the cardiovascular system mediated directly via Sirtuins. CR has also been shown to have considerable impact on specific metabolic organs, leading to the production of small molecules that enter systemic circulation and subsequently regulate Sirtuin activity within the cardiovascular system. The direct and indirect effects of CR offer a potential mechanism for Sirtuin modulation and subsequent cardiovascular protection. Understanding the interplay between CR and Sirtuins will provide new insights for the development of interventions to prevent and treat cardiovascular diseases.
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Affiliation(s)
- Ziyu Wei
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Bo Yang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Huiyu Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Shuangjie Lv
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Houzao Chen
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Depei Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
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Ali MA, Gioscia-Ryan R, Yang D, Sutton NR, Tyrrell DJ. Cardiovascular aging: spotlight on mitochondria. Am J Physiol Heart Circ Physiol 2024; 326:H317-H333. [PMID: 38038719 PMCID: PMC11219063 DOI: 10.1152/ajpheart.00632.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/02/2023]
Abstract
Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.
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Affiliation(s)
- Md Akkas Ali
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Rachel Gioscia-Ryan
- Department of Anesthesiology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Dongli Yang
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Nadia R Sutton
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
| | - Daniel J Tyrrell
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States
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Liu Y, Wei H, Li J. A review on SIRT3 and its natural small molecule activators as a potential Preventive and therapeutic target. Eur J Pharmacol 2024; 963:176155. [PMID: 37914065 DOI: 10.1016/j.ejphar.2023.176155] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/03/2023]
Abstract
Sirtuins (SIRTs) were originally characterized by yeast Sir2 as a lifespan regulator that is conserved in all three structural domains of bacteria, archaea and eukaryotes and belong to histone deacetylases consisting of seven members (SIRT1-SIRT7). Surprisingly, SIRTs have been shown to play important regulatory roles in almost all cellular functions, including mitochondrial biogenesis, oxidative stress, inflammation, cell growth, energy metabolism, neural function, and stress resistance. Among the SIRT members, sirtuin 3 (SIRT3) is one of the most important deacetylases that regulates the mitochondrial acetylation and plays a role in pathological processes, such as metabolism, DNA repair, oxidative stress, apoptosis and ferroptosis. Therefore, SIRT3 is considered as a potential target for the treatment of a variety of pathological diseases, including metabolic diseases, neurodegenerative diseases, age-related diseases and others. Furthermore, the isolation, screening, and development of SIRT3 signaling agonists, especially from natural products, have become a widely investigated objective. This paper describes the structure of SIRT3 protein, discusses the pathological process of SIRT3-mediated acetylation modification, and reviews the role of SIRT3 in diseases, SIRT3 activators and its related disease studies.
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Affiliation(s)
- Yuanyuan Liu
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Haidong Wei
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
| | - Jianhong Li
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China; Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin, 150030, China.
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Matouk AI, Awad EM, Mousa AAK, Abdelhafez SMN, Fahmy UA, El-Moselhy MA, Abdel-Naim AB, Anter A. Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2. Life Sci 2024; 336:122318. [PMID: 38035992 DOI: 10.1016/j.lfs.2023.122318] [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: 11/06/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
AIM Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.
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Affiliation(s)
- Asmaa I Matouk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt.
| | - Eman M Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Amr A K Mousa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Sara M N Abdelhafez
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Usama A Fahmy
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohamed A El-Moselhy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt; Clinical Pharmacy and Pharmacology Department, Ibn Sina National College for Medical Studies, Jeddah 21589, Saudi Arabia
| | - Ashraf B Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aliaa Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt
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11
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Renu K, Mukherjee AG, Gopalakrishnan AV, Wanjari UR, Kannampuzha S, Murali R, Veeraraghavan VP, Vinayagam S, Paz-Montelongo S, George A, Vellingiri B, Madhyastha H. Protective effects of macromolecular polyphenols, metals (zinc, selenium, and copper) - Polyphenol complexes, and different organs with an emphasis on arsenic poisoning: A review. Int J Biol Macromol 2023; 253:126715. [PMID: 37673136 DOI: 10.1016/j.ijbiomac.2023.126715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 08/28/2023] [Accepted: 09/03/2023] [Indexed: 09/08/2023]
Abstract
For the potential health benefits and nutritional value, polyphenols are one of the secondary metabolites of plants that have received extensive research. It has anti-inflammatory and cytotoxicity-reducing properties in addition to a high antioxidant content. Macromolecular polyphenols and polysaccharides are biologically active natural polymers with antioxidant and anti-inflammatory potential. Arsenic is an ecologically toxic metalloid. Arsenic in drinking water is the most common way people come into contact with this metalloid. While arsenic is known to cause cancer, it is also used to treat acute promyelocytic leukemia (APL). The treatment's effectiveness is hampered by the adverse effects it can cause on the body. Oxidative stress, inflammation, and the inability to regulate cell death cause the most adverse effects. Polyphenols and other macromolecules like polysaccharides act as neuroprotectants by mitigating free radical damage, inhibiting nitric oxide (NO) production, lowering A42 fibril formation, boosting antioxidant levels, and controlling apoptosis and inflammation. To prevent the harmful effects of toxins, polyphenols and pectin lower oxidative stress, boost antioxidant levels, improve mitochondrial function, control apoptosis, and suppress inflammation. Therefore, it prevents damage to the heart, liver, kidneys, and reproductive system. This review aims to identify the effects of the polyphenols in conjugation with polysaccharides as an ameliorative strategy for arsenic-induced toxicity in various organs.
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Affiliation(s)
- Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India.
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
| | - Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India.
| | - Sathishkumar Vinayagam
- Department of Biotechnology, Periyar University, Centre for Postgraduate and Research Studies, Dharmapuri 635205, Tamil Nadu, India.
| | - Soraya Paz-Montelongo
- Area de Toxicologia, Universidad de La Laguna, 38071 La Laguna, Tenerife, Islas Canarias, Spain; Grupo interuniversitario de Toxicología Alimentaria y Ambiental, Universidad de La Laguna, 38071 La Laguna, Tenerife, Islas Canarias, Spain.
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India.
| | - Balachandar Vellingiri
- Stem cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda 151401, Punjab, India.
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 889 1692, Japan.
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12
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Xiao Q, Wang D, Li D, Huang J, Ma F, Zhang H, Sheng Y, Zhang C, Ha X. Protein kinase C: A potential therapeutic target for endothelial dysfunction in diabetes. J Diabetes Complications 2023; 37:108565. [PMID: 37540984 DOI: 10.1016/j.jdiacomp.2023.108565] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/13/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
Protein kinase C (PKC) is a family of serine/threonine protein kinases that play an important role in many organs and systems and whose activation contributes significantly to endothelial dysfunction in diabetes. The increase in diacylglycerol (DAG) under high glucose conditions mediates PKC activation and synthesis, which stimulates oxidative stress and inflammation, resulting in impaired endothelial cell function. This article reviews the contribution of PKC to the development of diabetes-related endothelial dysfunction and summarizes the drugs that inhibit PKC activation, with the aim of exploring therapeutic modalities that may alleviate endothelial dysfunction in diabetic patients.
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Affiliation(s)
- Qian Xiao
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Dan Wang
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Danyang Li
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Jing Huang
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Feifei Ma
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; College of Veterinary Medicine, Gansu Agriculture University, Lanzhou 730070, Gansu, China
| | - Haocheng Zhang
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; The Second School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yingda Sheng
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Caimei Zhang
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
| | - Xiaoqin Ha
- Department of Laboratory, Ninth Forty Hospital of the Chinese People's Liberation Army Joint Security Force, Lanzhou 730050, Gansu, China; School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China.
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13
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Liu L, Wang B, Yang W, Jiang Q, Loor JJ, Ouyang L, Tang H, Chang R, Peng T, Xu C. Sirtuin 3 relieves inflammatory responses elicited by lipopolysaccharide via the PGC1α-NFκB pathway in bovine mammary epithelial cells. J Dairy Sci 2023; 106:1315-1329. [PMID: 36494223 DOI: 10.3168/jds.2022-22114] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 09/04/2022] [Indexed: 12/12/2022]
Abstract
Excessive inflammation in bovine mammary endothelial cells (BMEC) due to mastitis leads to disease progression and eventual culling of cattle. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, downregulates pro-inflammatory cytokines in BMEC exposed to high concentrations of nonesterified fatty acids by blunting nuclear factor-κB (NFκB) signaling. In nonruminants, SIRT3 is under the control of PGC1α, a transcriptional cofactor. Specific aims were to study (1) the effect of SIRT3 on inflammatory responses of lipopolysaccharide (LPS)-challenged bovine mammary epithelial cells (bovine mammary alveolar cells-T, MAC-T) models, and (2) the role of PGC1α in the attenuation of NFκB signaling via SIRT3. To address these objectives, first, MAC-T cells were incubated in triplicate with 0, 50, 100, 150, or 200 μg/mL LPS (derived from Escherichia coli O55:B5) for 12 h with or without a 2-h incubation of the NFκB inhibitor ammonium pyrrolidine dithiocarbamate (APDC, 10 μM). Second, SIRT3 was overexpressed using adenoviral expression (Ad-SIRT3) at different multiplicity of infection (MOI) for 6 h followed by a 12 h incubation with 150 μg/mL LPS. Third, cells were treated with the PGC1α agonist ZLN005 (10 μg/mL) for 24 h and then challenged with 150 μg/mL LPS for 12 h. Fourth, cells were initially treated with the PGC1α inhibitor SR-18292 (100 μM) for 6 h followed by a 6-h culture with or without 50 MOI Ad-SIRT3 and a challenge with 150 μg/mL LPS for 12 h. Data were analyzed using one-way ANOVA with subsequent Bonferroni correction. Linear and quadratic contrasts were used to determine dose-responses to LPS. There were linear and quadratic effects of LPS dosage on cell viability. Incubation with 150 and 200 μg/mL LPS for 12 h decreased cell viability to 78.6 and 34.9%, respectively. Compared with controls, expression of IL1B, IL6, and TNFA was upregulated by 5.2-, 5.9-, and 2.7-fold with 150 μg/mL LPS; concentrations of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in cell medium also increased. Compared with the LPS group, LPS+APDC increased cell viability and reversed the upregulation of IL1B, IL6, and TNFA expression. However, mRNA and protein abundance of SIRT3 decreased linearly with increasing LPS dose. Ad-SIRT3 infection (50 MOI) reduced IL1B, IL6, and TNFA expression and also their concentrations in cell medium, and decreased pNFκB P65/NFκB P65 ratio and nuclear abundance of NFκB P65. The PGC1α agonist increased SIRT3 expression, whereas it decreased cytokine expression, pNFκB P65/NFκB P65 ratio, and prevented NFκB P65 nuclear translocation. Contrary to the agonist, the PGC1α inhibitor had opposite effects, and elevated the concentrations of IL-1β, IL-6, and TNF-α in cell medium. Overall, data suggested that SIRT3 activity could attenuate LPS-induced inflammatory responses in mammary cells via alterations in the PGC1α-NFκB pathway. As such, there may be potential benefits for targeting SIRT3 in vivo to help prevent or alleviate negative effects of mastitis.
