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1
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Bell KC, Chrysostomou V, Karlsson M, Jones BW, Williams PA, Crowston JG. Excitatory and inhibitory neurotransmitter alterations with advancing age and injury in the mouse retina. Neurobiol Aging 2025; 150:69-79. [PMID: 40073716 DOI: 10.1016/j.neurobiolaging.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 01/23/2025] [Accepted: 03/02/2025] [Indexed: 03/14/2025]
Abstract
Increasing age and elevated intraocular pressure (IOP) are the two major risk factors for glaucoma, the most common cause of irreversible blindness worldwide. Accumulating evidence is pointing to metabolic failure predisposing to neuronal loss with advancing age and IOP injury. Many neurotransmitters are synthesized from endogenous metabolites and are essential for correct cell to cell signaling along the visual pathways. We performed detailed, small molecule metabolomic profiling of the aging mouse retina and further explored the impact of IOP elevation at different ages. The resultant metabolomic profiles showed clear discrimination between young and middle-aged retinas and these changes are accentuated following eye pressure elevation. Alterations in glutamate and Gamma-aminobutyric acid (GABA) related metabolites were the most apparent changes with advancing age with further reductions in GABA and related pathways after IOP elevation. These changes were further confirmed using immunohistochemistry and patch-clamp electrophysiological recording experiments.
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Affiliation(s)
- Katharina C Bell
- NHMRC Clinical Trial Centre, University of Sydney, 92-94 Parramatta Rd, Camperdown, NSW 2050, Australia; Neuroscience and Behavioural Diseases and Eye-ACP, SERI/SNEC, Centre for Vision Research, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
| | - Vicki Chrysostomou
- Neuroscience and Behavioural Diseases and Eye-ACP, SERI/SNEC, Centre for Vision Research, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
| | - Markus Karlsson
- Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
| | - Bryan W Jones
- John Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, United States.
| | - Pete A Williams
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
| | - Jonathan G Crowston
- Neuroscience and Behavioural Diseases and Eye-ACP, SERI/SNEC, Centre for Vision Research, Duke-NUS Medical School, 8 College Road, 169857, Singapore; Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
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2
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Locatelli E, Torsello B, De Marco S, Lombardi M, Remelli F, Pampolini G, Ferrighi E, Bursi M, Bellotti A, Pasquale V, Ducci G, Navaei O, Candeloro R, Ferrara MC, Guo W, Cucini E, Bellelli G, Castellazzi M, Sacco E, Paglia G, Mazzola P, Bernasconi DP, Bianchi C, Trevisan C. Mitochondrial dysfunction as a biomarker of frailty: The FRAMITO study protocol. Arch Gerontol Geriatr 2025; 133:105803. [PMID: 40043348 DOI: 10.1016/j.archger.2025.105803] [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: 12/16/2024] [Revised: 02/04/2025] [Accepted: 02/23/2025] [Indexed: 04/05/2025]
Abstract
Frailty syndrome often coexists with multimorbidity, sharing several risk factors and outcomes. Therefore, considering multimorbidity when exploring frailty biomarkers may deepen our understanding of these conditions' pathophysiology. In this regard, most studies focused on inflammation, but markers of mitochondrial dysfunction, such as mitochondrial DNA damage, cell respiratory impairment, and oxidative stress, are less explored. The FRAMITO project aims to evaluate mitochondrial dysfunction in frailty, with and without multimorbidity. This cross-sectional study will enroll 75 individuals aged ≥65 years from inpatient and outpatient clinics at the Geriatrics Units of the University Hospital of Ferrara (Ferrara, Italy) and Fondazione IRCCS San Gerardo dei Tintori (Monza, Italy). Participants will be categorized into three groups: 25 without frailty and multimorbidity, 25 with frailty but not multimorbidity, and 25 with frailty and multimorbidity. Blood samples will be collected to isolate Peripheral Blood Mononuclear Cells. Frailty biomarkers will be identified using untargeted metabolomics and functional studies on mitochondrial dysfunctions in PBMCs and their subpopulations, evaluating mitochondrial DNA damage, mitochondrial and glycolytic cellular bioenergetics, and intracellular reactive oxygen species. This project will advance our understanding of mitochondrial dysfunctions in frailty, particularly when combined with multimorbidity, revealing potential synergistic effects. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT06433427.
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Affiliation(s)
- Edoardo Locatelli
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy
| | - Barbara Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Sofia De Marco
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Martina Lombardi
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy.
| | - Francesca Remelli
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy
| | - Giulia Pampolini
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy
| | - Elena Ferrighi
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy
| | - Marialucia Bursi
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy
| | - Andrea Bellotti
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy
| | - Valentina Pasquale
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy; SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Giacomo Ducci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy; SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Ouldouz Navaei
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Raffaella Candeloro
- Department of Neurosciences and Rehabilitation, University of Ferrara, 44121, Ferrara, Italy
| | | | - Wenxiang Guo
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Eleonora Cucini
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Giuseppe Bellelli
- School of Medicine and Surgery, University of Milano-Bicocca and Acute Geriatric Unit, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | | | - Elena Sacco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy; SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Giuseppe Paglia
- School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Paolo Mazzola
- School of Medicine and Surgery, University of Milano-Bicocca and Acute Geriatric Unit, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Davide Paolo Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging Center, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy; Department of Clinical Research and Innovation, ASST Grande Ospedale Metropolitano Niguarda, 20126 Milan, Italy
| | - Cristina Bianchi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Caterina Trevisan
- Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; Geriatrics and Orthogeriatrics Unit, Azienda Ospedaliero-Universitaria of Ferrara, 44121 Ferrara, Italy; Aging Research Center, Karolinska Institutet, Stockholm, Sweden
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Buckley Y, Stoll MSK, Hoppel CL, Mears JA. Fis1 regulates mitochondrial morphology, bioenergetics and removal of mitochondrial DNA damage in irradiated glioblastoma cells. J Cell Sci 2025; 138:jcs263459. [PMID: 39704270 PMCID: PMC11828467 DOI: 10.1242/jcs.263459] [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: 07/26/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024] Open
Abstract
In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress, and we uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered electron transport chain (ETC) activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.
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Affiliation(s)
- Yuli Buckley
- Department of Pharmacology and Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA
| | - Maria S. K. Stoll
- Department of Pharmacology and Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA
| | - Charles L. Hoppel
- Department of Pharmacology and Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA
| | - Jason A. Mears
- Department of Pharmacology and Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44016, USA
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Gao S, Liu B, Yuan S, Quan Y, Song S, Jin W, Wang Y, Wang Y. Cross-talk between signal transduction systems and metabolic networks in antibiotic resistance and tolerance. Int J Antimicrob Agents 2025; 65:107479. [PMID: 40024604 DOI: 10.1016/j.ijantimicag.2025.107479] [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: 11/21/2024] [Revised: 02/19/2025] [Accepted: 02/23/2025] [Indexed: 03/04/2025]
Abstract
The comprehensive antibiotic resistance of pathogens signifies the oneset of the "post-antibiotic era", and the myriad treatment challenges posed by "superbugs" have emerged as the primary threat to human health. Recent studies indicate that bacterial resistance and tolerance development are mediated at the metabolic level by various signalling networks (e.g., quorum sensing systems, second messenger systems, and two-component systems), resulting in metabolic rearrangements and alterations in bacterial community behaviour. This review focuses on current research, highlighting the intrinsic link between signalling and metabolic networks in bacterial resistance and tolerance.
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Affiliation(s)
- Shuji Gao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Baobao Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Shuo Yuan
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Yingying Quan
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Shenao Song
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Wenjie Jin
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China
| | - Yuxin Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China.
| | - Yang Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China; Henan Provincial Engineering Research Center for Detection and Prevention and Control of Emerging Infectious Diseases in Livestock and Poultry, Luoyang, China.
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5
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Luo Y, Zhang Y, Chen F, Zhao Y, Li X, Liu X, Shakir MZ, Shan C, Jiang N. Chronic unpredictable mild stress-induced anxiety is linked to inflammatory responses and disruptions in tryptophan metabolism in male C57BL/6N mice. Behav Brain Res 2025; 484:115506. [PMID: 39999912 DOI: 10.1016/j.bbr.2025.115506] [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: 11/26/2024] [Revised: 02/06/2025] [Accepted: 02/21/2025] [Indexed: 02/27/2025]
Abstract
Chronic stress can affect brain function through various mechanisms, leading to the development of anxiety disorders. The chronic unpredictable mild stress (CUMS) is a classic model of chronic stress. This study evaluated the effects of different durations of CUMS on anxiety-like behavior, inflammation, and tryptophan metabolism in C57BL/6N mice. The results of behavioral assessments showed that after 3 and 4 weeks of CUMS exposure, the mice exhibited significant decreases in open arms ratio and time ratio in the elevated plus maze (EPM), prolonged latency in the novelty-suppressed feeding test (NSFT), and reduced transitions in the light/dark box (LDB), all indicative of anxiety-like behavior. The inflammatory factors expressions were quantified using qPCR, showing that pro-inflammatory and anti-inflammatory markers began to rise following 1-2 weeks of CUMS exposure. After 3 weeks of stress, TNF-α significantly increased, TGF-β levels started to decrease, and by 4 weeks of CUMS, Arg-1 expression also declined. In terms of tryptophan metabolism, 5-HT content in the hippocampus of the mice began to decrease after 3 weeks of CUMS, while the levels of neuroprotective kynurenic acid (KYNA) continued to rise. Concurrently, neurotoxic substances, including 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), accumulated; after 4 weeks of CUMS, the KYNA content also started to decline. In conclusion, CUMS exposure for 3-4 weeks in male C57BL/6 N mice induces anxiety-like behavior alongside the occurrence of inflammatory responses and disturbances in tryptophan metabolism. These findings highlight the complex interplay between stress, inflammation, and metabolic pathways in the etiology of anxiety-related behaviors.
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Affiliation(s)
- Yanqin Luo
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Yiwen Zhang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Chen
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongzhi Zhao
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Xueyan Li
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang 832000, China
| | - Xinmin Liu
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | | | - Chunhui Shan
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang 832000, China.
| | - Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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6
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Wang Y, Zheng Y, Liang X, Chang Y, Liu Y, Cheng X, Zhang M, Gao W, Li T. α-Lipoic acid alleviate myocardial infarction by suppressing age-independent macrophage senescence. Sci Rep 2025; 15:11996. [PMID: 40199978 DOI: 10.1038/s41598-025-92328-7] [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: 07/08/2024] [Accepted: 02/26/2025] [Indexed: 04/10/2025] Open
Abstract
Myocardial infarction (MI) has high morbidity and mortality, and the macrophage senescence-associated secretory phenotype (SASP) plays a central role in M1 healing. α-Lipoic acid (ALA) alleviates MI by regulating the function of macrophages, although the relationship between ALA and macrophage senescence remains unclear. To investigate macrophage SASP in MI, we performed single-cell RNA sequencing (scRNA-seq) on the GEO GSE163465 dataset, along with qPCR and western blot analyses to assess SASP expression in macrophages subjected to hypoxia and ALA treatment. Immunofluorescence was used to detect SASP distribution. Coculture and animal experiments were performed to assess the therapeutic effects of ALA on macrophage senescence and cardiomyocyte ischemic injury. scRNA-seq revealed an age-independent senescent propensity of macrophages in MI. Increased expression of H2A.X, CCL7, IL1β, and CDKN1A, along with decreased SOD2 expression, confirmed that macrophage SASP occurred after hypoxia, with oxidative stress and energy metabolism involved in the process. ALA inhibited the degradation of SIRT1 and promoted the Nrf2 nuclear translocation, alleviating macrophage senescence and myocardial ischemic injury. Age-independent macrophage SASP occurred during MI. Macrophage SASP was induced by ROS and mitochondrial dysfunction. ALA alleviated SASP by decreasing ROS generation and autophagy flux while increasing SIRT1 levels, and Nrf2 nuclear translocation. ALA ameliorated MI injury.
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Affiliation(s)
- Yuchao Wang
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yue Zheng
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Xiaoyu Liang
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- The Third Central, Clinical College of Tianjin Medical University, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yun Chang
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Yanwu Liu
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- The Third Central, Clinical College of Tianjin Medical University, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Xian Cheng
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- The Third Central, Clinical College of Tianjin Medical University, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Meng Zhang
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China
- The Third Central, Clinical College of Tianjin Medical University, Tianjin, 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
| | - Wenqing Gao
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China.