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Affiliation(s)
- Lei Liu
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China
| | - Baogen Wang
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China
| | - Wei Yang
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, 163319, China
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Lu Ouyang
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China
| | - Huilun Tang
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China
| | - Renxu Chang
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China; College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, 163319, China
| | - Tao Peng
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Agricultural University, Changsha, 410128, China
| | - Chuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang, 163319, China.
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14
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Wu S, Liu H. Sirtuins-Novel Regulators of Epigenetic Alterations in Airway Inflammation. Front Genet 2022; 13:862577. [PMID: 35620467 PMCID: PMC9127257 DOI: 10.3389/fgene.2022.862577] [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: 01/26/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Histone modification is an important epigenetic alteration, and histone deacetylases are involved in the occurrence and development of various respiratory diseases. Sirtuins (SIRTs) have been demonstrated to play an important role in the formation and progression of chronic inflammatory diseases of the respiratory tract. SIRTs participate in the regulation of oxidative stress and inflammation and are related to cell structure and cellular localization. This paper summarizes the roles and mechanisms of SIRTs in airway inflammation and describes the latest research on SIRT modulators, aiming to provide a theoretical basis for the study of potential epigenetic alteration-inducing drug targets.
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Affiliation(s)
- Shunyu Wu
- Department of Otolaryngological, the Second Affiliated Hospital of the Naval Military Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Huanhai Liu
- Department of Otolaryngological, the Second Affiliated Hospital of the Naval Military Medical University (Shanghai Changzheng Hospital), Shanghai, China
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15
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Abstract
Significance: Aging is a natural process that affects most living organisms, resulting in increased mortality. As the world population ages, the prevalence of age-associated diseases, and their associated health care costs, has increased sharply. A better understanding of the molecular mechanisms that lead to cellular dysfunction may provide important targets for interventions to prevent or treat these diseases. Recent Advances: Although the mitochondrial theory of aging had been proposed more than 40 years ago, recent new data have given stronger support for a central role for mitochondrial dysfunction in several pathways that are deregulated during normal aging and age-associated disease. Critical Issues: Several of the experimental evidence linking mitochondrial alterations to age-associated loss of function are correlative and mechanistic insights are still elusive. Here, we review how mitochondrial dysfunction may be involved in many of the known hallmarks of aging, and how these pathways interact in an intricate net of molecular relationships. Future Directions: As it has become clear that mitochondrial dysfunction plays causative roles in normal aging and age-associated diseases, it is necessary to better define the molecular interactions and the temporal and causal relationship between these changes and the relevant phenotypes seen during the aging process. Antioxid. Redox Signal. 36, 824-843.
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Affiliation(s)
- Caio M P F Batalha
- Lab. Genética Mitocondrial, Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Anibal Eugênio Vercesi
- Departamento de Patologia Clínica, Faculdade de Medicina, Universidade de Campinas, Campinas, Brazil
| | - Nadja C Souza-Pinto
- Lab. Genética Mitocondrial, Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
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16
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Zhang XY, Li W, Zhang JR, Li CY, Zhang J, Lv XJ. Roles of sirtuin family members in chronic obstructive pulmonary disease. Respir Res 2022; 23:66. [PMID: 35313881 PMCID: PMC8939123 DOI: 10.1186/s12931-022-01986-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
The globally increasing annual incidence of chronic obstructive pulmonary disease (COPD), a common chronic disease, poses a serious risk to public health. Although the exact mechanism underlying the pathogenesis of COPD remains unclear, a large number of studies have shown that its pathophysiology and disease course are closely related to oxidative stress, inflammation, apoptosis, autophagy, and aging. The key players involved in COPD include the sirtuin family of NAD-dependent deacetylases that comprise seven members (SIRT1-7) in mammals. Sirtuins play an important role in metabolic diseases, cell cycle control, proliferation, apoptosis, and senescence. Owing to differences in subcellular localization, sirtuins exhibit anisotropy. In this narrative review, we discuss the roles and molecular pathways of each member of the sirtuin family involved in COPD to provide novel insights into the prevention and treatment of COPD and how sirtuins may serve as adjuvants for COPD treatment.
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Affiliation(s)
- Xi-Yue Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jin-Rong Zhang
- Department of Pathogeny Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Chun-Yan Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jie Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China.
| | - Xue-Jiao Lv
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China.
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17
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Murugasamy K, Munjal A, Sundaresan NR. Emerging Roles of SIRT3 in Cardiac Metabolism. Front Cardiovasc Med 2022; 9:850340. [PMID: 35369299 PMCID: PMC8971545 DOI: 10.3389/fcvm.2022.850340] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 01/31/2022] [Indexed: 12/17/2022] Open
Abstract
The heart is a highly metabolically active organ that predominantly utilizes fatty acids as an energy substrate. The heart also derives some part of its energy by oxidation of other substrates, including glucose, lactose, amino acids and ketones. The critical feature of cardiac pathology is metabolic remodeling and loss of metabolic flexibility. Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins (SIRT1 to SIRT7), with NAD+ dependent deacetylase activity. SIRT3 is expressed in high levels in healthy hearts but downregulated in the aged or diseased hearts. Experimental evidence shows that increasing SIRT3 levels or activity can ameliorate several cardiac pathologies. The primary deacetylation targets of SIRT3 are mitochondrial proteins, most of which are involved in energy metabolism. Thus, SIRT3 improves cardiac health by modulating cardiac energetics. In this review, we discuss the essential role of SIRT3 in regulating cardiac metabolism in the context of physiology and pathology. Specifically, we summarize the recent advancements that emphasize the critical role of SIRT3 as a master regulator of cardiac metabolism. We also present a comprehensive view of all known activators of SIRT3, and elaborate on their therapeutic potential to ameliorate energetic abnormalities in various cardiac pathologies.
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Yu W, Chen C, Xu C, Xie D, Wang Q, Liu W, Zhao H, He F, Chen B, Xi Y, Yan Y, Yu L, Cheng J. Activation of p62-NRF2 Axis Protects against Doxorubicin-Induced Ferroptosis in Cardiomyocytes: A Novel Role and Molecular Mechanism of Resveratrol. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:2103-2123. [DOI: 10.1142/s0192415x22500902] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. However, the role and mechanism of RSV in DOX-mediated ferroptosis in cardiomyocytes is unclear. This study showed that DOX decreased cell viability, increased iron accumulation and lipid peroxidation in H9c2 cells; however, these effects were reversed by RSV and ferroptosis inhibitor ferrostatin-1 (Fer-1) pre-treatment. Additionally, RSV significantly increased the cell viability of H9c2 cells treated with ferroptosis inducers Erastin (Era) and RSL3. Mechanistically, RSV inhibited mitochondrial reactive oxygen species (mtROS) overproduction and upregulated the p62-NRF2/HO-1 pathway. RSV-induced NRF2 activation was partially dependent on p62, and the selective inhibition of p62 (using p62-siRNA interference) or NRF2 (using NRF2 specific inhibitor, ML385) significantly abolished the anti-ferroptosis function of RSV. Furthermore, RSV treatment protected mice against DOX-induced cardiotoxicity, including significantly improving left ventricular function, ameliorating myocardial fibrosis and suppressing ferroptosis. Consistent with in vitro results, RSV also upregulated the p62-NRF2/HO-1 expression, which was inhibited by DOX, in the myocardium. Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation.
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Affiliation(s)
- Wei Yu
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Chunjuan Chen
- Department of Cardiology, The Second Affiliated Hospital of Shantou, University Medical College, Shantou, P. R. China
| | - Chenxi Xu
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - De Xie
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Qiang Wang
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Weidong Liu
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Hairong Zhao
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Furong He
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Bingyang Chen
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Yuemei Xi
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Yunbo Yan
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Linqian Yu
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
| | - Jidong Cheng
- Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China
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19
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Zhao W, Sui M, Chen R, Lu H, Zhu Y, Zhang L, Zeng L. SIRT3 protects kidneys from ischemia-reperfusion injury by modulating the DRP1 pathway to induce mitochondrial autophagy. Life Sci 2021; 286:120005. [PMID: 34606850 DOI: 10.1016/j.lfs.2021.120005] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 12/24/2022]
Abstract
Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and may influence renal graft survival. In this study, we investigate the involvement of SIRT3 and DRP1 in mitochondrial autophagy and AKI in a mouse model of IRI. Autophagy was detected in the absence of SIRT3, and hypoxic reoxygenation (H/R) experiments using renal tubular epithelial cells NRK52E were performed in vitro to validate these results. We found that autophagosomes increased following IRI and that the expression of autophagy-related genes was up-regulated. The inhibition of autophagy with 3-methyladenine exacerbated IRI, whereas the DRP1 inhibitor Mdivi-1 reversed this inhibition. Mdivi-1 did not reverse the inhibition of autophagy in the absence of SIRT3. During IRI, Mdivi-1 reduced autophagy and DRP1 expression, whereas SIRT3 overexpression attenuated this condition. Rescue experiment showed that autophagy was increased when both SIRT3 or DRP1 were over- or under-expressed or just DRP1 was under-expressed but expression was reduced when just SIRT3 was under-expressed. However, the expression of DRP1-related molecules was reduced when SIRT3 was overexpressed and when DRP1 was under-expressed. Taken together, these findings indicate that SIRT3 protects against kidney damage from IRI by modulating the DRP1 pathway to induce mitochondrial autophagy.
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Affiliation(s)
- Wenyu Zhao
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Mingxing Sui
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Rui Chen
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Hanlan Lu
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Youhua Zhu
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Lei Zhang
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
| | - Li Zeng
- Department of Organ Transplantation, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
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20
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Tubeimoside I Ameliorates Myocardial Ischemia-Reperfusion Injury through SIRT3-Dependent Regulation of Oxidative Stress and Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5577019. [PMID: 34795840 PMCID: PMC8595016 DOI: 10.1155/2021/5577019] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/13/2021] [Accepted: 10/23/2021] [Indexed: 12/31/2022]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is a phenomenon that reperfusion leads to irreversible damage to the myocardium and increases mortality in acute myocardial infarction (AMI) patients. There is no effective drug to treat MIRI. Tubeimoside I (TBM) is a triterpenoid saponin purified from Chinese traditional medicine tubeimu. In this study, 4 mg/kg TBM was given to mice intraperitoneally at 15 min after ischemia. And TBM treatment improved postischemic cardiac function, decreased infarct size, diminished lactate dehydrogenase release, ameliorated oxidative stress, and reduced apoptotic index. Notably, ischemia-reperfusion induced a significant decrease in cardiac SIRT3 expression and activity, while TBM treatment upregulated SIRT3's expression and activity. However, the cardioprotective effects of TBM were largely abolished by a SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). This suggests that SIRT3 plays an essential role in TBM's cardioprotective effects. In vitro, TBM also protected H9c2 cells against simulated ischemia/reperfusion (SIR) injury by attenuating oxidative stress and apoptosis, and siSIRT3 diminished its protective effects. Taken together, our results demonstrate for the first time that TBM protects against MIRI through SIRT3-dependent regulation of oxidative stress and apoptosis. TBM might be a potential drug candidate for MIRI treatment.
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The Effect of Resveratrol on the Cardiovascular System from Molecular Mechanisms to Clinical Results. Int J Mol Sci 2021; 22:ijms221810152. [PMID: 34576315 PMCID: PMC8466271 DOI: 10.3390/ijms221810152] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/02/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular diseases are the leading causes of death worldwide. The cardioprotective effects of natural polyphenols such as resveratrol (3,5,4-trihydroxystilbene) have been extensively investigated throughout recent decades. Many studies of RES have focused on its favorable effects on pathological conditions related to cardiovascular diseases and their risk factors. The aim of this review was to summarize the wide beneficial effects of resveratrol on the cardiovascular system, including signal transduction pathways of cell longevity, energy metabolism of cardiomyocytes or cardiac remodeling, and its anti-inflammatory and antioxidant properties. In addition, this paper discusses the significant preclinical and human clinical trials of recent years with resveratrol on cardiovascular system. Finally, we present a short overview of antiviral and anti-inflammatory properties and possible future perspectives on RES against COVID-19 in cardiovascular diseases.
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22
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Liu L, Lu H, Loor JJ, Aboragah A, Du X, He J, Peng T, Su J, Wang Z, Liu G, Li X. Sirtuin 3 inhibits nuclear factor-κB signaling activated by a fatty acid challenge in bovine mammary epithelial cells. J Dairy Sci 2021; 104:12871-12880. [PMID: 34482974 DOI: 10.3168/jds.2021-20536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/22/2021] [Indexed: 11/19/2022]
Abstract
Susceptibility to mastitis is highest during the peripartal (transition) period and is often concomitant with other comorbidities such as ketosis. Although infection with pathogenic microorganisms and immune-dysfunction around calving clearly play key roles in mastitis development, other metabolic factors also contribute. Sirtuin 3 (SIRT3), a mitochondrial deacetylase regulating energy and redox homeostasis, antagonizes the lipotoxic effects of nonesterified fatty acids (NEFA). Thus, we hypothesized that increases in circulating NEFA concentrations, as observed in the transition period, provokes inflammatory responses that can be reversed via activation of SIRT3. Here we aimed to study (1) proinflammatory NF-κB signaling and SIRT3 abundance in mammary tissue of ketotic cows and healthy controls, and (2) the effect of SIRT3 on NF-κB activation in bovine mammary epithelial cells (BMEC) treated with high levels of NEFA. The mammary gland biopsy samples were from a previous study, which included 15 healthy cows and 15 ketotic cows. Primary BMEC were isolated from 3 healthy Holstein cows with collagenase III digestion. Purified BMEC were incubated with or without SIRT3 overexpression adenovirus for 48 h, then treated with 0, 0.6, 1.2, or 2.4 mM NEFA for 24 h. Mammary tissue of ketotic cows was associated with lower protein abundance of SIRT3 along with greater NF-κB P65 phosphorylation levels (p-NF-κB P65), p-NF-κB P65:NF-κB P65 ratio, and mRNA abundance of IL1B and IL6. In BMEC, exogenous NEFA dose-dependently reduced protein abundance of SIRT3, but increased p-NF-κB P65, p-NF-κB P65:NF-κB P65 ratio, and mRNA abundance of IL1B and IL6. Compared with green fluorescent protein adenovirus vector + NEFA, overexpression of SIRT3 in NEFA-treated BMEC downregulated p-NF-κB P65 and mRNA abundance of IL1B and IL6. Immunofluorescence indicated that overexpression of SIRT3 inhibited nuclear translocation of NF-κB P65. Overall, our data demonstrated that ketosis is associated with a reduction in SIRT3 abundance and activation of NF-κB signaling in the mammary gland. In vitro data provided evidence that high NEFA concentrations inhibit SIRT3, which contributes to enhanced NF-κB signaling including nuclear translocation and a pro-inflammatory response. The data suggest a promising role of SIRT3 as a target for helping alleviate localized inflammation of the mammary gland resulting from exposure to high concentrations of NEFA.
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Affiliation(s)
- Lei Liu
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Collaborative Innovation Center for Safety Production of Livestock and Poultry, Hunan Agricultural University, Changsha 410128, China
| | - Hong Lu
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Collaborative Innovation Center for Safety Production of Livestock and Poultry, Hunan Agricultural University, Changsha 410128, China
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Ahmad Aboragah
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Xiliang Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, Jilin, China
| | - Jianhua He
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Collaborative Innovation Center for Safety Production of Livestock and Poultry, Hunan Agricultural University, Changsha 410128, China
| | - Tao Peng
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Collaborative Innovation Center for Safety Production of Livestock and Poultry, Hunan Agricultural University, Changsha 410128, China
| | - Jianming Su
- College of Veterinary Medicine, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Hunan Collaborative Innovation Center for Safety Production of Livestock and Poultry, Hunan Agricultural University, Changsha 410128, China
| | - Zhe Wang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, Jilin, China
| | - Guowen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, Jilin, China
| | - Xinwei Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, Jilin, China.
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Ushio-Fukai M, Ash D, Nagarkoti S, Belin de Chantemèle EJ, Fulton DJR, Fukai T. Interplay Between Reactive Oxygen/Reactive Nitrogen Species and Metabolism in Vascular Biology and Disease. Antioxid Redox Signal 2021; 34:1319-1354. [PMID: 33899493 PMCID: PMC8418449 DOI: 10.1089/ars.2020.8161] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Reactive oxygen species (ROS; e.g., superoxide [O2•-] and hydrogen peroxide [H2O2]) and reactive nitrogen species (RNS; e.g., nitric oxide [NO•]) at the physiological level function as signaling molecules that mediate many biological responses, including cell proliferation, migration, differentiation, and gene expression. By contrast, excess ROS/RNS, a consequence of dysregulated redox homeostasis, is a hallmark of cardiovascular disease. Accumulating evidence suggests that both ROS and RNS regulate various metabolic pathways and enzymes. Recent studies indicate that cells have mechanisms that fine-tune ROS/RNS levels by tight regulation of metabolic pathways, such as glycolysis and oxidative phosphorylation. The ROS/RNS-mediated inhibition of glycolytic pathways promotes metabolic reprogramming away from glycolytic flux toward the oxidative pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant defense. This review summarizes our current knowledge of the mechanisms by which ROS/RNS regulate metabolic enzymes and cellular metabolism and how cellular metabolism influences redox homeostasis and the pathogenesis of disease. A full understanding of these mechanisms will be important for the development of new therapeutic strategies to treat diseases associated with dysregulated redox homeostasis and metabolism. Antioxid. Redox Signal. 34, 1319-1354.
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Affiliation(s)
- Masuko Ushio-Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Dipankar Ash
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Sheela Nagarkoti
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Eric J Belin de Chantemèle
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Medicine (Cardiology) and Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - David J R Fulton
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Tohru Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.,Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
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24
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López-Pedrera C, Villalba JM, Patiño-Trives AM, Luque-Tévar M, Barbarroja N, Aguirre MÁ, Escudero-Contreras A, Pérez-Sánchez C. Therapeutic Potential and Immunomodulatory Role of Coenzyme Q 10 and Its Analogues in Systemic Autoimmune Diseases. Antioxidants (Basel) 2021; 10:antiox10040600. [PMID: 33924642 PMCID: PMC8069673 DOI: 10.3390/antiox10040600] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Coenzyme Q10 (CoQ10) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ10 is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ10 and the stabilization of reduced CoQ10 (ubiquinol) have improved its bioavailability and efficacy. Synthetic analogues with increased solubility, such as idebenone, or accumulated selectively in mitochondria, such as MitoQ, have also demonstrated promising properties. CoQ10 has shown beneficial effects in autoimmune diseases. Leukocytes from antiphospholipid syndrome (APS) patients exhibit an oxidative perturbation closely related to the prothrombotic status. In vivo ubiquinol supplementation in APS modulated the overexpression of inflammatory and thrombotic risk-markers. Mitochondrial abnormalities also contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). Idebenone and MitoQ improved clinical and immunological features of lupus-like disease in mice. Clinical trials and experimental models have further demonstrated a therapeutic role for CoQ10 in Rheumatoid Arthritis, multiple sclerosis and type 1 diabetes. This review summarizes the effects of CoQ10 and its analogs in modulating processes involved in autoimmune disorders, highlighting the potential of these therapeutic approaches for patients with immune-mediated diseases.
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Affiliation(s)
- Chary López-Pedrera
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
- Correspondence: ; Tel.: +34-957-213795
| | - José Manuel Villalba
- Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, ceiA3, 14014 Córdoba, Spain; (J.M.V.); (C.P.-S.)
| | - Alejandra Mª Patiño-Trives
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Maria Luque-Tévar
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Nuria Barbarroja
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Mª Ángeles Aguirre
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Alejandro Escudero-Contreras
- Rheumatology Service, Reina Sofia Hospital/Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, 14004 Córdoba, Spain; (A.M.P.-T.); (M.L.-T.); (N.B.); (M.Á.A.); (A.E.-C.)
| | - Carlos Pérez-Sánchez
- Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, ceiA3, 14014 Córdoba, Spain; (J.M.V.); (C.P.-S.)