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China.
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China.
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China.
- Artificial Cell Engineering Technology Research Center, Tianjin, China.
| | - Tong Li
- School of Medicine, Nankai University, Tianjin, 300071, China.
- Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China.
- Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China.
- The Third Central, Clinical College of Tianjin Medical University, Tianjin, 300170, China.
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China.
- Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China.
- Artificial Cell Engineering Technology Research Center, Tianjin, China.
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Li M, Wu K, Zhao X, Yu Q, Li J, Wu Y, Liu X. Dose-Response Metabolomics Unveils Liver Metabolic Disruptions and Pathway Sensitivity to Alkylimidazolium Ionic Liquids: Benchmark Dose Estimation for Health Risk Assessment. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:6414-6427. [PMID: 40133052 DOI: 10.1021/acs.est.4c12617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Alkylimidazolium-based ionic liquids (AILs), once hailed as ″green solvents,″ have seen widespread use, but recent concerns have emerged regarding their environmental and health risks. This study integrates in vitro and in vivo dose-response metabolomics to investigate liver metabolic disturbances and pathway sensitivity to 1-octyl-3-methylimidazolium (M8OI) exposure. Important liver function indicators, including catalase, alanine aminotransferase, aspartate aminotransferase, and glycosylated serum protein, showed significant alterations (P < 0.05), indicating liver dysfunction. Metabolomics analysis revealed dose-dependent changes in energy metabolism and oxidative stress pathways in both cell and rat models, characterized by increased levels of thiamine and lipopolysaccharides, and decreased levels of nicotinamide and adenine. Key intermediates of the tricarboxylic acid cycle, such as citrate and isocitrate, exhibited significant alterations (P < 0.05). Pathway analysis identified disruptions in arginine, proline, and purine metabolism. Quantitative risk characterization based on effective concentration (EC) values identified key metabolites─adenine (EC-10 = 0.004 mg/kg), (±)12(13)-DiHOME (EC-10 = 0.024 mg/kg), and nicotinamide (EC-10 = 0.05 mg/kg) in vivo, and isocitrate (EC-10 = 0.22 μM), d-threo-isocitric acid (EC-10 = 0.23 μM), and citric acid (EC-10 = 0.40 μM) in vitro─as potential biomarkers of M8OI-induced metabolic disruption. These findings highlight hepatic metabolic disturbances induced by M8OI, with dose-response metabolomics identifying benchmark dose values based on regression models, thereby providing a basis for health risk assessment.
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Affiliation(s)
- Ming Li
- Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
| | - Kejia Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Xiaole Zhao
- Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
| | - Qingqing Yu
- Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
| | - Jingguang Li
- Department of Nutrition and Food Safety, Peking Union Medical College, Research Unit of Food Safety, Chinese Academy of Medical Sciences, Beijing 100010, China
- NHC Key Lab of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100010, China
| | - Yongning Wu
- Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
- Department of Nutrition and Food Safety, Peking Union Medical College, Research Unit of Food Safety, Chinese Academy of Medical Sciences, Beijing 100010, China
- NHC Key Lab of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100010, China
| | - Xin Liu
- Key Laboratory for Deep Processing of Major Grain and Oil (The Chinese Ministry of Education), College of Food Science and Engineering, Wuhan Polytechnic University, Wuhan, Hubei 430023, China
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Wang S, Qin L, Liu F, Zhang Z. Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies. Cell Commun Signal 2025; 23:171. [PMID: 40197235 PMCID: PMC11977922 DOI: 10.1186/s12964-025-02169-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/23/2025] [Indexed: 04/10/2025] Open
Abstract
The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.
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Affiliation(s)
- Siwei Wang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Qin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology), Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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9
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Tao X, Zhang J, Liu J, Gu F, Li L, Wu X, Dai K, Shen H, Li X, Li H, Wang Z, Wang Z. SARM1 Modulates calcium influx in secondary brain injury after experimental Intracerebral hemorrhage. Neuroscience 2025; 571:32-43. [PMID: 40021079 DOI: 10.1016/j.neuroscience.2025.02.052] [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: 10/25/2024] [Revised: 02/11/2025] [Accepted: 02/24/2025] [Indexed: 03/03/2025]
Abstract
Intracerebral hemorrhage (ICH), defined as spontaneous bleeding within brain tissue, is associated with high mortality and severe disability, often resulting in poor clinical outcomes. Early intervention to mitigate secondary brain injury is critical for neuronal protection. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a member of the MyD88 family, is predominantly expressed in neurons, where it localizes to the outer membrane of mitochondria. Under physiological conditions, SARM1 is expressed at low levels; however, its expression increases following injury, resulting in excessive NAD+ hydrolysis. While NAD+ degradation products can influence calcium channels, their role in calcium regulation after ICH remains unclear. This study established an in vivo ICH model in adult SD rats via autologous blood injection into the basal ganglia and validated the findings using an in vitro model of primary neurons treated with oxyhemoglobin. SARM1 knockdown was achieved using a lentiviral vector. Following ICH, SARM1 expression significantly increased and colocalized with the neuronal marker NeuN. SARM1 knockdown reduced both SARM1 and mitochondrial calcium uniporter (MCU) expression, decreased NAD+ degradation, and attenuated neuronal death. Behavioral assessments demonstrated improved short- and long-term neurological outcomes in SARM1-knockdown rats compared with the lentiviral vector group. In in vitro experiments, Rhod-2 staining revealed reduced mitochondrial calcium levels, while TMRM staining indicated decreased mitochondrial membrane potential loss. Additionally, Hoechst staining showed reduced neuronal mitochondrial death following SARM1 downregulation. These findings suggest that targeting SARM1 may enhance neurological recovery and represents a potential therapeutic strategy for early intervention in secondary brain injury following ICH.
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Affiliation(s)
- Xinyu Tao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Juyi Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Jiangang Liu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Feng Gu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Longyuan Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Xin Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Kun Dai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China
| | - Zongqi Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006 China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
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10
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Zhao FL, Zhang JR, Liu MH, Liu HY, Mao CJ, Wang F, Chen JP, Liu CF. Tan I modulates astrocyte inflammatory responses through enhanced NAD +-Sirt1 pathway: Insights from metabolomics studies. Int Immunopharmacol 2025; 151:114364. [PMID: 40024217 DOI: 10.1016/j.intimp.2025.114364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
Over the past decade, research has increasingly demonstrated that oligomeric α-synuclein (O-αS) plays a pivotal role in the pathogenesis of Parkinson's disease (PD), particularly in mediating dopaminergic neuron injury and neuroinflammation. In this study, we investigated the anti-inflammatory effects of tanshinone I (Tan I), an active component of the traditional Chinese medicine Danshen, on O-αS-induced inflammation in primary mouse astrocytes. Using metabolomics analysis, we identified key pathways regulated by Tan I. Our results showed that Tan I significantly suppressed O-αS-induced mRNA expression of pro-inflammatory cytokines, including interleukin-1β, IL-6, tumor necrosis factor-α and cyclooxygenase-2. Metabolomic profiling revealed that Tan I enhanced NAD+ metabolism, leading to activation of the NAD+-Sirt1 pathway and subsequent inhibition of nuclear factor-κB activity. Together, these findings suggest that Tan I attenuates neuroinflammatory response in astrocytes by modulating NAD+-dependent signaling mechanisms.
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Affiliation(s)
- Feng-Lun Zhao
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Jia-Rui Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Man-Hua Liu
- Department of Neurology, Changshu Hospital affiliated to Nanjing University of Chinese Medicine, Changshu 215500, China
| | - Hui-Yi Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Cheng-Jie Mao
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Fen Wang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Ju-Ping Chen
- Department of Neurology, Changshu Hospital affiliated to Nanjing University of Chinese Medicine, Changshu 215500, China.
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
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11
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Lautrup S, Zhang SQ, Funayama S, Lirussi L, Visnovska T, Cheung HH, Niere M, Tian Y, Nilsen HL, Selbæk G, Saarela J, Maezawa Y, Yokote K, Nilsson P, Chan WY, Kato H, Ziegler M, Bohr VA, Fang EF. Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation. Aging (Albany NY) 2025; null:206236. [PMID: 40179319 DOI: 10.18632/aging.206236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 03/18/2025] [Indexed: 04/05/2025]
Abstract
Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD+ causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD+ changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD+ augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with WRN knockout (WRN-/-) and in primary fibroblasts derived from WS patients compared to controls. Moreover, WRN deficiency results in decreased mitochondrial NAD+ (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD+ is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of WRN, highlighting an indispensable role of WRN in proliferation even in an NAD+ affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.
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Affiliation(s)
- Sofie Lautrup
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
| | - Shi-Qi Zhang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
| | - Shinichiro Funayama
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Lisa Lirussi
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
- Department of Microbiology, Oslo University Hospital, Oslo 0450, Norway
| | - Tina Visnovska
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
| | - Hoi-Hung Cheung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Marc Niere
- Department of Biomedicine, University of Bergen, Bergen 5009, Norway
| | - Yuyao Tian
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | - Hilde Loge Nilsen
- Department of Microbiology, Oslo University Hospital, Oslo 0450, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo 0372, Norway
| | - Geir Selbæk
- Institute of Clinical Medicine, University of Oslo, Oslo 0372, Norway
- The Norwegian National Centre for Aging and Health, Vestfold Hospital Trust, Tønsberg 3103, Norway
- Department of Geriatric Medicine, Oslo University Hospital, Oslo 0450, Norway
| | - Janna Saarela
- Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo 0372, Norway
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Medical Genetics, Oslo University Hospital, Oslo 0450, Norway
| | - Yoshiro Maezawa
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Koutaro Yokote
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Per Nilsson
- Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna 17164, Sweden
| | - Wai-Yee Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Hisaya Kato
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Mathias Ziegler
- Department of Biomedicine, University of Bergen, Bergen 5009, Norway
- Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena 07745, Germany
| | - Vilhelm A Bohr
- Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Copenhagen 1172, Denmark
| | - Evandro F Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
- The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer’s Disease (NO-AD) Networks, Oslo 0372, Norway
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12
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Zhu S, Zhang R, Yao L, Lin Z, Li Y, Li S, Wu L. De novo NAD + synthesis is ineffective for NAD + supply in axenically cultured Caenorhabditis elegans. Commun Biol 2025; 8:545. [PMID: 40175694 PMCID: PMC11965519 DOI: 10.1038/s42003-025-07984-2] [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: 10/07/2024] [Accepted: 03/22/2025] [Indexed: 04/04/2025] Open
Abstract
To secure an adequate nicotinamide adenine dinucleotide (NAD+) supply for survival, organisms typically rely on two complementary mechanisms: the de novo synthesis pathway and the salvage pathway. Notably, the classic quinolinic acid phosphoribosyltransferase (QPRTase) for de novo NAD+ synthesis is absent in Caenorhabditis elegans (C. elegans), despite the reported alternative mechanism involving uridine monophosphate phosphoribosyltransferase (UMPS). However, the effectiveness of this proposed mechanism for NAD+ production of C. elegans remains unclear. Here, using a chemically defined medium, we observed that removing NAD+ salvage precursors from the medium results in a significant decrease in NAD+ levels, causing severe developmental delay and fecundity loss in C. elegans. Strikingly, these defects cannot be restored by any metabolites from the de novo synthesis pathway, including the direct QPRTase substrate quinolinic acid (QA). Furthermore, the deficiency of umps-1 does not cause any significant changes in the NAD+ levels of C. elegans. Moreover, the growth defects of the umps-1 mutant could be rescued by uridine, but not the salvage NAD+ supply. Additionally, we discovered that commercially available QA products contain substantial amounts of nicotinic acid, potentially producing misleading information. Collectively, our results demonstrate that C. elegans lacks the necessary mechanisms for de novo synthesis of NAD+.
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Affiliation(s)
- Shihao Zhu
- Fudan University, Shanghai, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Runshuai Zhang
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Luxia Yao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Zhirong Lin
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Yanjie Li
- Fudan University, Shanghai, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Siyuan Li
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Lianfeng Wu
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
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Zandona A, Szecskó A, Žunec S, Jovanović IN, Bušić V, Sokač DG, Deli MA, Katalinić M, Veszelka S. Nicotinamide derivatives protect the blood-brain barrier against oxidative stress. Biomed Pharmacother 2025; 186:118018. [PMID: 40174541 DOI: 10.1016/j.biopha.2025.118018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/04/2025] Open
Abstract
Nicotinamides play a crucial role in energy metabolism and maintenance of the redox homeostasis counteracting oxidative stress and elevated reactive oxidative species (ROS) in human cells. The levels of nicotinamides decline with age and are associated with various pathologies, including ones linked with the blood-brain barrier disorder. Therefore, the investigation of the bioactivity of synthetic nicotinamide derivates (NAs) and evaluation of their potential to protect the blood-brain barrier (BBB) from oxidative stress is emerging as an important new strategy. In the current study, we tested different NAs as potential exogenous substitutes for such biological processes. All tested derivatives were non-toxic and attenuated elevation of ROS production in brain endothelial cells induced by tert-butyl hydroperoxide (tBHP), but one specifically was protective on the cell-cultured model of the BBB. The most promising NA was a derivative containing methoxy moiety (NA-4OCH3), which not only increased cell impedance, but had a protective effect on brain endothelial cells barrier against tBHP-induced oxidative stress on several levels: reducing the ROS level and restoring the activity of glutathione, mitochondrial membrane potential, superoxide dismutase enzymes activity to the basal level. In addition, NA-4OCH3 increased the integrity of both human and rat cell-based BBB model after tBHP-treatment seen by the elevated transendothelial electrical resistance, tight junction protein claudin-5 level as well as the decreased permeability of markers across the barrier. This study highlights novel approach to protect the BBB from oxidative stress-induced dysfunction, positioning NA-4OCH3 as potential neuroprotective agent for ROS-mediated disease interventions, with implications for neurodegeneration and BBB.
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Affiliation(s)
- Antonio Zandona
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb HR-10001, Croatia
| | - Anikó Szecskó
- Institute of Biophysics, HUN-REN Biological Research Centre, Temesvári krt. 62, Szeged 6726, Hungary; Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Suzana Žunec
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb HR-10001, Croatia
| | - Ivana Novak Jovanović
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb HR-10001, Croatia
| | - Valentina Bušić
- Faculty of Food Technology Osijek, Josip Juraj Strossmayer University of Osijek, Kuhačeva 20, Osijek HR-31000, Croatia
| | - Dajana Gašo Sokač
- Faculty of Food Technology Osijek, Josip Juraj Strossmayer University of Osijek, Kuhačeva 20, Osijek HR-31000, Croatia
| | - Mária A Deli
- Institute of Biophysics, HUN-REN Biological Research Centre, Temesvári krt. 62, Szeged 6726, Hungary
| | - Maja Katalinić
- Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb HR-10001, Croatia.
| | - Szilvia Veszelka
- Institute of Biophysics, HUN-REN Biological Research Centre, Temesvári krt. 62, Szeged 6726, Hungary.
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14
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Mandal D, Akhtar N, Shafi S, Gupta J. Phytoestrogens and Sirtuin Activation for Renal Protection: A Review of Potential Therapeutic Strategies. PLANTA MEDICA 2025; 91:146-166. [PMID: 39626791 DOI: 10.1055/a-2464-4354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Significant health and socio-economic challenges are posed by renal diseases, leading to millions of deaths annually. The costs associated with treating and caring for patients with renal diseases are considerable. Current therapies rely on synthetic drugs that often come with side effects. However, phytoestrogens, natural compounds, are emerging as promising renal protective agents. They offer a relatively safe, effective, and cost-efficient alternative to existing therapies. Phytoestrogens, being structurally similar to 17-β-estradiol, bind to estrogen receptors and produce both beneficial and, in some cases, harmful health effects. The activation of sirtuins has shown promise in mitigating fibrosis and inflammation in renal tissues. Specifically, SIRT1, which is a crucial regulator of metabolic activities, plays a role in protecting against nephrotoxicity, reducing albuminuria, safeguarding podocytes, and lowering reactive oxygen species in diabetic glomerular injury. Numerous studies have highlighted the ability of phytoestrogens to activate sirtuins, strengthen antioxidant defense, and promote mitochondrial biogenesis, playing a vital role in renal protection during kidney injury. These findings support further investigation into the potential role of phytoestrogens in renal protection. This manuscript reviews the potential of phytoestrogens such as resveratrol, genistein, coumestrol, daidzein, and formononetin in regulating sirtuin activity, particularly SIRT1, and thereby providing renal protection. Understanding these mechanisms is crucial for designing effective treatment strategies using naturally occurring phytochemicals against renal diseases.
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Affiliation(s)
- Debojyoti Mandal
- School of Bioengineering and Biosciences, Lovely Professional University (LPU), Phagwara, Punjab, India
| | - Nahid Akhtar
- School of Bioengineering and Biosciences, Lovely Professional University (LPU), Phagwara, Punjab, India
| | - Sana Shafi
- Molecular Medicine & Pathology (MMP) Matauranga Hauora, Faculty of Medical and Health Sciences Waipapa Taumata Rau, University of Auckland, Aotearoa, New Zealand
| | - Jeena Gupta
- School of Bioengineering and Biosciences, Lovely Professional University (LPU), Phagwara, Punjab, India
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15
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Takahashi K, Sato E, Yamakoshi S, Ogane M, Sekimoto A, Ishikawa T, Kisu K, Oe Y, Okamoto K, Miyazaki M, Tanaka T, Takahashi N. Nicotinamide ameliorates podocyte injury and albuminuria in adriamycin-induced nephropathy. Am J Physiol Renal Physiol 2025; 328:F501-F516. [PMID: 40033940 DOI: 10.1152/ajprenal.00297.2024] [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: 10/15/2024] [Revised: 11/06/2024] [Accepted: 02/26/2025] [Indexed: 03/05/2025] Open
Abstract
Podocytes are key components of the glomerular filtration barrier, and their injury leads to proteinuria, chronic kidney disease (CKD), and nephrotic syndrome. Effective treatments for these conditions are not well established, and prevention of podocyte injury is a crucial challenge. Nicotinamide (NAM), a form of vitamin B3, has been reported to exert beneficial effects in various renal disease models due to its antioxidant and anti-inflammatory properties and its ability to replenish nicotinamide adenine dinucleotide (NAD+). However, its impact on adriamycin (ADR)-induced nephropathy, a model of nephrotic syndrome caused by podocyte injury, remains unclear. We investigated the effects of NAM administration in a mouse model of ADR nephropathy. BALB/c mice were intravenously administered ADR to induce nephropathy. In the NAM-treated group, mice received 0.6% NAM in drinking water ad libitum starting 7 days before ADR administration. After 14 days, NAM treatment decreased albuminuria, glomerular sclerosis, and podocyte injury, and reduced inflammation and oxidative stress markers in the kidneys. NAM and NAD+ levels were decreased in ADR-treated kidneys, and the expression of the NAD+-consuming enzymes SIRT1 and poly(ADP-ribose) polymerase 1 (PARP-1) was decreased and increased, respectively. Nicotinamide N-methyltransferase expression was increased. NAM canceled these abnormalities. In cultured rat podocytes, NAD+ alleviated ADR-induced cytotoxicity, apoptosis, and inflammation. These findings suggest that NAM prevents ADR nephropathy and podocyte injury, likely through NAD+ replenishment.NEW & NOTEWORTHY Nephrotic syndrome can lead to end-stage kidney disease and cause severe complications. Currently, effective treatments for nephrotic syndrome have not been established, and new therapeutic approaches targeting podocyte injury are needed. Nicotinamide prevents podocyte injury in adriamycin-induced nephropathy in mice and ameliorates albuminuria, pathological changes, oxidative stress, and inflammation. Here, we provide evidence that pretreatment with nicotinamide can attenuate podocyte injury and subsequent nephropathy in mice.
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Affiliation(s)
- Kei Takahashi
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Emiko Sato
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
| | - Seiko Yamakoshi
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
| | - Mizuki Ogane
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
| | - Akiyo Sekimoto
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
| | - Takamasa Ishikawa
- Infinity Lab, Inc., Tsuruoka, Japan
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
| | - Kiyomi Kisu
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuji Oe
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Okamoto
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mariko Miyazaki
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuhiro Tanaka
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nobuyuki Takahashi
- Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan
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16
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Zhu S, Zhang L, Tong P, Chen J, Wang C, Wang Z, Liu J, Duan P, Jiang Q, Zhou Y, Tan G, Zhang X, Jiang B. Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis. Invest Ophthalmol Vis Sci 2025; 66:14. [PMID: 40192637 DOI: 10.1167/iovs.66.4.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025] Open
Abstract
Purpose Microglial activation plays a pivotal role in the pathogenesis of retinal degeneration, contributing to neuroinflammation within the retina. Previous studies identified that nicotinamide riboside (NR) mitigated light-induced retinal degeneration (LIRD) and inhibited microglial activation. The cGAS-STING signaling pathway has been recognized as a key mediator of inflammation in response to cellular stress and tissue damage. This study further explores the regulatory impact of NR on microglial activation and STING-mediated pyroptosis in retinal degeneration. Methods Balb/c mice were subjected to bright light exposure to induce retinal degeneration. Bioinformatics analysis was used to identify the upregulated key genes and signaling pathways involved in the progression of retinal degeneration, based on mouse transcriptomes from the LIRD model. Molecular biology techniques and immunofluorescence staining were used to assess cGAS-STING activation and expression of pyroptosis-associated molecules. Retinal function, photoreceptor apoptosis and inflammatory response were evaluated in the presence and absence of NR supplementation. Results Exposure to bright light resulted in mitochondrial dysfunction and the release of dsDNA, significantly triggering the activation of cGAS-STING pathway and microglial pyroptosis. In contrast, NR treatment preserved mitochondrial biosynthesis, inhibited STING expression in reactive microglia, and dampened the pro-inflammatory response. Additionally, intraperitoneal administration of the STING inhibitor H151 reduced light-induced microglial activation and pyroptosis, while improving retinal function and promoting photoreceptor survival. Conclusions These findings suggest that NR confers neuroprotection by attenuating damaged DNA-triggered STING-mediated microglial activation and pyroptosis. Targeting the cGAS-STING pathway presents a promising therapeutic avenue for retinal degeneration.
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Affiliation(s)
- Shanshan Zhu
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Lusi Zhang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Ping Tong
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Jiawei Chen
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Cong Wang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Zewei Wang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Jingyuan Liu
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Peiyun Duan
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Qian Jiang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Yubing Zhou
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Guangshuang Tan
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Xian Zhang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
| | - Bing Jiang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China
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17
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Zhai X, He X, Huang A, Liu Z, Chen S, Chang B, Zhu Y, Xie H, Bai Z, Xiao X, Sun Y, Wang J, Lu Y, Zou Z. Analysis of Immunometabolic Profiles in Patients With Chronic Drug-Induced Liver Injury and Validation in Mice to Reveal Potential Mechanisms. J Gastroenterol Hepatol 2025; 40:987-1003. [PMID: 39797719 DOI: 10.1111/jgh.16876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 12/09/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND The mechanism underlying chronic drug-induced liver injury (DILI) remains unclear. Immune activation is a common feature of DILI progression and is closely associated with metabolism. We explored the immunometabolic profile of chronic DILI and the potential mechanism of chronic DILI progression. METHODS Plasma and peripheral blood mononuclear cells from patients with chronic DILI were analyzed using multiplex immunoassays and untargeted metabolomics to reveal their immunometabolic profile. The effects and potential mechanisms of chronic DILI-related metabolite on acute or chronic liver injury induced by LPS or CCl4 in mice were investigated. RESULTS Patients with chronic DILI exhibited elevated plasma IL-6, IL-12p70, IL-15 and reduced IL-10 levels. The percentage of IL-12+ monocytes was higher, while that of CD206+ monocytes, IL-10+ monocytes, Th2, Treg, and IL-10+ CD4+ T cells were lower in patients with chronic DILI compared to those with acute DILI. We identified the most significantly increased metabolite in patients with chronic DILI was cis-aconitic acid (CAA). Administration of CAA can attenuate liver injury in mice with acute liver injury induced by LPS or CCl4 and promote the spontaneous resolution of liver fibrosis in mice with chronic live injury induced by CCl4. The protective mechanism of CAA against liver injury is associated with the inhibition of hepatic macrophage infiltration and polarization, which is achieved by inhibiting the secretion of neutrophil-derived IL-33 and subsequent phosphorylation of GATA3. CONCLUSIONS CAA, which is elevated in patients with chronic DILI, protects against liver injury by inhibiting hepatic macrophage infiltration and polarization through the suppression of the IL-33/GATA3 pathway, suggesting that CAA may serve as a potential target for regulating tissue repair in liver injury.