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Checa J, Aran JM. Reactive Oxygen Species: Drivers of Physiological and Pathological Processes. J Inflamm Res 2020; 13:1057-1073. [PMID: 33293849 PMCID: PMC7719303 DOI: 10.2147/jir.s275595] [Citation(s) in RCA: 497] [Impact Index Per Article: 99.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022] Open
Abstract
Since the Great Oxidation Event, about 2.4 billion years ago, the Earth is immersed in an oxidizing atmosphere. Thus, it has been proposed that excess oxygen, originally a waste product of photosynthetic cyanobacteria, induced oxidative stress and the production of reactive oxygen species (ROS), which have since acted as fundamental drivers of biologic evolution and eukaryogenesis. Indeed, throughout an organism’s lifespan, ROS affect directly (as mutagens) or indirectly (as messengers and regulators) all structural and functional components of cells, and many aspects of cell biology. Whether left unchecked by protective antioxidant systems, excess ROS not only cause genomic mutations but also induce irreversible oxidative modification of proteins (protein oxidation and peroxidation), lipids and glycans (advanced lipoxidation and glycation end products), impairing their function and promoting disease or cell death. Conversely, low-level local ROS play an important role both as redox-signaling molecules in a wide spectrum of pathways involved in the maintenance of cellular homeostasis (MAPK/ERK, PTK/PTP, PI3K-AKT-mTOR), and regulating key transcription factors (NFκB/IκB, Nrf2/KEAP1, AP-1, p53, HIF-1). Consequently, ROS can shape a variety of cellular functions, including proliferation, differentiation, migration and apoptosis. In this review, we will give a brief overview of the relevance of ROS in both physiological and pathological processes, particularly inflammation and aging. In-depth knowledge of the molecular mechanisms of ROS actuation and their influence under steady-state and stressful conditions will pave the way for the development of novel therapeutic interventions. This will mitigate the harmful outcomes of ROS in the onset and progression of a variety of chronic inflammatory and age-related diseases.
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Affiliation(s)
- Javier Checa
- Immune-Inflammatory Processes and Gene Therapeutics Group, IDIBELL, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona 08907, Spain
| | - Josep M Aran
- Immune-Inflammatory Processes and Gene Therapeutics Group, IDIBELL, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona 08907, Spain
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Antioxidant Effect of Standardized Extract of Propolis (EPP-AF®) in Healthy Volunteers: A "Before and After" Clinical Study. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7538232. [PMID: 33123209 PMCID: PMC7585652 DOI: 10.1155/2020/7538232] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/18/2020] [Accepted: 09/21/2020] [Indexed: 11/18/2022]
Abstract
Background Propolis is rich in polyphenols, especially flavonoids and phenolic acids, and has significant antioxidant activity, shown mainly in “in vitro” studies. Objective The aim of this study was to evaluate the antioxidant efficacy and safety of a standardized propolis extract in healthy volunteers. Design A two-phase sequential, open-label, nonrandomized, before and after clinical trial. Methods Healthy participants received two EPP-AF® doses (375 and 750 mg/d, P.O, tid) during 7 ± 2 days, starting with the lower doses. Immediately before starting EPP-AF® administration and at the end of each 7-day dosing schedule, blood and urine samples were collected for quantification of 8-OHDG (8-hydroxydeoxyguanosine) and 8-ISO (8-isoprostanes) in urine and GSH (reduced glutathione), GSSG (oxidized glutathione), SOD (superoxide dismutase), FRAP (Ferric Reducing Antioxidant Power), vitamin E, and MDA (malondialdehyde) in plasma. Results In our study, we had 34 healthy participants (67.7% women, 30 ± 8 years old, 97% white). The 8-ISO, a biomarker of lipid peroxidation, decreased with both doses of EPP-AF® compared to baseline (8-ISO, 1.1 (0.9–1.3) versus 0.85 (0.75–0.95) and 0.89 (0.74–1.0), ng/mg creatinine, P < 0.05, for 375 and 750 mg/d EPP-AF® doses versus baseline, mean and CI 95%, respectively). 8-OHDG, a biomarker of DNA oxidation, was also reduced compared to baseline with 750 mg/d doses (8-OHDG, 15.7 (13.2–18.1) versus 11.6 (10.2–13.0), baseline versus 750 mg/d, respectively, ng/mg creatinine, P < 0.05). Reduction of biomarkers of oxidative stress damage was accompanied by increased plasma SOD activity (68.8 (66.1–73.3) versus 78.2 (72.2–80.5) and 77.7 (74.1–82.6), %inhibition, P < 0.0001, 375 and 750 mg/d versus baseline, median and interquartile range 25–75%, respectively) and by increased GSH for 375 mg/d EPP-AF® doses (1.23 (1.06–1.34) versus 1.33 (1.06–1.47), μmol/L, P < 0.05). Conclusion EPP-AF® reduced biomarkers of oxidative stress cell damage in healthy humans, with increased antioxidant enzymatic capacity, especially of SOD. This trial is registered with the Brazilian Registry of Clinical Trials (ReBEC, RBR-9zmfs9).
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Trinh D, Israwi AR, Arathoon LR, Gleave JA, Nash JE. The multi-faceted role of mitochondria in the pathology of Parkinson's disease. J Neurochem 2020; 156:715-752. [PMID: 33616931 DOI: 10.1111/jnc.15154] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022]
Abstract
Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and regulate reactive oxygen species that cause oxidative cellular stress. Mitochondria have also been shown to regulate protein synthesis within themselves, as well as within the nucleus, and also influence synaptic plasticity. These roles are especially important for neurons, which have higher energy demands and greater susceptibility to stress. Dysfunction of mitochondria has been associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, Glaucoma and Amyotrophic Lateral Sclerosis. The focus of this review is on how and why mitochondrial function is linked to the pathology of Parkinson's disease (PD). Many of the PD-linked genetic mutations which have been identified result in dysfunctional mitochondria, through a wide-spread number of mechanisms. In this review, we describe how susceptible neurons are predisposed to be vulnerable to the toxic events that occur during the neurodegenerative process of PD, and how mitochondria are central to these pathways. We also discuss ways in which proteins linked with familial PD control mitochondrial function, both physiologically and pathologically, along with their implications in genome-wide association studies and risk assessment. Finally, we review potential strategies for disease modification through mitochondrial enhancement. Ultimately, agents capable of both improving and/or restoring mitochondrial function, either alone, or in conjunction with other disease-modifying agents may halt or slow the progression of neurodegeneration in Parkinson's disease.
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Affiliation(s)
- Dennison Trinh
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Ahmad R Israwi
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Lindsay R Arathoon
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Jacqueline A Gleave
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
| | - Joanne E Nash
- Department of Biological Sciences, University of Toronto Scarborough, Centre for Neurobiology of Stress, Toronto, ON, Canada
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Hong YA, Kim JE, Jo M, Ko GJ. The Role of Sirtuins in Kidney Diseases. Int J Mol Sci 2020; 21:ijms21186686. [PMID: 32932720 PMCID: PMC7555196 DOI: 10.3390/ijms21186686] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.
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Affiliation(s)
- Yu Ah Hong
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Daejeon St. Mary Mary’s Hospital, Daejeon 34943, Korea;
| | - Ji Eun Kim
- Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea; (J.E.K.); (M.J.)
| | - Minjee Jo
- Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea; (J.E.K.); (M.J.)
| | - Gang-Jee Ko
- Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea; (J.E.K.); (M.J.)
- Correspondence: ; Tel.: +82-2-2626-3039
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Wang Z, Zhao YT, Zhao TC. Histone deacetylases in modulating cardiac disease and their clinical translational and therapeutic implications. Exp Biol Med (Maywood) 2020; 246:213-225. [PMID: 32727215 DOI: 10.1177/1535370220944128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Cardiovascular diseases are the leading cause of mortality and morbidity worldwide. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of genetic transcription in response to stress or pathological conditions. HDACs interact with a complex co-regulatory network of transcriptional regulators, deacetylate histones or non-histone proteins, and modulate gene expression in the heart. The selective HDAC inhibitors have been considered to be a critical target for the treatment of cardiac disease, especially for ameliorating cardiac dysfunction. In this review, we discuss our current knowledge of the cellular and molecular basis of HDACs in mediating cardiac development and hypertrophy and related pharmacologic interventions in heart disease.
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Affiliation(s)
- Zhengke Wang
- Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Providence, RI 02908, USA
| | - Yu Tina Zhao
- University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Ting C Zhao
- Departments of Surgery and Plastic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA
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The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2082145. [PMID: 32774665 PMCID: PMC7396016 DOI: 10.1155/2020/2082145] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/08/2020] [Indexed: 01/01/2023]
Abstract
Oxidative stress (OS) has the ability to damage different molecules and cellular structures, altering the correct function of organs and systems. OS accumulates in the body by endogenous and exogenous mechanisms. Increasing evidence points to the involvement of OS in the physiopathology of various chronic diseases that require prolonged periods of pharmacological treatment. Long-term treatments may contribute to changes in systemic OS. In this review, we discuss the involvement of OS in the pathological mechanisms of some chronic diseases, the pro- or antioxidant effects of their pharmacological treatments, and possible adjuvant antioxidant alternatives. Diseases such as high blood pressure, arteriosclerosis, and diabetes mellitus contribute to the increased risk of cardiovascular disease. Antihypertensive, lipid-lowering, and hypoglycemic treatments help reduce the risk with an additional antioxidant benefit. Treatment with methotrexate in autoimmune systemic inflammatory diseases, such as rheumatoid arthritis, has a dual role in stimulating the production of OS and producing mitochondrial dysfunction. However, it can also help indirectly decrease the systemic OS induced by inflammation. Medicaments used to treat neurodegenerative diseases tend to decrease the mechanisms related to the production of reactive oxygen species (ROS) and balance OS. On the other hand, immunosuppressive treatments used in cancer or human immunodeficiency virus infection increase the production of ROS, causing significant oxidative damage in different organs and systems without widely documented exogenous antioxidant administration alternatives.