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Affiliation(s)
- Xingran Zhai
- Peking University 302 Clinical Medical School, Beijing, China
| | - Xian He
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ang Huang
- Department of Gastroenterology and Hepatology, the First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zherui Liu
- Peking University 302 Clinical Medical School, Beijing, China
| | - Shaoting Chen
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Binxia Chang
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yun Zhu
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Huan Xie
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhaofang Bai
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiaohe Xiao
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ying Sun
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jiabo Wang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Yawen Lu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zhengsheng Zou
- Peking University 302 Clinical Medical School, Beijing, China
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
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18
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Zhang J, Hu X, Geng Y, Xiang L, Wu Y, Li Y, Yang L, Zhou K. Exploring the role of parthanatos in CNS injury: Molecular insights and therapeutic approaches. J Adv Res 2025; 70:271-286. [PMID: 38704090 PMCID: PMC11976428 DOI: 10.1016/j.jare.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Central nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest. AIM OF REVIEW Our review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research. KEY SCIENTIFIC CONCEPTS OF REVIEW Parthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.
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Affiliation(s)
- Jiacheng Zhang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Xinli Hu
- Department of Orthopedics, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Yibo Geng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Linyi Xiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Yuzhe Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
| | - Yao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China.
| | - Liangliang Yang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325027, China.
| | - Kailiang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China.
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19
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Gao J, Meng X, Yang X, Xie C, Tian C, Gong J, Zhang J, Dai S, Gao T. The protection of nicotinamide riboside against diabetes mellitus-induced bone loss via OXPHOS. Bone 2025; 193:117411. [PMID: 39884488 DOI: 10.1016/j.bone.2025.117411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 01/21/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
Diabetes mellitus is a global disease that results in various complications, including diabetic osteoporosis. Prior studies have indicated a correlation between low levels of nicotinamide adenine dinucleotide (NAD+) and diabetes-related complications. Nicotinamide riboside (NR), a widely utilized precursor vitamin of NAD+, has been demonstrated to enhance age-related osteoporosis through the Sirt1/FOXO/β-catenin pathway in osteoblast progenitors. However, the impact of NR on bone health in diabetes mellitus remains unclear. In this study, we assessed the potential effects of NR on bone in diabetic mice. NR was administered to high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic mice (T2DM), and various parameters, including metabolic indicators, bone quality, bone metabolic markers, and RNA sequences, were measured. Our findings confirmed that HFD/STZ-induced T2DM impaired bone microstructures, resulting in bone loss. NR effectively ameliorated insulin resistance, improved bone microarchitecture, and bone quality, reduced bone resorption, enhanced the Forkhead box O (FOXO) signaling pathway, mitigated the nuclear factor kappa B (NF-kB) signaling pathway, and ameliorated the disorder of the oxidative phosphorylation process (OXPHOS) in diabetic mice. In conclusion, NR demonstrated the capacity to alleviate T2DM-induced bone loss through the modulation of OXPHOS in type 2 diabetic mice. Our results underscore the potential of NR as a therapeutic target for addressing T2DM-related bone metabolism and associated diseases. Further cell-based studies under diabetic conditions, such as in vitro cultures of key cell types (e.g., osteoblasts and osteoclasts), are necessary to validate these findings.
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Affiliation(s)
- Jie Gao
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao 266000, China; School of Public Health, Qingdao University, Qingdao 266071, China.
| | - Xiangyuan Meng
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Xingxiang Yang
- School of Public Health, Qingdao University, Qingdao 266071, China.
| | - Chenqi Xie
- School of Public Health, Qingdao University, Qingdao 266071, China.
| | - Chunyan Tian
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Jianbao Gong
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao 266000, China
| | - Junwei Zhang
- Shandong Wendeng Osteopathic Hospital, Weihai 264400, China
| | - Shiyou Dai
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao 266000, China.
| | - Tianlin Gao
- School of Public Health, Qingdao University, Qingdao 266071, China.
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20
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Zhang Z, Liu J, Wang M, Li Y, Hou M, Cao J, Wu J, Su L. Systematic modification of high nicotinamide mononucleotide production in Escherichia coli. J Biotechnol 2025:S0168-1656(25)00072-0. [PMID: 40157454 DOI: 10.1016/j.jbiotec.2025.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/21/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
Nicotinamide mononucleotide (NMN) serves as a crucial precursor in the biosynthesis of NAD+ and has garnered significant attention in the food, dietary supplement, and cosmetic industries. This study engineered an Escherichia coli strain capable of high NMN production. Firstly, the strain with reduced NMN degradation and the ability to transport NMN extracellularly was constructed. Meanwhile, the gene encoding nicotinamide phosphoribosyltransferase (pncA) was disrupted to minimize substrate nicotinamide (NAM) degradation. Then, the induction starting point was optimized to alleviate the metabolic burden on the engineered strain. Subsequently, systematic remodeling of E. coli's glucose metabolism was conducted to enhance its suitability for NMN production by overexpressing key enzymes of the pentose phosphate pathway (Zwf and Gnd), knocking out genes related to the Entner-Doudoroff pathway (gntR and edd), and further attenuating the glycolytic pathway. Then, we concentrated on optimizing the cellular metabolic state, meticulously balancing intracellular redox homeostasis. Finally, using glucose and 2g/L of NAM as substrates, the extracellular NMN yield reached 4.96g/L, which is the highest yield reported so far in similar research. These findings contribute to the commercial production of NMN and offer valuable insights for constructing efficient cell factories for other nucleotide compounds.
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Affiliation(s)
- Zhaoyuan Zhang
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jiehu Liu
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Meng Wang
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Yang Li
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Minglei Hou
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jiaren Cao
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jing Wu
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Lingqia Su
- School of Biotechnology, State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Key Laboratory of Industrial Biotechnology Ministry of Education, and International Joint Laboratory on Food Safety, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China.
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21
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Yuan Y, Sun C, Liu X, Hu L, Wang Z, Li X, Zhang J, Li D, Zhang X, Wu M, Liu L. The Role of Neutrophil Extracellular Traps in Atherosclerosis: From the Molecular to the Clinical Level. J Inflamm Res 2025; 18:4421-4433. [PMID: 40162077 PMCID: PMC11955173 DOI: 10.2147/jir.s507330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/13/2025] [Indexed: 04/02/2025] Open
Abstract
Atherosclerosis is a chronic inflammatory condition that is typified by the deposition of lipids and the subsequent inflammation of medium and large arteries. Neutrophil extracellular traps (NETs) are fibrous meshworks of DNA, histones, and granzymes expelled by activated neutrophils in response to a variety of pathogenic conditions. In addition to their role in pathogen eradication, NETs have been demonstrated to play a pivotal role in the development of atherosclerosis. This article presents a review of the bidirectional interactions in which atherosclerosis-related risk factors stimulate the formation of NETs, which in turn support disease progression. This article emphasizes the involvement of NETs in the various stages of atherogenesis and development, influencing multiple factors such as the vascular endothelium, platelets, the inflammatory milieu, and lipid metabolism. The findings of this study offer new insights and avenues for further investigation into the processes underlying the formation and regulation of the vascular inflammatory microenvironment in atherosclerosis. Finally, potential targeted therapeutic strategies for NETs are discussed to facilitate their progression to clinical practice (Graphical Abstract).
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Affiliation(s)
- Yongfang Yuan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Changxin Sun
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Xinyi Liu
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Lanqing Hu
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Zeping Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Xiaoya Li
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Jingyi Zhang
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Dexiu Li
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Xiaonan Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
| | - Min Wu
- Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China
| | - Longtao Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome/National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of China
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22
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Zhu H, Fang G, Nie N, Xie J, Tseng PH, Xiong Z, Jiang D, Mao CJ, Zhu JJ, Chew SY, Chen YC. Breathing Laser-Spectral Mapping of Cavity-Enhanced Redox Reactions with Subcellular Resolution. ACS NANO 2025; 19:10955-10965. [PMID: 40062912 PMCID: PMC11948617 DOI: 10.1021/acsnano.4c16389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/26/2025]
Abstract
Precise and dynamic observation of redox reactions in living organisms holds significant importance for the study of physiological processes and pathological mechanisms. However, the current technologies still make it challenging to monitor this process in a nondestructive and highly sensitive manner. Herein, we introduced a bioactive laser approach for ultrasensitive and real-time monitoring of intracellular redox reactions. Resazurin, as a popular cell viability assay reagent, has lasing behaviors and photostability, which makes it suitable for the development of bioactive lasers. Due to the strong interactions of light and matter within the laser cavity, subtle changes in resazurin concentration during the redox reaction can be translated into detectable wavelength shifts in the lasing spectrum. With narrow laser peaks, the sensing resolution can reach down to 30 pM per 10 pm wavelength shift. Combined with a scanning platform, we mapped the intracellular and intercellular heterogeneities in metabolism. Further applications in cell identification, oxidative stress assessment, and drug evaluation revealed the universal applicability of this method in cell assays and biomedical analysis, providing insights into disease diagnosis and drug screening.
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Affiliation(s)
- Hui Zhu
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
- Key
Laboratory
of Structure and Functional Regulation of Hybrid Materials (Ministry
of Education), School of Chemistry & Chemical Engineering, Anhui University, Hefei, Anhui 230601, China
| | - Guocheng Fang
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
| | - Ningyuan Nie
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
| | - Jun Xie
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
| | - Po-Hao Tseng
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
| | - Zhongshu Xiong
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
| | - Dechen Jiang
- State Key
Laboratory of Analytical Chemistry for Life Science, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Chang-Jie Mao
- Key
Laboratory
of Structure and Functional Regulation of Hybrid Materials (Ministry
of Education), School of Chemistry & Chemical Engineering, Anhui University, Hefei, Anhui 230601, China
| | - Jun-Jie Zhu
- State Key
Laboratory of Analytical Chemistry for Life Science, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Sing Yian Chew
- Lee
Kong
Chian School of Medicine, 11 Mandalay Road, Singapore 308232, Singapore
| | - Yu-Cheng Chen
- School of
Electrical and Electronics Engineering, Nanyang Technological University, 50 Nanyang Ave., Singapore 639798, Singapore
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23
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Ali MM, Nookaew I, Resende-Coelho A, Marques-Carvalho A, Warren A, Fu Q, Kim HN, O'Brien CA, Almeida M. Mechanisms of mitochondrial reactive oxygen species action in bone mesenchymal cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.643319. [PMID: 40196660 PMCID: PMC11974693 DOI: 10.1101/2025.03.24.643319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Mitochondrial (mt)ROS, insufficient NAD + , and cellular senescence all contribute to the decrease in bone formation with aging. ROS can cause senescence and decrease NAD + , but it remains unknown whether these mechanisms mediate the effects of ROS in vivo . Here, we generated mice lacking the mitochondrial antioxidant enzyme Sod2 in osteoblast lineage cells targeted by Osx1-Cre and showed that Sod2 ΔOsx1 mice had low bone mass. Osteoblastic cells from these mice had impaired mitochondrial respiration and attenuated NAD + levels. Administration of an NAD + precursor improved mitochondrial function in vitro but failed to rescue the low bone mass of Sod2 ΔOsx1 mice. Single-cell RNA-sequencing of bone mesenchymal cells indicated that ROS had no significant effects on markers of senescence but disrupted parathyroid hormone signaling, iron metabolism, and proteostasis. Our data supports the rationale that treatment combinations aimed at decreasing mtROS and senescent cells and increasing NAD + should confer additive effects in delaying age-associated osteoporosis.