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Logan SM, Watts AJ, Posautz A, Kübber-Heiss A, Painer J, Stalder G, Giroud S, Storey KB. The Ratio of Linoleic and Linolenic Acid in the Pre-hibernation Diet Influences NFκB Signaling in Garden Dormice During Torpor. Front Mol Biosci 2020; 7:97. [PMID: 32528974 PMCID: PMC7253707 DOI: 10.3389/fmolb.2020.00097] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/27/2020] [Indexed: 11/13/2022] Open
Abstract
The fatty acid composition of a pre-hibernation diet can influence the depth and duration of metabolic suppression achieved by hibernators. More specifically, a diet high in n-6 polyunsaturated fatty acids (PUFAs) relative to n-3 PUFAs is essential to maximize torpor expression. However, few studies have investigated how diets with different n-6/n-3 PUFA ratios change stress-inducible cell signaling. Garden dormice (Eliomys quercinus) were fed one of three diets designed with different ratios of n-6 PUFA linoleic acid (LA) and n-3 PUFA linolenic acid (ALA). Then, NFκB signaling was assessed in the white adipose, brown adipose, and liver tissues of euthermic and hibernating dormice via multiplex and RT-qPCR analyses of relative protein and transcript levels, respectively. Dormice fed a high LA diet regulated NFκB signaling in a protective manner in all tissues. NFκB signaling was generally decreased in the high LA group, with significant decreases in the protein levels of NFκB mediators IKKα/β, IκBα, and downstream pro-apoptotic protein FADD. Liver and white adipose from torpid dormice fed a high LA diet increased sod2 expression relative to the other diets or relative to euthermic controls, indicating protection against ROS generated from potentially increased β-oxidation of n-6 PUFAs. The low LA diet increased biomarkers for apoptosis relative to other diets and relative to euthermia, suggesting low LA diets may be detrimental to hibernator health. Overall, this study suggests that changes in the ratio of n-6/ n-3 PUFAs in the diet influences apoptotic and antioxidant responses in white adipose, brown adipose, and liver of hibernating garden dormice.
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Affiliation(s)
| | | | - Annika Posautz
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna, Austria
| | - Anna Kübber-Heiss
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna, Austria
| | - Johanna Painer
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna, Austria
| | - Gabrielle Stalder
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna, Austria
| | - Sylvain Giroud
- Department of Interdisciplinary Life Sciences, Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna, Austria
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Zhang DY, Gao T, Xu RJ, Sun L, Zhang CF, Bai L, Chen W, Liu KY, Zhou Y, Jiao X, Zhang GH, Guo RL, Li JX, Gao Y, Jiao WJ, Tian H. SIRT3 Transfection of Aged Human Bone Marrow-Derived Mesenchymal Stem Cells Improves Cell Therapy-Mediated Myocardial Repair. Rejuvenation Res 2020; 23:453-464. [PMID: 32228121 DOI: 10.1089/rej.2019.2260] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Sirtuin 3 (SIRT3) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that SIRT3 improve oxidative resistance of aged cells and improve cell therapy in aged patients. In vitro, the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of SIRT3 in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after SIRT3 overexpression. The antioxidant capacity of O-hMSCs increased after SIRT3 overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of SIRT3. When two inhibitors were used together, the antioxidant function of SIRT3 almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats in vivo, the survival rate of O-hMSCs increased by SIRT3 transfection. The cardiac function of rats was improved after SIRT3-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with SIRT3-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and SIRT3 might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by SIRT3 overexpression.
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Affiliation(s)
- Dong-Yang Zhang
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tong Gao
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rong-Jian Xu
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Sun
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chun-Feng Zhang
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Long Bai
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Chen
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kai-Yu Liu
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Zhou
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuan Jiao
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gui-Huan Zhang
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui-Lin Guo
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Jing-Xuan Li
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Ying Gao
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Wen-Jie Jiao
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Tian
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Yamagata K. Polyphenols Regulate Endothelial Functions and Reduce the Risk of Cardiovascular Disease. Curr Pharm Des 2020; 25:2443-2458. [PMID: 31333108 DOI: 10.2174/1381612825666190722100504] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 07/20/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Previous studies have shown that intake of polyphenols through the consumption of vegetables and fruits reduces the risk of Cardiovascular Disease (CVD) by potentially influencing endothelial cell function. OBJECTIVE In this review, the effects and molecular mechanisms of plant polyphenols, particularly resveratrol, epigallocatechin gallate (EGCG), and quercetin, on endothelial functions, and their putative protective effects against CVD are described. METHODS Epidemiologic studies examined the effect of the CVD risk of vegetables and the fruit. Furthermore, studies within vitro models investigated the underlying molecular mechanisms of the action of the flavonoid class of polyphenols. These findings help elucidate the effect of polyphenols on endothelial function and CVD risk reduction. RESULTS Epidemiologic and in vitro studies have demonstrated that the consumption of vegetables and fruits decreases the incidence of CVDs. Furthermore, it has also been indicated that dietary polyphenols are inversely related to the risk of CVD. Resveratrol, EGCG, and quercetin prevent oxidative stress by regulating the expression of oxidase and the antioxidant enzyme genes, contributing to the prevention of stroke, hypertension, heart failure, and ischemic heart disease. CONCLUSION High intake of dietary polyphenols may help prevent CVD. Polyphenols inhibit endothelial dysfunction and induce vascular endothelium-dependent vascular relaxation viz. redox regulation and nitric oxide production. The polyphenol-induced healthy endothelial cell function may be related to CVD prevention.
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Affiliation(s)
- Kazuo Yamagata
- Laboratory of Molecular Health Science of Food, Department of Food Science & Technology, Nihon University (NUBS), 1866 Kameino, Fujisawa, Kanagawa, 252-8510, Japan
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Chen Y, Zhang F, Wang D, Li L, Si H, Wang C, Liu J, Chen Y, Cheng J, Lu Y. Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8076105. [PMID: 32089781 PMCID: PMC7024095 DOI: 10.1155/2020/8076105] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/25/2019] [Accepted: 01/23/2020] [Indexed: 02/05/2023]
Abstract
Diabetes affects a variety of organs such as the kidneys, eyes, and liver, and there is increasing evidence that the lung is also one of the target organs of diabetes and imbalance of Sirt3-mediated stress responses such as inflammation, oxidative stress, apoptosis, autophagy, and ER stress may contribute to diabetic lung fibrosis. Although previous studies have reported that mesenchymal stem cells (MSCs) have beneficial effects on various diabetic complications, the effect and mechanisms of MSCs on diabetes-induced lung injury are not clear. In this study, the STZ-induced diabetes model was constructed in rats, and the effect and potential mechanisms of bone marrow MSCs on diabetic lung fibrosis were investigated. The results revealed that fibrotic changes in the lung were successfully induced in the diabetic rats, while MSCs significantly inhibited or even reversed the changes. Specifically, MSCs upregulated the expression levels of Sirt3 and SOD2 and then activated the Nrf2/ARE signaling pathway, thereby controlling MDA, GSH content, and iNOS and NADPH oxidase subunit p22phox expression levels in the lung tissue. Meanwhile, high levels of Sirt3 and SOD2 induced by MSCs reduced the expression levels of IL-1β, TNF-α, ICAM-1, and MMP9 by suppressing the NF-κB/HMGB1/NLRP3/caspase-1 signaling pathway, as well as regulating the expression levels of cleaved caspasese-3, Bax, and Bcl2 by upregulating the expression level of P-Akt, thereby inhibiting the apoptosis of the lung tissue. In addition, MSCs also regulated the expression levels of LC3, P62, BiP, Chop, and PERK, thereby enhancing autophagy and attenuating endoplasmic reticulum stress. Taken together, our results suggest that MSCs effectively attenuate diabetic lung fibrosis via adjusting Sirt3-mediated responses, including inflammation, oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress, providing a theoretical foundation for further exploration of MSC-based diabetic therapeutics.
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Affiliation(s)
- Yang Chen
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Fuping Zhang
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Di Wang
- Research Core Facility, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Haibo Si
- Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chengshi Wang
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Regenerative Medicine Research Center, Sichuan University, Chengdu 610041, China
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Yu X, Hu Y, Huang W, Ye N, Yan Q, Ni W, Jiang X. Role of AMPK/SIRT1-SIRT3 signaling pathway in affective disorders in unpredictable chronic mild stress mice. Neuropharmacology 2019; 165:107925. [PMID: 31877320 DOI: 10.1016/j.neuropharm.2019.107925] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 12/17/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To explore the role of 5' adenosine monophosphate-activated protein kinase/sirtuin1-sirtuin3 (AMPK/SIRT1-SIRT3) signaling pathway in behavioral and neuroinflammation/oxidative stress alterations in unpredictable chronic mild stress (UCMS) model mice. METHODS Male ICR mice weighing 20-22 g were used in this study. Behavior performance was evaluated from the 14th day of drug treatment. Expression levels of AMPK, SIRT1, SIRT3, and NF-κBp65 were tested by immuno-blot analysis. Contents of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). Reactive oxygen species (ROS), superoxide dismutase (SOD) and glutathione (GSH) expressions were tested by neurochemical and biochemical assays. RESULTS Behavioral disorders and decreases of AMPK, SIRT1 and SIRT3 induced by UCMS were all reversed by AICA Riboside (AICAR) treatment. These effects were correlated with alterations of oxidative stress (ROS, GSH, SOD) and inflammation (pNF-κBp65, TNF-α, IL-1β, IL-6) status. Co-treatment with SIRT3 inhibitor (3-TYP) in addition to AICAR abolished AICAR's effects on behavior and expression level of inflammation/oxidative stress-related factors of mice, without affecting the content of SIRT1. Contrarily, combining use of AICAR and SIRT1 inhibitor (Sirtinol or EX-527) increased SIRT3 level, which led to better alleviation of behavioral disorders, compared with single AICAR treatment. Interestingly, in normal or UCMS mice, up or down regulation of SIRT1 did not affect SIRT3 level. CONCLUSION Provided that AMPK is activated, SIRT1 inhibition could induce the increase of SIRT3, and SIRT3 exerts more beneficial function in alleviation of consequences of chronic stress than SIRT1.
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Affiliation(s)
- Xuefeng Yu
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China
| | - Ying Hu
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China
| | - Wenkai Huang
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China
| | - Nuo Ye
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China
| | - Qizhi Yan
- Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, China
| | - Wenjuan Ni
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China
| | - Xi Jiang
- Department of Pharmacy, Zhejiang Pharmaceutical College, Zhejiang Province, 315000, China; Zhejiang University Mingzhou Hospital, Zhejiang Province, 315000, China.
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Liu L, Chen H, Jin J, Tang Z, Yin P, Zhong D, Li G. Melatonin ameliorates cerebral ischemia/reperfusion injury through SIRT3 activation. Life Sci 2019; 239:117036. [PMID: 31697951 DOI: 10.1016/j.lfs.2019.117036] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/21/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023]
Abstract
AIMS Previous literature has shown that melatonin plays a critical role in protecting against cerebral ischemia/reperfusion (I/R) injury. Sirtuin3(SIRT3), as one member of the sirtuin family, protects against oxidative stress-related diseases. However, the association between melatonin and SIRT3 in cerebral I/R injury is not well understood. Our experiment was planned to investigate whether melatonin protects against cerebral I/R injury through SIRT3 activation. MAIN METHODS We selected transient middle cerebral artery occlusion (tMCAO) mice as the model of cerebral I/R injury. Male C57/BL6 mice were pre-treated with or without a selective SIRT3 inhibitor and then subjected to tMCAO surgery. Melatonin (20 mg/kg) was given to mice by intraperitoneal injection after ischemia and before reperfusion. Then, we observed the changes in the SIRT3 and downstream relative proteins, infarction volume, neurological score, Nissl, H&E and TUNEL staining, and the expression of apoptosis proteins after tMCAO. KEY FINDINGS Melatonin upregulated the expression of SIRT3 after tMCAO, and alleviated the neurological dysfunction and cell apoptosis through SIRT3 activation. SIGNIFICANCE Our research proved that melatonin promoted SIRT3 expression after tMCAO and alleviated cerebral I/R injury by activating the SIRT3 signaling pathway. This study provides novel therapeutic targets and mechanisms for the treatment of ischemic stroke in the clinic, especially during cerebrovascular reperfusion.
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Affiliation(s)
- Lili Liu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China
| | - Hongping Chen
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China
| | - Jing Jin
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China
| | - Zhanbin Tang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China
| | - Pengqi Yin
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China
| | - Di Zhong
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China.
| | - Guozhong Li
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, Heilongjiang Province, PR China.
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Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9710352. [PMID: 31534623 PMCID: PMC6732625 DOI: 10.1155/2019/9710352] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/17/2019] [Indexed: 12/29/2022]
Abstract
Sepsis still causes death, often through cardiac failure and mitochondrial dysfunction. Dietary ω3 polyunsaturated fatty acids are known to protect against cardiac dysfunction and sepsis lethality. This study set out to determine whether early low-severity sepsis alters the cardiac mitochondrial function in animals fed a Western-type diet and whether dietary eicosapentaenoic acid (EPA) administration protects the myocardium against the deleterious effects of sepsis and if so to seek possible mechanisms for its effects. Rats were divided into two groups fed either an ω3 PUFA-deficient diet (“Western diet,” DEF group) or an EPA-enriched diet (EPA group) for 5 weeks. Each group was subdivided into two subgroups: sham-operated rats and rats subjected to cecal ligation and puncture (CLP). In vivo cardiac mechanical function was examined, and mitochondria were harvested to determine their functional activity. Oxidative stress was evaluated together with several factors involved in the regulation of reactive oxygen species metabolism. Sepsis had little effect on cardiac mechanical function but strongly depressed mitochondrial function in the DEF group. Conversely, dietary EPA greatly protected the mitochondria through a decreased oxidative stress of the mitochondrial matrix. The latter was probably due to an increased uncoupling protein-3 expression, already seen in the sham-operated animals. CLP rats in the EPA group also displayed increased mitochondrial sirtuin-3 protein expression that could reinforce the upholding of oxidative phosphorylation. Dietary EPA preconditioned the heart against septic damage through several modifications that protect mitochondrial integrity. This preconditioning can explain the cardioprotective effect of dietary EPA during sepsis.
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Yang L, Ren S, Xu F, Ma Z, Liu X, Wang L. Recent Advances in the Pharmacological Activities of Dioscin. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5763602. [PMID: 31511824 PMCID: PMC6710808 DOI: 10.1155/2019/5763602] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 07/28/2019] [Indexed: 02/07/2023]
Abstract
Dioscin is a typical saponin with multiple pharmacological activities. The past few years have seen an emerging interest in and growing research on this pleiotropic saponin. Here, we review the emerging pharmacological activities reported recently, with foci on its antitumor, antimicrobial, anti-inflammatory, antioxidative, and tissue-protective properties. The potential use of dioscin in therapies of diverse clinical disorders is also discussed.
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Affiliation(s)
- Longfei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China
| | - Shengnan Ren
- Department of Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Fei Xu
- Department of Acupuncture and Moxibustion, The Second Hospital of Jilin University, Changchun 130041, China
| | - Zhiming Ma
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun 130041, China
| | - Xin Liu
- Eye Center, The Second Hospital of Jilin University, Changchun 130024, China
| | - Lufei Wang
- Eye Center, The Second Hospital of Jilin University, Changchun 130024, China
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Yu H, Pan W, Huang H, Chen J, Sun B, Yang L, Zhu P. Screening Analysis of Sirtuins Family Expression on Anti-Inflammation of Resveratrol in Endothelial Cells. Med Sci Monit 2019; 25:4137-4148. [PMID: 31158122 PMCID: PMC6561145 DOI: 10.12659/msm.913240] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Resveratrol has been shown to possess beneficial activities including antioxidant, anti-inflammatory, and cardioprotective effects through activating a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. The current study was undertaken to investigate the role of sirtuin family members (SIRT1–SIRT7) on the anti-inflammation activities of resveratrol in endothelial cells. Material/Methods Primary human umbilical vein endothelial cells (HUVECs) were pretreated with resveratrol before tumor necrosis factor (TNF)-α (10–20 μg/L) stimulation. Cell viability was measured using the Cell Counting Kit-8 method. Total RNA was extracted after different treatments and the NimbleGen Human 12×135K Gene Expression Array was applied to screen and analyze SIRTs expression. Quantitative real-time polymerase chain reaction and western blot were applied to verify the results of the gene expression microarrays. Reactive oxygen species (ROS) production was examined using flow cytometry analysis. Results Microarray analysis showed that the expressions of SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 showed the tendency to increase while SIRT4 showed the tendency to decrease. SIRT1, SIRT2, SIRT5, and SIRT7 gene expression could be upregulated by pretreatment with resveratrol compared with TNF-α alone while there were no obvious differences of SIRT3, SIRT4, and SIRT6 expressions observed in TNF-α alone treated cells and resveratrol-TNF-α co-treated cells. Interestingly, SIRT1, SIRT2, SIRT3, SIRT4, and SIRT5 siRNA could reverse the effect of resveratrol on ROS production; SIRT1 and SIRT5 siRNA could significantly increase CD40 expression inhibited by resveratrol in TNF-α treated cells. Conclusions Our results suggest that resveratrol inhibiting oxidative stress production is associated with SIRT1, SIRT2, SIRT3, SIRT4, and SIRT5 pathways; attenuating CD40 expression was only associated with SIRT1 and SIRT5 pathways in TNF-α-induced endothelial cells injury.
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Affiliation(s)
- Huizhen Yu
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland).,Department of Medicine, Fujian Provincial Hospital South Branch, Fuzhou, Fujian, China (mainland)
| | - Wei Pan
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland).,Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China (mainland)
| | - Huashan Huang
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Junming Chen
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Baohua Sun
- Department of Medicine, Fujian Provincial Hospital South Branch, Fuzhou, Fujian, China (mainland)
| | - Linxin Yang
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
| | - Pengli Zhu
- Key Laboratory of Geriatrics, Provincial Clinical Medicine College of Fujian Medical University, Fujian Institute of Clinical Geriatrics, Fuzhou, Fujian, China (mainland)
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Li R, Liu Y, Xie J, Huang X, Zhang L, Liu H, Li L. Sirt3 mediates the protective effect of hydrogen in inhibiting ROS-induced retinal senescence. Free Radic Biol Med 2019; 135:116-124. [PMID: 30735837 DOI: 10.1016/j.freeradbiomed.2019.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/30/2019] [Accepted: 02/04/2019] [Indexed: 02/07/2023]
Abstract
Hydrogen possesses antioxidative effects and cures numerous types of ophthalmopathy, but the mechanism of hydrogen on ROS-induced retinal senescence remains elusive. In this study, retinal morphology revealed that hydrogen reduced the number and size of vitreous black deposits in Bruch's membrane in NaIO3 mice. Hydrogen also reduced ROS levels in the retina as assessed by DHE staining. Moreover, this result was consistent with the downregulation of expression of the oxidative stress hallmark OGG1. These findings suggested that hydrogen can reduce retinal oxidative stress induced by NaIO3, and this result was further verified using the antioxidant ALCAR. Mechanistic analysis revealed that hydrogen significantly inhibited the downregulation of Sirt3 expression, and this notion was confirmed using AICAR, which restores Sirt3 expression and activity. Moreover, hydrogen reduced the expression of p53, p21 and p16 and the number of blue-green precipitations in the retinas of NaIO3 mice as assessed by SA-β-gal staining. We also found that hydrogen decreased the expression of the DNA damage-related protein ATM, cyclinD1 and NF-κB but increased the expression of the DNA repair-related protein HMGB1, suggesting that hydrogen inhibits senescence in retinas of NaIO3 mice. Additionally, OCT examination revealed that hydrogen suppressed retinal high reflex formation significantly and prevented the retina from thinning. This result was supported by ERG assays that demonstrated that hydrogen prevented the reduction in a- and b-wave amplitude induced by NaIO3 in mice. Thus, our data suggest that hydrogen may inhibit retinal senescence by suppressing the downregulation of Sirt3 expression through reduced oxidative stress reactions.
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Affiliation(s)
- Ruichan Li
- Department of Cell Biology, Taizhou University, Taizhou, PR China.
| | - Yanli Liu
- Department of Cell Biology, Taizhou University, Taizhou, PR China.
| | - Jing Xie
- Department of Cell Biology, Taizhou University, Taizhou, PR China.
| | - Xudong Huang
- Chemistry and Life College, Chengdu Normal University, Chengdu, PR China.
| | - Li Zhang
- Jinzhoushi Oral Cavity Hospital, Jinzhou, PR China.
| | - Hua Liu
- Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
| | - Lihua Li
- Department of Cell Biology, Taizhou University, Taizhou, PR China.