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24
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Obisi JN, Abimbola ANJ, Babaleye OA, Atidoglo PK, Usin SG, Nwanaforo EO, Patrick-Inezi FS, Fasogbon IV, Chimezie J, Dare CA, Kuti OO, Uti DE, Omeoga HC. Unveiling the future of cancer stem cell therapy: a narrative exploration of emerging innovations. Discov Oncol 2025; 16:373. [PMID: 40120008 PMCID: PMC11929669 DOI: 10.1007/s12672-025-02102-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
Cancer stem cells (CSCs), are a critical subpopulation within tumours, and are defined by their capacity for self-renewal, differentiation, and tumour initiation. These unique traits contribute to tumour progression, metastasis, and resistance to conventional treatments like chemotherapy and radiotherapy, often resulting in cancer recurrence and poor patient outcomes. As such, CSCs have become focal points in developing advanced cancer therapies. This review highlights progress in CSC-targeted treatments, including chimeric antigen receptor T-cell (CAR-T) therapy, immunotherapy, molecular targeting, and nanoparticle-based drug delivery systems. Plant-derived compounds and gene-editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR), are explored for their potential to enhance precision and minimize side effects. Metabolic pathways integral to CSC survival, such as mitochondrial dynamics, mitophagy (regulated by dynamin-related protein 1 [DRP1] and the PINK1/Parkin pathway), one-carbon metabolism, amino acid metabolism (involving enzymes like glutaminase (GLS) and glutamate dehydrogenase (GDH]), lipid metabolism, and hypoxia-induced metabolic reprogramming mediated by hypoxia-inducible factors (HIF-1α and HIF-2α), are examined as therapeutic targets. The adaptability of CSCs through autophagy, metabolic flexibility, and epigenetic regulation by metabolites like α-ketoglutarate, succinate, and fumarate is discussed. Additionally, extracellular vesicles and nicotinamide adenine dinucleotide (NAD⁺) metabolism are identified as pivotal in redox balance, DNA repair, and epigenetic modifications. Addressing challenges such as tumour heterogeneity, immune evasion, and treatment durability requires interdisciplinary collaboration. Advancing CSC-targeted therapies is essential for overcoming drug resistance and preventing cancer relapse, paving the way for transformative cancer treatments. This review underscores the importance of leveraging innovative technologies and fostering collaboration to revolutionize cancer treatment.
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Affiliation(s)
| | | | - Oluwasegun Adesina Babaleye
- Center for Human Virology and Genomics, Department of Microbiology, Nigerian Institute of Medical Research, Lagos, Nigeria
| | - Peter Kwame Atidoglo
- Department of Biomedical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Saviour God'swealth Usin
- Cancer Research and Molecular Biology Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Eudora Obioma Nwanaforo
- Environmental Health Science Department, School of Heath Technology, Federal University of Technology Owerri, Owerri, Nigeria
| | | | | | - Joseph Chimezie
- Department of Physiology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | | | - Daniel Ejim Uti
- Department of Biochemistry/Research and Publications, Kampala International University, P.O. Box 20000, Kampala, Uganda.
- Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Federal University of Health Sciences, Otukpo, Benue State, Nigeria.
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25
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Niu YR, Xiang MD, Yang WW, Fang YT, Qian HL, Sun YK. NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer. World J Gastroenterol 2025; 31:100785. [PMID: 40124268 PMCID: PMC11924001 DOI: 10.3748/wjg.v31.i11.100785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/13/2024] [Accepted: 02/13/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells. AIM To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells. METHODS We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays. RESULTS Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition. CONCLUSION SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.
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Affiliation(s)
- Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mi-Dan Xiang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hai-Li Qian
- National Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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26
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Wang Y, Zhang Y, Wang W, Zhang Y, Dong X, Liu Y. Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease. Metabolites 2025; 15:210. [PMID: 40137174 PMCID: PMC11943880 DOI: 10.3390/metabo15030210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/27/2025] Open
Abstract
Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism. The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine. Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions. These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities. Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases. These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease. Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation. The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health.
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Affiliation(s)
| | | | | | | | | | - Yang Liu
- Shandong Food Ferment Industry & Design Institute, QiLu University of Technology (Shandong Academy of Sciences), No. 41, Jiefang Road, Jinan 250013, China
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27
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Wu H, Jin M, Hu J, Li F. Nicotinamide adenine dinucleotide alleviates neuroinflammation in rats with traumatic brain injury. Neurosci Lett 2025; 852:138178. [PMID: 39993483 DOI: 10.1016/j.neulet.2025.138178] [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: 11/22/2024] [Revised: 02/18/2025] [Accepted: 02/21/2025] [Indexed: 02/26/2025]
Abstract
OBJECTIVE To characterize the pathology and pathophysiological processes within 6 h after Traumatic brain injury (TBI) in rats, elucidate the neuroprotective effects and the underlying mechanisms of Nicotinamide Adenine Dinucleotide (NAD) in the early stage of TBI to explore the feasibility and clinical benefits of applying NAD directly to the localized injury after TBI. MATERIAL AND METHODS 54 male Sprague-Dawley (SD) rats aged 6-8 weeks were randomly assigned equally to three groups, sham-operated surgery (SO) with saline treatment (SO + Saline), TBI with saline treatment (TBI + Saline), and TBI with 10 μM NAD treatment (TBI + NAD). The whole brain tissues were collected at 1, 3, and 6 h following the procedure. Levels of biomarkers for TBI including S100β, TNF-α, occludin, PPARβ/δ were measured. RESULTS Significant neuroinflammation was observed in the rat brains after TBI, which peaked at 3 h following injury. Significant changes in S100β, TNF-α, PPARβ/δ, and occluding were also observed. Treatment with NAD significantly alleviated neuroinflammation at 1 h following TBI. CONCLUSIONS TBI caused severe neuroinflammation in rat brains, which peaked at 3 h following injury. Treatment with NAD alleviated neuroinflammation in TBI rats.
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Affiliation(s)
- Huancheng Wu
- Department of Neurosurgery, Tianjin Beichen Hospital, Tianjin 300400, China.
| | - Mengli Jin
- Core Laboratory, Tianjin Beichen Hospital, Tianjin 300400, China
| | - Jiandong Hu
- Core Laboratory, Tianjin Beichen Hospital, Tianjin 300400, China
| | - Fenge Li
- Core Laboratory, Tianjin Beichen Hospital, Tianjin 300400, China.
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28
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Chen M, Su Z, Xue J. Targeting T-cell Aging to Remodel the Aging Immune System and Revitalize Geriatric Immunotherapy. Aging Dis 2025:AD.2025.0061. [PMID: 40153576 DOI: 10.14336/ad.2025.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/12/2025] [Indexed: 03/30/2025] Open
Abstract
The aging immune system presents profound challenges, notably through the decline of T cell function, which is critical for effective immune responses. As age-related changes lead to diminished T cell diversity and heighten immunosuppressive environments, older individuals face increased susceptibility to infections, autoimmune diseases, and reduced efficacy of immunotherapies. This review investigates the intricate mechanisms by which T cell aging drives immunosenescence, including immune suppression, immune evasion, reduced antigen reactivity, and the overexpression of immune checkpoint molecules. By delving into innovative therapeutic strategies aimed at rejuvenating T cell populations and modifying the immunological landscape, we highlight the potential for enhancing immune resilience in the elderly. Ultimately, our goal is to outline actionable pathways for restoring immune function, thereby improving health outcomes for aging individuals facing immunological decline.
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Affiliation(s)
- Mi Chen
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Oncology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Zhou Su
- Department of Oncology, Mianyang 404 Hospital, Mianyang, Sichuan, China
| | - Jianxin Xue
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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29
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Zhang H, Ya J, Sun M, Du X, Ren J, Qu X. Inhibition of the cGAS-STING pathway via an endogenous copper ion-responsive covalent organic framework nanozyme for Alzheimer's disease treatment. Chem Sci 2025:d4sc07963a. [PMID: 40144496 PMCID: PMC11934151 DOI: 10.1039/d4sc07963a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Inhibition of cGAS-STING overactivation has recently emerged as a promising strategy to counteract Alzheimer's disease (AD). However, current cGAS-STING inhibitors as immunosuppressants suffer from instability, non-specific targeting, and innate immune disruption. Here, an endogenous AD brain copper ion-responsive covalent organic framework (COF)-based nanozyme (denoted as TP@PB-COF@NADH) has been designed for targeted inhibition of the cGAS-STING pathway for AD treatment. The effective trapping of excess brain endogenous copper ions by TP@PB-COF@NADH not only inhibits the Cu2+-induced harmful reactive oxygen species (ROS) production which is one of the mediators of cGAS-STING activation, but also activates the nanozyme activity of TP@PB-COF@NADH. Furthermore, the well-prepared nanozyme catalytically generates NAD+ and consumes hydrogen peroxide (H2O2) through second near-infrared (NIR-II) enhanced nicotinamide adenine dinucleotide (NADH) peroxidase (NPX)-like activity, realizing the efficient inhibition of the cGAS-STING pathway and associated neuroinflammation. Moreover, replenishing NAD+ levels efficiently restores mitochondrial function and ATP supply. In vivo studies demonstrate that TP@PB-COF@NADH with NIR-II irradiation significantly improves cognitive function in 3× Tg-AD mice, with a reduction in amyloid-β (Aβ) plaque, neuroinflammation and neuronal damage. Collectively, this work presents a promising approach for AD treatment by using an AD brain harmful excess endogenous copper ion-responsive and efficient nanozyme.
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Affiliation(s)
- Haochen Zhang
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 China
- School of Applied Chemistry and Engineering, University of Science and Technology of China Hefei Anhui 230029 China
| | - Junlin Ya
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 China
- School of Applied Chemistry and Engineering, University of Science and Technology of China Hefei Anhui 230029 China
| | - Mengyu Sun
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 China
- School of Applied Chemistry and Engineering, University of Science and Technology of China Hefei Anhui 230029 China
| | - Xiubo Du
- College of Life Sciences and Oceanography, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University Shenzhen 518060 China
| | - Jinsong Ren
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 China
- School of Applied Chemistry and Engineering, University of Science and Technology of China Hefei Anhui 230029 China
| | - Xiaogang Qu
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun Jilin 130022 China
- School of Applied Chemistry and Engineering, University of Science and Technology of China Hefei Anhui 230029 China
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30
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Guo X, Lu J, Miao L, Shen E. Mitochondrial Proteome Reveals Metabolic Tuning by Restricted Insulin Signaling to Promote Longevity in Caenorhabditis elegans. BIOLOGY 2025; 14:279. [PMID: 40136535 PMCID: PMC11940386 DOI: 10.3390/biology14030279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025]
Abstract
Aging is a time-dependent process of functional decline influenced by genetic and environmental factors. Age-related mitochondrial changes remain incompletely understood. Here, we found that compared to the wild type, the mitochondria of long-lived daf-2 C. elegans maintain youthful morphology and function. Through quantitative proteomic analysis on isolated mitochondria, we identified 257 differentially expressed candidates. Analysis of these changed mitochondrial proteins reveals a significant upregulation of five key mitochondrial metabolic pathways in daf-2 mutants, including branched-chain amino acids (BCAA), reactive oxygen species (ROS), propionate, β-alanine, and fatty acids (FA), all of which are related to daf-2-mediated longevity. In addition, mitochondrial ribosome protein abundance slightly decreased in daf-2 mutants. A mild reduction in mitochondrial elongation factor G (gfm-1) by RNAi extends the lifespan of wild type while decreasing lipid metabolic process and cytoplasmic fatty acid metabolism, suggesting that proper inhibition of mitochondrial translation activity might be important for lifespan extension. Overall, our findings indicate that mitochondrial metabolic modulation contributes to the longevity of daf-2 mutants and further highlights the crucial role of mitochondria in aging.