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Xu RY, Xu XW, Deng YZ, Ma ZX, Li XR, Zhao L, Qiu LJ, Liu HY, Chen HP. Resveratrol attenuates myocardial hypoxia/reoxygenation-induced cell apoptosis through DJ-1-mediated SIRT1-p53 pathway. Biochem Biophys Res Commun 2019; 514:401-406. [PMID: 31053297 DOI: 10.1016/j.bbrc.2019.04.165] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 02/04/2023]
Abstract
Resveratrol, a multi-functional phytoalexin, has been well indicated to exert cardioprotective effects by weakening ischemia/reperfusion (I/R) injury, and cell apoptosis is a vital way in I/R injury. SIRT1-p53 pathway has strong significance in regulating cell apoptosis. DJ-1 can directly bind to SIRT1 and stimulate the activity of SIRT1-p53. Therefore, the current study was determined whether Resveratrol attenuates hypoxia/reoxygenation (H/R)-induced cell apoptosis, and whether DJ-1-mediated SIRT1 activation involves in the cardioprotective effects of Resveratrol. The results showed that remarkable decrease in the number of apoptotic cells along with reduction of lactate dehydrogenase release and restoration of cell viability emerged when Resveratrol was applied in the H9c2 cells exposed to H/R. Moreover, Resveratrol increased DJ-1 expression and promoted the interaction of DJ-1 with SIRT1, which further contributed to subsequent restoration of SIRT1 activity and decrease of acetylation level of p53. However, above cardioprotective effects of Resveratrol were abrogated by DJ-1 siRNA and SIRT1 specific inhibitor Sirtinol. In conclusion, the current study demonstrated that Resveratrol suppressed H/R-induced cell apoptosis, which may be conducted by up-regulating DJ-1, and later activating SIRT1 activity and subsequently inhibiting p53 acetylation level in the H9c2 cells.
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Affiliation(s)
- Rui-Yuan Xu
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Xing-Wang Xu
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Yi-Zhang Deng
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Zhao-Xia Ma
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Xiao-Ran Li
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Le Zhao
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Le-Jia Qiu
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - Hao-Yue Liu
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China
| | - He-Ping Chen
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, PR China.
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A carnosine analog with therapeutic potentials in the treatment of disorders related to oxidative stress. PLoS One 2019; 14:e0215170. [PMID: 30964920 PMCID: PMC6456212 DOI: 10.1371/journal.pone.0215170] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 03/27/2019] [Indexed: 01/01/2023] Open
Abstract
Interactive relationships among metabolism, mitochondrial dysfunction and inflammation at skeletal muscle level play a key role in the pathogenesis of disorders related to oxidative stress. Mitochondrial dysfunction and oxidative stress result in cellular energy deficiency, inflammation and cell death inducing a vicious cycle that promotes muscle wasting. The histidine-containing dipeptides, carnosine and anserine, are carbonyl scavengers whose cytoprotective contributions extend beyond the antioxidant defence, but the physiological meaning of these capacities is actually limited. In the present study, we compared and investigated the potential protective effects of three different histidine-containing dipeptides: carnosine, anserine and carnosinol, a carnosine-mimetic new compound, against oxidative stress induction in rat L6 skeletal muscle cells. The hydrogen peroxide induced-oxidative stress significantly altered cell morphology, induced apoptosis, oxidative stress and inflammation, decreased mitochondrial peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)/sirtuin3 pathway and the antioxidant system. Notably, all three investigated dipeptides in the present study, with a different extent and in a concentration-dependent manner, reduced myotube oxidative stress, apoptosis and inflammation. The present study underlined that carnosinol, maintaining the safety condition of carnosine and anserine, was the more efficient studied dipeptide in the preservation of mitochondrial environment mediated by PGC-1α and sirtuin3 expression and thereby in the reduction of oxidative stress-related alterations in this in vitro skeletal muscle model. Furthermore, we observed that carnosinol's antioxidant effects are not blocked inhibiting sirtuin3, but are maintained with almost the same extend, indicating its multiple capacities of reactive carbonyl species-scavenging and of mitochondrial modulation through PGC-1α. In conclusion, carnosinol retained and surpassed the efficacy of the well-known investigated histidine-containing dipeptides improving oxidative stress, inflammation and also cell metabolism and so becoming a greatly promising therapeutic carnosine derivate.
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Jahanifar F, Astani A, Shekarforoosh S, Jamhiri M, Safari F, Zarei F, Safari F. 1.25 Dihydroxyvitamin D3 Attenuates Hypertrophy Markers in Cardiomyoblast H9c2 Cells: Evaluation of Sirtuin3 mRNA and Protein Level. INT J VITAM NUTR RES 2019; 89:144-151. [PMID: 30856082 DOI: 10.1024/0300-9831/a000469] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background: The cellular and molecular mechanisms of cardioprotective effects of Vitamin D are poorly understood. Given the essential role of sirtuin-3 (SIRT3) as an endogenous negative regulator of cardiac hypertrophy, this study was designed to investigate the effect of 1, 25-dihydroxyvitamin D3 (calcitriol) on hypertrophy markers and SIRT3 mRNA and protein levels following angiotensin II induced - hypertrophy in cardiomyoblast H9c2 cells. Methods: Rat cardiomyoblast H9c2 cells were treated for 48 hr with angiotensin II alone (Ang group) or in combination with 1, 10 and 100 nM of calcitriol (C + Ang groups). Intact cells served as control (Ctl). The cell area was measured using methylene blue staining. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and SIRT3 transcription levels were measured by real time RT-PCR. SIRT3 protein expression was evaluated using western blot technique. Results: The results showed that in Ang group cell size was increase by 128.4 ± 15% (P < 0.001 vs. Ctl) whereas in C100 + Ang group it was increased by 21.3 ± 6% (P < 0.001 vs. Ang group). Calcitriol pretreatment decreased ANP mRNA level significantly (P < 0.05) in comparison with Ang group (Ang: 75.5 ± 15%, C100 + Ang: 19.2 ± 9%). There were no significant differences between Ang group and cells pretreated with 1 and 10 nM of calcitriol. SIRT3 at mRNA and protein levels did not change significantly among the experimental groups. Conclusions: In conclusion, pretreatment with calcitriol (100 nM) prevents Ang II-induced hypertrophy in cardiomyoblast H9c2 cells. This probably occurs through other pathways except SIRT3 upregulation.
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Affiliation(s)
- Fatemeh Jahanifar
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Akram Astani
- Department of Microbiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Mohabbat Jamhiri
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Farideh Zarei
- Premature Neonates Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Safari
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Jiang T, Liu Y, Meng Q, Lv X, Yue Z, Ding W, Liu T, Cui X. Hydrogen sulfide attenuates lung ischemia-reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats. Surgery 2019; 165:1014-1026. [PMID: 30824287 DOI: 10.1016/j.surg.2018.12.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/26/2018] [Accepted: 12/21/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND Lung ischemia-reperfusion injury is a complex pathophysiologic process associated with high morbidity and mortality. We have demonstrated elsewhere that diabetes mellitus aggravated ischemia-induced lung injury. Oxidative stress and mitochondrial dysfunction are drivers of diabetic lung ischemia-reperfusion injury; however, the pathways that mediate these events are unexplored. In this study using a high-fat diet-fed model of streptozotocin-induced type 2 diabetes in rats, we determined the effect of hydrogen sulfide on lung ischemia-reperfusion injury with a focus on Sirtuin3 signaling. METHODS Rats with type 2 diabetes were exposed to GYY4137, a slow release donor of hydrogen sulfide with or without administration of the Sirtuin3 short hairpin ribonucleic acid plasmid, and then subjected to a surgical model of ischemia-reperfusion injury of the lung (n = 8). Lung function, oxidative stress, inflammation, cell apoptosis, and mitochondrial function were measured. RESULTS Compared with nondiabetic rats, animals with type 2 diabetes at baseline exhibited significantly decreased Sirtuin3 signaling in lung tissue and increased oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction (P < .05 each). In addition, further impairment in Sirtuin3 signaling was found in diabetic rats subjected to this model of lung ischemia-reperfusion. Simultaneously, the indexes showed further aggravation. Treatment with hydrogen sulfide restored Sirtuin3 expression and decreased lung ischemia-reperfusion injury in animals with type 2 diabetes mellitus by improving lung functional recovery, decreasing oxidative damage, suppressing inflammation, ameliorating cell apoptosis, and preserving mitochondrial function (P < .05). Conversely, these protective effects were largely reversed in Sirtuin3 knockdown rats. CONCLUSION Impaired lung Sirtuin3 signaling associated with type 2 diabetic conditions was further attenuated by an ischemia-reperfusion insult. Hydrogen sulfide ameliorated reperfusion-induced oxidative stress and mitochondrial dysfunction via activation of Sirtuin3 signaling, thereby decreasing lung ischemia-reperfusion damage in rats with a model of type II diabetes.
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Affiliation(s)
- Tao Jiang
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Yanhong Liu
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Qiuming Meng
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Xiangqi Lv
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Ziyong Yue
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Wengang Ding
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Tianhua Liu
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China
| | - Xiaoguang Cui
- Department of Anesthesiology, Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine, The Second Affiliated Hospital, Harbin Medical University, China.
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45
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Velichkovska M, Surnar B, Nair M, Dhar S, Toborek M. Targeted Mitochondrial COQ 10 Delivery Attenuates Antiretroviral-Drug-Induced Senescence of Neural Progenitor Cells. Mol Pharm 2019; 16:724-736. [PMID: 30592424 PMCID: PMC6364271 DOI: 10.1021/acs.molpharmaceut.8b01014] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
HIV infection is associated with symptoms of accelerated or accentuated aging that are likely to be driven not only by HIV itself but also by the toxicity of long-term use of antiretroviral drugs. Therefore, it is crucially important to understand the mechanisms by which antiretroviral drugs may contribute to aging. The aim of this study was to investigate the hypothesis that antiretroviral drugs cause increased reactive oxygen species (ROS) generation that results in mitochondrial dysfunction and culminates in promoting cellular senescence. In addition, we applied targeted nanoparticle (NP)-based delivery to specifically enrich mitochondria with coenzyme Q10 (CoQ10) in order to enhance antioxidant protection. The studies employed neural progenitor cells (NPCs), as differentiation of these cells into mature neurons is affected both during HIV infection and in the aging process. Exposure of cultured NPCs to various combinations of HIV antiretroviral therapy (ART) induced a more than 2-fold increase in mitochondrial ROS generation and mitochondrial membrane potential, a more than 50% decrease in oxygen consumption and ATP levels, a 60% decrease in SIRT3 expression, and a 42% decrease in cell proliferation relative to control levels. These alterations were accompanied by a 37% increase in beta-galactosidase staining and a shortening of the telomere length to more than half of the length of controls as assessed by quantitative telomere-FISH labeling, indicating accelerated NPC senescence in response to ART exposure. Importantly, CoQ10 delivered by targeted nanoparticles effectively attenuated these effects. Overall, these results indicate that ART promotes cellular senescence by causing mitochondrial dysfunction, which can be successfully reversed by supplementation with mitochondria-targeted CoQ10.