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Affiliation(s)
- Xuanxuan Guo
- School of Medicine, Zhejiang University, Hangzhou 310058, China;
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
| | - Jiuwei Lu
- Department of Biochemistry, University of California Riverside, Riverside, CA 92521, USA;
| | - Long Miao
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
- University of Chinese Academy of Sciences, Beijing 100049, China
- Center for Biological Imaging, Core Facilities for Protein Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- MOE Key Laboratory of Cell Proliferation and Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Enzhi Shen
- School of Medicine, Zhejiang University, Hangzhou 310058, China;
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, China
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31
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Liu CJ, Wang LK, Tsai FM. The Application and Molecular Mechanisms of Mitochondria-Targeted Antioxidants in Chemotherapy-Induced Cardiac Injury. Curr Issues Mol Biol 2025; 47:176. [PMID: 40136430 PMCID: PMC11941228 DOI: 10.3390/cimb47030176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/27/2025] Open
Abstract
Chemotherapeutic agents play a crucial role in cancer treatment. However, their use is often associated with significant adverse effects, particularly cardiotoxicity. Drugs such as anthracyclines (e.g., doxorubicin) and platinum-based agents (e.g., cisplatin) cause mitochondrial damage, which is one of the main mechanisms underlying cardiotoxicity. These drugs induce oxidative stress, leading to an increase in reactive oxygen species (ROS), which in turn damage the mitochondria in cardiomyocytes, resulting in impaired cardiac function and heart failure. Mitochondria-targeted antioxidants (MTAs) have emerged as a promising cardioprotective strategy, offering a potential solution. These agents efficiently scavenge ROS within the mitochondria, protecting cardiomyocytes from oxidative damage. Recent studies have shown that MTAs, such as elamipretide, SkQ1, CoQ10, and melatonin, significantly mitigate chemotherapy-induced cardiotoxicity. These antioxidants not only reduce oxidative damage but also help maintain mitochondrial structure and function, stabilize mitochondrial membrane potential, and prevent excessive opening of the mitochondrial permeability transition pore, thus preventing apoptosis and cardiac dysfunction. In this review, we integrate recent findings to elucidate the mechanisms of chemotherapy-induced cardiotoxicity and highlight the substantial therapeutic potential of MTAs in reducing chemotherapy-induced heart damage. These agents are expected to offer safer and more effective treatment options for cancer patients in clinical practice.
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Affiliation(s)
- Chih-Jen Liu
- Division of Cardiology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan;
| | - Lu-Kai Wang
- Veterinary Diagnostic Division, National Laboratory Animal Center, National Institutes of Applied Research, Taipei City 115, Taiwan;
| | - Fu-Ming Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
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32
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Shi Y, Wan L, Jiao M, Zhong CQ, Cui H, Yuan J. Elevated NAD + drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection. Nat Commun 2025; 16:2259. [PMID: 40050296 PMCID: PMC11885453 DOI: 10.1038/s41467-025-57517-y] [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: 10/03/2024] [Accepted: 02/25/2025] [Indexed: 03/09/2025] Open
Abstract
cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GCβ polarizes to a unique localization "ookinete extrados site" (OES) until ookinete maturation and activates cGMP signaling for initiating parasite motility. However, the mechanism underlying GCβ translocation from cytosol to OES remains elusive. Here, we use protein proximity labeling to search the GCβ-interacting proteins in ookinetes of the rodent malaria parasite P. yoelii, and find the top hit Sir2A, a NAD+-dependent sirtuin family deacetylase. Sir2A interacts with GCβ throughout ookinete development. In mature ookinetes, Sir2A co-localizes with GCβ at OES in a mutually dependent manner. Parasites lacking Sir2A lose GCβ localization at OES, ookinete gliding, and mosquito infection, phenocopying GCβ deficiency. GCβ is acetylated at gametocytes but is deacetylated by Sir2A for OES localization at mature ookinetes. We further demonstrate that the level of NAD+, an essential co-substrate for sirtuin, increases during the ookinete development. NAD+ at its maximal level in mature ookinetes promotes Sir2A-catalyzed GCβ deacetylation, ensuring GCβ localization at OES. This study highlights the spatiotemporal coordination of cytosolic NAD+ level and NAD+-dependent Sir2A in regulating GCβ deacetylation and dynamic localization for Plasmodium ookinete gliding.
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Affiliation(s)
- Yang Shi
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Lin Wan
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Mengmeng Jiao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Chuan-Qi Zhong
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
| | - Huiting Cui
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
| | - Jing Yuan
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
- Department of Infectious Disease, Xiang'an Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
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33
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Habeichi NJ, Amin G, Boitard S, Tannous C, Ghali R, Momken I, Diab R, Booz GW, Mericskay M, Zouein FA. Nicotinamide Riboside: A Promising Treatment for Type 1 Cardiorenal Syndrome in Myocardial Infarction-Induced Acute Kidney Injury by Upregulating Nicotinamide Phosphoribosyltransferase-Mediated Nicotinamide Dinucleotide Levels. J Am Heart Assoc 2025; 14:e038603. [PMID: 40008513 DOI: 10.1161/jaha.124.038603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 12/20/2024] [Indexed: 02/27/2025]
Abstract
BACKGROUND Cardiorenal syndrome type 1 is characterized by the development of acute kidney injury following acute cardiac illness and notably acute myocardial infarction (MI). Acute kidney injury is considered an independent risk factor that increases mortality rate substantially. Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in energy metabolism and oxidative phosphorylation, and in its oxidized form it is a substrate for multiple NAD+-dependent enzymes such as sirtuins and poly-ADP ribose polymerases. Decreased cardiac NAD levels, along with a downregulation of NAMPT (nicotinamide phosphoribosyl transferase), have been reported following MI. A compensatory upregulation in NMRK (nicotinamide riboside kinase) 2, an NAD+ biosynthetic enzyme that uses nicotinamide riboside (NR) to generate NAD+, takes place in the heart after MI, but the impact on kidney NAD metabolism and function has not been addressed before. METHODS AND RESULTS MI was induced by ligating the left anterior descending coronary artery in 2-month-old C57BL6/J mice, followed by the administration of NR (IP injection, 400 mg/kg per day) for 4 and 7 days. We hypothesized that NR treatment could be a potentially promising therapy for MI-induced acute kidney injury. Our findings showed no significant improvement in cardiac ejection fraction following NR treatment at days 4 and 7 post-MI, whereas kidney functions were enhanced and morphological alterations and cell death decreased. The observed renal protection seems to be mediated by an upregulation of NAMPT-mediated increase in renal NAD levels, notably in the distal tubules. CONCLUSIONS Our findings indicate that NR could potentially be a promising therapy for acute kidney injury following an early stage of MI.
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Affiliation(s)
- Nada J Habeichi
- Université Paris-Saclay, INSERM, Signaling and Cardiovascular Pathophysiology UMR-S 1180 Orsay France
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
| | - Ghadir Amin
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
- Department of Pharmacology and Toxicology School of Medicine, University of Mississippi Medical Center Jackson MS
| | - Solene Boitard
- Université Paris-Saclay, INSERM, Signaling and Cardiovascular Pathophysiology UMR-S 1180 Orsay France
| | - Cynthia Tannous
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
| | - Rana Ghali
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
| | - Iman Momken
- Université Paris-Saclay, INSERM, Signaling and Cardiovascular Pathophysiology UMR-S 1180 Orsay France
| | - Reine Diab
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
| | - George W Booz
- Department of Pharmacology and Toxicology School of Medicine, University of Mississippi Medical Center Jackson MS
| | - Mathias Mericskay
- Université Paris-Saclay, INSERM, Signaling and Cardiovascular Pathophysiology UMR-S 1180 Orsay France
| | - Fouad A Zouein
- Université Paris-Saclay, INSERM, Signaling and Cardiovascular Pathophysiology UMR-S 1180 Orsay France
- Department of Pharmacology and Toxicology American University of Beirut, Faculty of Medicine Beirut Lebanon
- The Cardiovascular, Renal, and Metabolic Diseases Research Center of Excellence American University of Beirut Medical Center Beirut Lebanon
- Department of Pharmacology and Toxicology School of Medicine, University of Mississippi Medical Center Jackson MS
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Gupta G, Afzal M, Moglad E, Goyal A, Almalki WH, Goyal K, Rana M, Ali H, Rekha1 A, Kazmi I, Alzarea SI, Singh SK. Parthanatos and apoptosis: unraveling their roles in cancer cell death and therapy resistance. EXCLI JOURNAL 2025; 24:351-380. [PMID: 40166425 PMCID: PMC11956527 DOI: 10.17179/excli2025-8251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 02/20/2025] [Indexed: 04/02/2025]
Abstract
Cell death is a fundamental process that needs to be maintained to balance cellular functions and prevent disease. There are several cell death pathways; however, apoptosis and parthanatos are the most prominent and have important roles in cancer biology. As an extremely well-regulated process, apoptosis removes damaged or abnormal cells via caspase activation and mitochondrial involvement. Unlike in the healthy cells, the loss of ability to induce apoptosis in cancer permits tumor cells to survive and multiply out of control and contribute to tumor progression and therapy resistance. On the contrary, parthanatos is a caspase-independent metabolic collapse driven by poly (ADP-ribose) polymerase 1 (PARP1) overactivation, translocation of apoptosis-inducing factor (AIF), and complete DNA damage. Several cancer models are involved with parthanatos. Deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells by excessive ROS generation, PARP1 upregulation, and AIF nuclear translocation. Like in acute myeloid leukemia (AML), the cannabinoid derivative WIN-55 triggers parthanatos, and the effects can be reversed by PARP inhibitors such as olaparib. Developing cancer treatment strategies involving advanced cancer treatment strategies relies on the interplay between apoptosis and parthanatos. However, such apoptosis-based cancer therapies tend to develop resistance, so there is an urgent need to look into alternative pathways like parthanatos, which may not always trigger apoptosis. In overcoming apoptosis resistance, there is evidence that combining apoptosis-inducing agents, such as BH3 mimetics, with PARP inhibitors synergistically enhances cell death. Oxidative stress modulators have been found to promote the execution of parthanatic and apoptotic pathways and allow treatment. In this review, apoptosis and parthanatos are thoroughly compared at the molecular level, and their roles in cancer pathogenesis as related to cancer therapeutic potential are discussed. We incorporate recent findings to demonstrate that not only can parthanatos be used to manage therapy resistance and enhance cancer treatment via the combination of parthanatos and apoptosis but also that immunity and bone deposition can feasibly be employed against long-circulating cancer stem cells to treat diverse forms of metastatic cancers.
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Affiliation(s)
- Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Arcot Rekha1
- Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Al-Jouf, Saudi Arabia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
- Sunway Biofunctional Molecules Discovery Centre (SBMDC), School of Medical and Life Sciences, Sunway University, Sunway, Malaysia
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Jiang H, Zhang J, Jia D, Liu L, Gao J, Zhang B, Dong Z, Sun X, Yang W, Ou T, Ding S, He L, Shi Y, Hu K, Sun A, Ge J. Histidine triad nucleotide-binding protein 2 attenuates doxorubicin-induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice. MedComm (Beijing) 2025; 6:e70075. [PMID: 39968501 PMCID: PMC11831189 DOI: 10.1002/mco2.70075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 12/16/2024] [Indexed: 02/20/2025] Open
Abstract
Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria-lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide-binding protein 2 (HINT2) in DOX-induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX-treated mice. Cardiac-specific Hint2 knockout mice exhibited significantly worse cardiac dysfunction, impaired autophagic flux, and lysosomal dysfunction after DOX treatment. Mechanistically, HINT2 deficiency reduced oxidative phosphorylation complex I activity and disrupted the nicotinamide adenine dinucleotide NAD+/NADH ratio, impairing lysosomal function. Further, HINT2 deficiency suppressed sterol regulatory element binding protein 2 activity, downregulating transcription factor A mitochondrial, a critical regulator of complex I. Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro, while cardiac-specific Hint2 overexpression using adeno-associated virus 9 or adenovirus alleviated DIC both in vivo and in vitro. These findings highlight HINT2 as a key cardioprotective factor that mitigates DIC by restoring the NAD+/NADH ratio, lysosomal function, and autophagy. Therapeutic strategies enhancing HINT2 expression or supplementing NMN may reduce cardiac damage and heart failure caused by DOX.
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Ahmadi A, Valencia AP, Begue G, Norman JE, Fan S, Durbin-Johnson BP, Jenner BN, Campbell MD, Reyes G, Kapahi P, Himmelfarb J, de Boer IH, Marcinek DJ, Kestenbaum BR, Gamboa JL, Roshanravan B. A Pilot Trial of Nicotinamide Riboside and Coenzyme Q10 on Inflammation and Oxidative Stress in CKD. Clin J Am Soc Nephrol 2025; 20:346-357. [PMID: 39847432 PMCID: PMC11905997 DOI: 10.2215/cjn.0000000624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/10/2025] [Indexed: 01/24/2025]
Abstract
Key Points Nicotinamide riboside and coenzyme Q10 supplementation showed distinct beneficial effects on whole-blood transcriptome, inflammatory cytokines, and oxidative stress. Nicotinamide riboside treatment altered the expression of genes associated with metabolism and immune response coinciding with a decrease in markers of oxidative stress. Coenzyme Q10 supplementation altered genes associated with lipid metabolism coinciding with reductions in markers of oxidative stress and inflammatory cytokines. Background Mitochondria-driven oxidative/redox stress and inflammation play a major role in CKD pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. Methods We conducted a pilot, randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/d of coenzyme Q10 (CoQ10) or 1000 mg/d of nicotinamide riboside (NR) supplementation with placebo in 25 patients with moderate-to-severe CKD (eGFR <60 ml/min per 1.73 m2). We assessed changes in blood transcriptome using 3′-Tag-Seq gene expression profiling and changes in prespecified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n =14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. Results The (mean±SD) age, eGFR, and body mass index of the participants were 61±11 years, 37±9 ml/min per 1.73 m2, and 28±5 kg/m2, respectively. Of the participants, 16% had diabetes and 40% were female. Compared with placebo, NR-mediated transcriptomic changes were enriched in gene ontology terms associated with carbohydrate/lipid metabolism and immune signaling, whereas CoQ10 changes were enriched in immune/stress response and lipid metabolism gene ontology terms. NR increased plasma IL-2 (estimated difference, 0.32; 95% confidence interval [CI], 0.14 to 0.49 pg/ml), and CoQ10 decreased both IL-13 (estimated difference, −0.12; 95% CI, −0.24 to −0.01 pg/ml) and C-reactive protein (estimated difference, −0.11; 95% CI, −0.22 to 0.00 mg/dl) compared with placebo. Both NR and CoQ10 reduced five-series F2-isoprostanes (estimated difference, −0.16 and −0.11 pg/ml, respectively; P < 0.05 for both). NR, but not CoQ10, increased the Bioenergetic Health Index (estimated difference, 0.29; 95% CI, 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52; 95% CI, 0.04 to 7 pmol/min per 10,000 cells) in monocytes. Conclusions Six weeks of NR and CoQ10 improved markers of oxidative stress, inflammation, and cell bioenergetics in patients with moderate-to-severe CKD. Clinical Trial registry name and registration number: NCT03579693 .
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Affiliation(s)
- Armin Ahmadi
- Division of Nephrology, Department of Medicine, University of California, Davis, California
| | - Ana P. Valencia
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | - Gwénaëlle Begue
- Kinesiology Department, California State University, Sacramento, California
| | - Jennifer E. Norman
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, California
| | - Sili Fan
- Department of Biostatistics, School of Medicine, University of California, Davis, California
| | | | - Bradley N. Jenner
- Department of Biostatistics, School of Medicine, University of California, Davis, California
| | | | - Gustavo Reyes
- Department of Radiology, University of Washington, Seattle, Washington
| | - Pankaj Kapahi
- The Buck Institute for Research on Aging, Novato, California
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Jonathan Himmelfarb
- Department of Medicine, Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington
| | - Ian H. de Boer
- Department of Medicine, Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington
| | - David J. Marcinek
- Department of Radiology and Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Bryan R. Kestenbaum
- Department of Medicine, Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington
| | - Jorge L. Gamboa
- School of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Baback Roshanravan
- Division of Nephrology, Department of Medicine, University of California, Davis, California
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37
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Zhang J, Tang Y, Zhang S, Xie Z, Ma W, Liu S, Fang Y, Zheng S, Huang C, Yan G, Abudupataer M, Xin Y, Zhu J, Han W, Wang W, Shen F, Lai H, Liu Y, Ye D, Yu FX, Xu Y, Pan C, Wang C, Zhu K, Zhang W. Mitochondrial NAD + deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm. NATURE CARDIOVASCULAR RESEARCH 2025; 4:275-292. [PMID: 39843801 DOI: 10.1038/s44161-024-00606-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025]
Abstract
Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.
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MESH Headings
- Humans
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Thoracic/metabolism
- Aortic Aneurysm, Thoracic/genetics
- Aortic Aneurysm, Thoracic/pathology
- NAD/metabolism
- Animals
- Mice, Knockout
- Male
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Collagen Type III/metabolism
- Collagen Type III/genetics
- Disease Models, Animal
- Female
- Middle Aged
- Mice, Inbred C57BL
- Aged
- Mitochondria, Muscle/metabolism
- Mitochondria, Muscle/pathology
- Genome-Wide Association Study
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Mitochondria/metabolism
- Mitochondria/pathology
- Mice
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
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Affiliation(s)
- Jingjing Zhang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China
- The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China
| | - Yuyi Tang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shan Zhang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhuxin Xie
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenrui Ma
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shaowen Liu
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yixuan Fang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shufen Zheng
- Greater Bay Area Institute of Precision Medicine, School of Life Sciences, Fudan University, Shanghai, China
| | - Ce Huang
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guoquan Yan
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | | | - Yue Xin
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jingqiao Zhu
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenjing Han
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weizhong Wang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fenglin Shen
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hao Lai
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dan Ye
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fa-Xing Yu
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanhui Xu
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cuiping Pan
- Greater Bay Area Institute of Precision Medicine, School of Life Sciences, Fudan University, Shanghai, China
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kai Zhu
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Weijia Zhang
- Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China.
- The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China.
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38
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Zhang H, Li Y, Li N, Miao Y, Sun S, Gu L, Xiong B. Nicotinamide mononucleotide enhances the developmental potential of mouse early embryos exposed to perfluorooctanoic acid. Reprod Toxicol 2025; 132:108762. [PMID: 39613165 DOI: 10.1016/j.reprotox.2024.108762] [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: 10/09/2024] [Revised: 11/17/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024]
Abstract
Perfluorooctanoic acid (PFOA) exposure severely affects the health of animals and humans, including early embryonic development, but the effective approaches to improve the quality of embryos exposed to PFOA have not been explored. Here, we report that nicotinamide mononucleotide (NMN) can be used to attenuate the impairment of mouse early embryos caused by PFOA exposure. We find that NMN supplementation maintains the normal spindle assembly and proper chromosome alignment by restoring the acetylation level of microtubule to enhance the mitotic capacity of embryos at zygotic cleavage stage under PFOA exposure. In addition, NMN exerts its beneficial effect by enhancing mitochondrial function and eliminating accumulated reactive oxygen species (ROS), which in turn alleviates DNA damage and apoptosis in PFOA-exposed 2-cell embryos. Moreover, NMN ameliorates the quality of PFOA-exposed blastocysts via recovering the octamer-binding transcription factor 4 (Oct4) expression, the actin dynamics, and the total number of cells. Collectively, our findings demonstrate that supplementation with NMN is a feasible strategy to restore the compromised early embryonic development under PFOA exposure, providing a scientific basis for application of NMN to increase the female fertility.
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Affiliation(s)
- Hanwen Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yu Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Na Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yilong Miao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Shaochen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Ling Gu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Bo Xiong
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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39
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Sinha A, Singh AK, Sharma S, Trivedi R, Varsha, Kumar D, Priya S, Sharma SK. Correlation of NADH/NAD + electrochemical potential and enzymatic activity for investigating protein folding and kinetics. Biochem Biophys Res Commun 2025; 750:151393. [PMID: 39892056 DOI: 10.1016/j.bbrc.2025.151393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 01/10/2025] [Accepted: 01/23/2025] [Indexed: 02/03/2025]
Abstract
The biological activity of a protein is determined by its native three-dimensional structure. Various stress factors induce structural changes in the proteins that leads to altered protein homeostasis with the accumulation of misfolded and aggregated protein conformers. Standard methods such as spectrophotometry, luminometry and fluorimetry are conventionally used to study protein activity. Here, an electrochemical method has been developed to measure the change in anodic peak current (Ip,a) of NADH generated during the oxidation reaction. The method showed a linear range of detection from 62.5 μM to 1.0 mM (R2 = 0.999) for NADH with calculated detection limit of 16.02 μM and sensitivity of 1.75 × 103 μA mM-1 cm-2. The method was further employed to investigate the enzymatic activity and folding kinetics of malate dehydrogenase (MDH) and glucose-6-phosphate dehydrogenase (G6PDH). Also, the effect of aluminium ion (Al3+) on the activity and folding kinetics was investigated electrochemically. The Al3+ induced structural alterations in MDH and G6PDH were assessed using circular dichroism (CD), Thioflavin-T (ThT) and nuclear magnetic resonance (NMR). The developed label-free electrochemical method provides an alternative method for investigating protein activity and folding kinetics.
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Affiliation(s)
- Anurag Sinha
- Food Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India; Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India
| | - Ashish K Singh
- Food Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
| | - Supriya Sharma
- System Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
| | - Rimjhim Trivedi
- Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India; Centre of BioMedical Research (CBMR), SGPGIMS Campus, Raibareli Road, Lucknow-226014, Uttar Pradesh, India
| | - Varsha
- Food Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India; Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India
| | - Dinesh Kumar
- Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India; Centre of BioMedical Research (CBMR), SGPGIMS Campus, Raibareli Road, Lucknow-226014, Uttar Pradesh, India
| | - Smriti Priya
- Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India; System Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India.
| | - Sandeep K Sharma
- Food Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India; Academy of Scientific and Industrial Research (AcSIR), Ghaziabad- 201002, India.
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40
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Ding S. Therapeutic Reprogramming toward Regenerative Medicine. Chem Rev 2025; 125:1805-1822. [PMID: 39907153 DOI: 10.1021/acs.chemrev.4c00332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Therapeutic reprogramming represents a transformative paradigm in regenerative medicine, developing new approaches in cell therapy, small molecule drugs, biologics, and gene therapy to address unmet medical challenges. This paradigm encompasses the precise modulation of cellular fate and function to either generate safe and functional cells ex vivo for cell-based therapies or to directly reprogram endogenous cells in vivo or in situ for tissue repair and regeneration. Building on the discovery of induced pluripotent stem cells (iPSCs), advancements in chemical modulation and CRISPR-based gene editing have propelled a new iterative medicine paradigm, focusing on developing scalable, standardized cell therapy products from universal starting materials and enabling iterative improvements for more effective therapeutic profiles. Beyond cell-based therapies, non-cell-based therapeutic strategies targeting endogenous cells may offer a less invasive, more convenient, accessible, and cost-effective alternative for treating a broad range of diseases, potentially rejuvenating tissues and extending healthspan.