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Affiliation(s)
- Martina Velichkovska
- †Department
of Biochemistry and Molecular Biology and §Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Bapurao Surnar
- †Department
of Biochemistry and Molecular Biology and §Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Madhavan Nair
- Department
of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United
States
| | - Shanta Dhar
- †Department
of Biochemistry and Molecular Biology and §Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Michal Toborek
- †Department
of Biochemistry and Molecular Biology and §Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States,Address: Department of Biochemistry
and Molecular Biology, University of Miami School of Medicine, Gautier
Bldg., Room 528, 1011 NW 15th Street, Miami, FL 33136. Phone: 305-243-0230. E-mail:
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46
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Si Y, Bao H, Han L, Chen L, Zeng L, Jing L, Xing Y, Geng Y. Dexmedetomidine attenuation of renal ischaemia-reperfusion injury requires sirtuin 3 activation. Br J Anaesth 2018; 121:1260-1271. [PMID: 30442253 DOI: 10.1016/j.bja.2018.07.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 06/20/2018] [Accepted: 07/12/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Dexmedetomidine attenuates renal ischaemia and reperfusion (I/R) injury, but its mechanism of action is unclear. As sirtuin 3 (SIRT3) activation can alleviate acute kidney injury, we investigated whether dexmedetomidine acts through SIRT3 to reduce renal I/R injury. METHODS The potential involvement of SIRT3 in dexmedetomidine attenuation of renal I/R injury was tested in HK2 cells subjected to hypoxia/reoxygenation and C57BL/6J mice subjected to renal I/R. A short interfering RNA targeting SIRT3 was used in some experiments to examine the potential role of SIRT3. Cell death and mitochondrial membrane potential (Δψm) were analysed in cultured cells. Mitochondrial damage in mice was assessed using electron microscopy and markers for renal function. Expression of cyclophilin D, cytochrome c, and SIRT3, and the level of cyclophilin D acetylation were determined. RESULTS Hypoxia/reoxygenation of HK2 cells increased cell death, cytochrome C expression, and cyclophilin D acetylation, and decreased Δψm and SIRT3 expression (P<0.05). Dexmedetomidine attenuated these changes. The dexmedetomidine effects were enhanced by SIRT3 overexpression and eliminated by SIRT3 knockdown. I/R in mice damaged renal function, and increased histological lesions, mitochondrial damage, cytochrome c expression, and cyclophilin D acetylation, while SIRT3 activity was decreased by 51% (P<0.05). Dexmedetomidine inhibited these changes in mice expressing normal levels of SIRT3, but not in SIRT3-knockdown mice. CONCLUSIONS Dexmedetomidine appears to act, at least in part, by up-regulating SIRT3 to inhibit mitochondrial damage and cell apoptosis and thereby protect against renal I/R injury.
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Affiliation(s)
- Y Si
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - H Bao
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
| | - L Han
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - L Chen
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - L Zeng
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - L Jing
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Y Xing
- Mechanical Engineering, Southeast University, Nanjing, People's Republic of China
| | - Y Geng
- Department of Anaesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
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Cho I, Jeong KH, Zhu J, Choi YH, Cho KH, Heo K, Kim WJ. Sirtuin3 Protected Against Neuronal Damage and Cycled into Nucleus in Status Epilepticus Model. Mol Neurobiol 2018; 56:4894-4903. [DOI: 10.1007/s12035-018-1399-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/17/2018] [Indexed: 12/31/2022]
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48
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Kang B, Wang X, Xu Q, Wu Y, Si X, Jiang D. Effect of 3-nitropropionic acid inducing oxidative stress and apoptosis of granulosa cells in geese. Biosci Rep 2018; 38:BSR20180274. [PMID: 30042167 PMCID: PMC6131328 DOI: 10.1042/bsr20180274] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 07/03/2018] [Accepted: 07/10/2018] [Indexed: 02/07/2023] Open
Abstract
The mechanism of action by which oxidative stress induces granulosa cell apoptosis, which plays a vital role in initiating follicular atresia, is not well understood. In the present study, the effect of 3-nitropropionic acid (3-NPA) on oxidative stress and apoptosis in granulosa cells in geese was investigated. Our results showed that treatment with 3-NPA at 5.0 mmol/l for 24 h increased intracellular reactive oxygen species (ROS) production by 25.4% and decreased granulosa cell viability by 45.5% (P<0.05). Catalase and glutathione peroxidase gene expression levels in granulosa cells treated with 3-NPA were 1.32- and 0.49-fold compared with those of the control cells, respectively (P <0.05). A significant decrease in the expression level of B-cell lymphoma 2 (Bcl-2) protein and remarkable increases in the levels of Bax, p53 and cleaved-Caspase 3 proteins and the ratio of Bax/Bcl-2 expression in granulosa cells treated with 3-NPA were observed (P<0.05). Furthermore, a 38.43% increase in the percentage of early apoptotic cells was also observed in granulosa cells treated with 3-NPA (P<0.05). Moreover, the expression levels of NF-κB, Nrf2, Fhc, Hspa2 and Ho-1 in granulosa cells treated with 3-NPA were elevated 4.36-, 1.63-, 3.62-, 27.54- and 10.48-fold compared with those of the control cells (P<0.05), respectively. In conclusion, the present study demonstrates that treatment with 3-NPA induces ROS production and apoptosis and inhibits the viability of granulosa cells in geese. Furthermore, 3-NPA triggers increases in the expression of cleaved-Caspase 3 protein and the ratio of Bax/Bcl-2 expression, and induces the early apoptosis of granulosa cells.
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Affiliation(s)
- Bo Kang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
| | - Xinxing Wang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
| | - Qilin Xu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
- Institute of Animal Science, Chengdu Academy of Agriculture and Forestry Sciences, Chengdu, People's Republic of China
| | - Yongsheng Wu
- Institute of Animal Science, Chengdu Academy of Agriculture and Forestry Sciences, Chengdu, People's Republic of China
| | - Xiaohui Si
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
| | - Dongmei Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
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Yu W, Qin J, Chen C, Fu Y, Wang W. Moderate calorie restriction attenuates age‑associated alterations and improves cardiac function by increasing SIRT1 and SIRT3 expression. Mol Med Rep 2018; 18:4087-4094. [PMID: 30132522 DOI: 10.3892/mmr.2018.9390] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/16/2017] [Indexed: 02/05/2023] Open
Abstract
Calorie restriction (CR) extends the lifespan of mammals and improves cardiac function by attenuation of age‑associated alterations. Sirtuins (SIRT) are involved in these mechanisms, however, the extent to which CR affects cardiac function and sirtuin expression remains unknown. Therefore, the present study aimed to determine to what extent CR affects cardiac function and sirtuin expression. A total of 60 female Sprague‑Dawley rats were randomly divided into four groups, including normal control (NC), 25% calorie restriction (25% CR), 45% calorie restriction (45% CR) and high‑fat diet (HF). The groups were maintained on these specific regimens for 2 months. CR rats were observed to have significantly lower body weight, heart weight, and left ventricle mass index compared with NC and HF rats. Visceral fat, triglyceride, and low density lipoprotein levels were significantly decreased in CR rats. Compared with the 25% CR group, the 45% CR group heart function decreased. The heart rate, left ventricular systolic pressure, +dp/dt and ‑dp/dt of the 45% CR rats decreased, whereas the left ventricular end‑diastolic pressure increased. To explore the molecular mechanism of CR on cardiac function, immunoblotting was used to detect the protein expression of SIRT1 and SIRT3. The 25% CR diet increased the expression of SIRT1 and SIRT3 in myocardium, whereas the 45% CR and HF diets resulted in a decrease in SIRT1 and SIRT3 expression. Moderate calorie restriction (25% CR) improves cardiac function by attenuation of age‑associated alterations in rats. SIRT1 and SIRT3 are associated with these effects.
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Affiliation(s)
- Wei Yu
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Jinjin Qin
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Chunjuan Chen
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yucai Fu
- Laboratory of Cell Senescence, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Wei Wang
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
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50
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Zhang DY, Zhang CF, Fu BC, Sun L, Wang XQ, Chen W, Liu W, Liu KY, Du GQ, Ma CY, Jiang SL, Li RK, Tian H. Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases. J Cell Mol Med 2018; 22:5504-5517. [PMID: 30091830 PMCID: PMC6201360 DOI: 10.1111/jcmm.13821] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/19/2018] [Accepted: 07/04/2018] [Indexed: 12/19/2022] Open
Abstract
Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. However, the possible mechanisms underlying its influence are unknown. We hypothesized that SIRT3 increases the antioxidant capacity of aged cells and improves the efficacy of human mesenchymal stem cell (hMSC) therapy for ischaemic heart diseases in aged patients. In vitro, the antioxidant capacity of old hMSCs (O‐hMSCs) was increased after SIRT3 overexpression using a gene transfection technique, while the antioxidant capacity of young hMSCs (Y‐hMSCs) was decreased by SIRT3 silencing. The levels of forkhead box O3a (FoxO3a) in the nucleus, and antioxidant enzymes Mn‐superoxide dismutase (MnSOD) and catalase (CAT) increased in SIRT3‐overexpressed O‐hMSCs while they decreased in SIRT3‐silenced Y‐hMSCs after oxidative stress. Following myocardial infarction in adult rats in vivo, infarct size decreased and cardiac function was significantly enhanced after cell transplantation with SIRT3 overexpressed O‐hMSCs. The number of apoptotic cells decreased and the survival rate of transplanted cells increased following SIRT3 overexpression in O‐hMSCs. SIRT3 protects aged hMSCs against oxidative stress by positively regulating antioxidant enzymes (MnSOD and CAT) via increasing the expression of FoxO3a in the nucleus. The efficacy of aged hMSC transplantation therapy for ischaemic heart diseases can be improved by SIRT3 overexpression.
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Affiliation(s)
- Dong-Yang Zhang
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Chun-Feng Zhang
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Bi-Cheng Fu
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Lu Sun
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Xue-Qing Wang
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Wei Chen
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Wei Liu
- Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Kai-Yu Liu
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Guo-Qing Du
- Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Chong-Yi Ma
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Shu-Lin Jiang
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Ren-Ke Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Hai Tian
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
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