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Affiliation(s)
- Sheng Ding
- New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Global Health Drug Discovery Institute, Beijing 100192, China
- CRE Life Institute, Beijing 100192, China
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41
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Zyoud SH, Shakhshir M. Global research trends on the link between skin ageing and antioxidants: a visualization analysis. Arch Dermatol Res 2025; 317:489. [PMID: 39998681 DOI: 10.1007/s00403-025-03973-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/07/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025]
Affiliation(s)
- Sa'ed H Zyoud
- Poison Control and Drug Information Center (PCDIC), College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Clinical Research Centre, An-Najah National University Hospital, Nablus, 44839, Palestine.
| | - Muna Shakhshir
- Department of Nutrition, An-Najah National University Hospital, Nablus, 44839, Palestine
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Gui T, Liu Y, Fu M, Wu H, Su P, Feng X, Zheng M, Huang Z, Luo X, Boron WF, Chen LM. Redox state of NAD modulates the activation of Na-bicarbonate cotransporter NBCe1-B via IRBIT and L-IRBIT. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2750-0. [PMID: 39985648 DOI: 10.1007/s11427-024-2750-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 09/29/2024] [Indexed: 02/24/2025]
Abstract
Nicotinamide adenine dinucleotide (NAD) is well known as a coenzyme involved in many redox reactions in cellular energy metabolism, or as a substrate for many NAD+-consuming enzymes, including those that generate the second messenger cyclic ADP-ribose or deacetylate proteins (e.g., histones). The role of NAD in non-catalytic proteins is poorly understood. IRBIT and L-IRBIT (the IRBITs) are two cytosolic proteins that are structurally related to dehydrogenases but lack catalytic activity. Instead, by interacting directly with their targets, the IRBITs modulate the function of numerous proteins with important roles, ranging from Ca2+ signaling and intracellular pH (pHi) regulation to DNA metabolism to autophagy. Among the targets of the IRBITs is the Na+-HCO3- cotransporter NBCe1-B, which plays a central role in intracellular pH (pHi) regulation and epithelial electrolyte transport. Here, we demonstrate that NAD modulates NBCe1-B activation by serving as a cofactor of IRBIT or L-IRBIT. Blocking NAD salvage pathway greatly decreases NBCe1-B activation by the IRBITs. Administration of the oxidized form NAD+ enhances, whereas the reduced form NADH decreases NBCe1-B activity. Our study represents the first example in which the redox state of NAD, via IRBIT or L-IRBIT, modulates the function of a membrane transport protein. Our findings reveal a new role of NAD and greatly expand our understanding of NAD biology. Because the NAD redox state fluctuates greatly with metabolic status, our work provides insight into how, via the IRBITs, energy metabolism could affect pHi regulation and many other IRBIT-dependent processes.
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Affiliation(s)
- Tianxiang Gui
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Ying Liu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China.
| | - Mingfeng Fu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Han Wu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Pan Su
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Xuhui Feng
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Mengmeng Zheng
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Zixuan Huang
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China
| | - Xudong Luo
- Institute of Biomedicine and Hubei Key Laboratory of Embryonic Stem Cell Research, College of Basic Medicine, Hubei University of Medicine, Shiyan, 442000, China
| | - Walter F Boron
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Li-Ming Chen
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science & Technology, Huazhong University of Science & Technology, Wuhan, 430074, China.
- Research Institute of Huazhong University of Science and Technology in Shenzhen, Shenzhen, 518063, China.
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Yuan CX, Wang X, Liu Y, Xu TC, Yu Z, Xu B. Electroacupuncture alleviates diabetic peripheral neuropathy through modulating mitochondrial biogenesis and suppressing oxidative stress. World J Diabetes 2025; 16:93130. [PMID: 39959279 PMCID: PMC11718478 DOI: 10.4239/wjd.v16.i2.93130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 09/15/2024] [Accepted: 10/31/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities. The effects mediated by the silent information regulator type 2 homolog-1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy (T2DPN), potentially breaking this harmful cycle. AIM To validate the effectiveness of electroacupuncture (EA) in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1α axis. METHODS The effects of EA were evaluated through assessments of metabolic changes, morphological observations, and functional examinations of the sciatic nerve, along with measurements of inflammation and oxidative stress. Proteins related to the SIRT1/PGC-1α axis, involved in the regulation of mitochondrial biogenesis and antioxidative stress, were detected in the sciatic nerve using Western blotting to explain the underlying mechanism. A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis. RESULTS In addition to diabetes-related metabolic changes, T2DPN rats showed significant reductions in pain threshold after 9 weeks, suggesting abnormal peripheral nerve function. EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats. The SIRT1/PGC-1α axis, which was downregulated in the model group, was upregulated by EA intervention. The endogenous antioxidant system related to the SIRT1/PGC-1α axis, previously inhibited in diabetic rats, was reactivated. A similar trend was observed in inflammatory markers. When SIRT1 was inhibited in diabetic rats, these beneficial effects were abolished. CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats, and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1α axis.
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Affiliation(s)
- Chong-Xi Yuan
- Department of Traditional Chinese Medicine, Suzhou Xiangcheng People's Hospital, Suzhou 215100, Jiangsu Province, China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Xuan Wang
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
- College of Traditional Chinese Medicine, Jiangsu Vocational College of Medicine, Yancheng 224000, Jiangsu Province, China
| | - Yun Liu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Tian-Cheng Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Bin Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Zhang R, Chang L, Shen X, Tang Q, Mu C, Fu S, Bu Z. Metabolomics Analysis Reveals Characteristic Functional Components in Pigeon Eggs. Metabolites 2025; 15:122. [PMID: 39997747 PMCID: PMC11857308 DOI: 10.3390/metabo15020122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/26/2025] Open
Abstract
We aimed to identify the characteristic functional components of pigeon eggs and the differences among pigeon, chicken, and quail eggs. We analyzed the metabolite profiles of three kinds of eggs using an untargeted metabolomics-based approach to better understand the differences in metabolites among pigeon, chicken, and quail eggs. Then, we quantitatively validated the differences in abundance of partial metabolites through a targeted metabolomics-based approach. A total of 692 metabolites were identified in the three types of eggs. A total of 263 significantly differentially abundant metabolites were found between pigeon eggs and chicken eggs, and 263 significantly differentially abundant metabolites were found between pigeon eggs and quail eggs. The metabolites that were significantly more abundant in pigeon eggs than in other eggs were mainly lipids, lipid-like molecules, nucleosides, nucleotides, and their analogues. We identified the eight metabolites that were significantly greater in abundance in pigeon eggs than in chicken eggs and quail eggs and quantitatively validated the differences in abundance of these metabolites. Our study demonstrates that there are more functional components in pigeon eggs than chicken eggs and quail eggs, especially for the prevention and treatment of various disordered glucose and lipid metabolism-related diseases. The discovery of these differentially abundant metabolites paves the way for further research on the unique nutritional functions of pigeon eggs and the further utilization of pigeon egg products.
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Affiliation(s)
| | | | | | | | | | | | - Zhu Bu
- Jiangsu Institute of Poultry Science, Yangzhou 225100, China; (R.Z.); (L.C.); (X.S.); (Q.T.); (C.M.); (S.F.)
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Liu X, Zhao Y, Feng Y, Wang S, Luo A, Zhang J. Ovarian Aging: The Silent Catalyst of Age-Related Disorders in Female Body. Aging Dis 2025:AD.2024.1468. [PMID: 39965250 DOI: 10.14336/ad.2024.1468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
Age-related diseases have emerged as a global concern as the population ages. Consequently, understanding the underlying causes of aging and exploring potential anti-aging interventions is imperative. In females, the ovaries serve as the principal organs responsible for ovulation and the production of female hormones. The aging ovaries are related to infertility, menopause, and associated menopausal syndromes, with menopause representing the culmination of ovarian aging. Current evidence indicates that ovarian aging may contribute to dysfunction across multiple organ systems, including, but not limited to, cognitive impairment, osteoporosis, and cardiovascular disease. Nevertheless, due to the widespread distribution of sex hormone receptors throughout the body, ovarian aging affects not only these specific organs but also influences a broader spectrum of age-related diseases in women. Despite this, the impact of ovarian aging on overall age-related diseases has been largely neglected. This review provides a thorough summary of the impact of ovarian aging on age-related diseases, encompassing the nervous, circulatory, locomotor, urinary, digestive, respiratory, and endocrine systems. Additionally, we have outlined prospective therapeutic approaches for addressing both ovarian aging and age-related diseases, with the aim of mitigating their impacts and preserving women's fertility, physical health, and psychological well-being.
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Affiliation(s)
- Xingyu Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuanqu Zhao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanzhi Feng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Aiyue Luo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jinjin Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China
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Tian L, Gao H, Yao T, Chen Y, Gao L, Han J, Zhu L, Huang H. Interactions between NAD+ metabolism and immune cell infiltration in ulcerative colitis: subtype identification and development of novel diagnostic models. Front Immunol 2025; 16:1479421. [PMID: 39975557 PMCID: PMC11835821 DOI: 10.3389/fimmu.2025.1479421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/16/2025] [Indexed: 02/21/2025] Open
Abstract
Background Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with increasing incidence worldwide. Growing evidence highlights the pivotal role of nicotinamide adenine dinucleotide (NAD+) metabolism in UC pathogenesis, prompting our investigation into the subtype-specific molecular underpinnings and diagnostic potential of NAD+ metabolism-related genes (NMRGs). Methods Transcriptome data from UC patients and healthy controls were downloaded from the GEO database, specifically GSE75214 and GSE87466. We performed unsupervised clustering based on differentially expressed NAD+ metabolism-related genes (DE-NMRGs) to classify UC cases into distinct subtypes. GSEA and GSVA identified potential biological pathways active within these subtypes, while the CIBERSORT algorithm assessed differential immune cell infiltration. Weighted gene co-expression network analysis (WGCNA) combined with differential gene expression analysis was used to pinpoint specific NMRGs in UC. Robust gene features for subtyping and diagnosis were selected using two machine learning algorithms. Nomograms were constructed and their effectiveness was evaluated using receiver operating characteristic (ROC) curves. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to verify gene expression in cell lines. Results In our study, UC patients were classified into two subtypes based on DE-NMRGs expression levels, with Cluster A exhibiting enhanced self-repair capabilities during inflammatory responses and Cluster B showing greater inflammation and tissue damage. Through comprehensive bioinformatics analyses, we identified four key biomarkers (AOX1, NAMPT, NNMT, PTGS2) for UC subtyping, and two (NNMT, PARP9) for its diagnosis. These biomarkers are closely linked to various immune cells within the UC microenvironment, particularly NAMPT and PTGS2, which were strongly associated with neutrophil infiltration. Nomograms developed for subtyping and diagnosis demonstrated high predictive accuracy, achieving area under curve (AUC) values up to 0.989 and 0.997 in the training set and up to 0.998 and 0.988 in validation sets. RT-qPCR validation showed a significant upregulation of NNMT and PARP9 in inflamed versus normal colonic epithelia, underscoring their diagnostic relevance. Conclusion Our study reveals two NAD+ subtypes in UC, identifying four biomarkers for subtyping and two for diagnosis. These findings could suggest potential therapeutic targets and contribute to advancing personalized treatment strategies for UC, potentially improving patient outcomes.
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Affiliation(s)
- Linglin Tian
- Department of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Huiyang Gao
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Tian Yao
- Department of Gastrointestinal Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Center of Clinical Epidemiology and Evidence Based Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yuhao Chen
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Linna Gao
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jingxiang Han
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lanqi Zhu
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - He Huang
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Gastrointestinal Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Nutrition and Food Hygiene, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China
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Gherardi G, Weiser A, Bermont F, Migliavacca E, Brinon B, Jacot GE, Hermant A, Sturlese M, Nogara L, Vascon F, De Mario A, Mattarei A, Garratt E, Burton M, Lillycrop K, Godfrey KM, Cendron L, Barron D, Moro S, Blaauw B, Rizzuto R, Feige JN, Mammucari C, De Marchi U. Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance. Cell Metab 2025; 37:477-495.e11. [PMID: 39603237 DOI: 10.1016/j.cmet.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/24/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024]
Abstract
Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
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Affiliation(s)
- Gaia Gherardi
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Anna Weiser
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland; Molecular Nutritional Medicine, Else Kröner Fresenius Center for Nutritional Medicine, Technische Universität München, 85354 Freising, Germany
| | - Flavien Bermont
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Eugenia Migliavacca
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Benjamin Brinon
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Guillaume E Jacot
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Aurélie Hermant
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Mattia Sturlese
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Leonardo Nogara
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Filippo Vascon
- Department of Biology, University of Padova, 35131 Padova, Italy
| | - Agnese De Mario
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Andrea Mattarei
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Emma Garratt
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Mark Burton
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Karen Lillycrop
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
| | - Keith M Godfrey
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton & University Hospital Southampton NHS Foundation Trust, Southampton, UK; Medical Research Council Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - Laura Cendron
- Department of Biology, University of Padova, 35131 Padova, Italy
| | - Denis Barron
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Stefano Moro
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Bert Blaauw
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Myology Center (CIR-Myo), University of Padova, 35131 Padova, Italy.
| | - Jerome N Feige
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
| | - Cristina Mammucari
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Myology Center (CIR-Myo), University of Padova, 35131 Padova, Italy.
| | - Umberto De Marchi
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produit Nestlé S.A., EPFL Innovation Park, 1015 Lausanne, Switzerland.
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Xu Y, Wang H, Li H, Wei C, Zhu Z, Zhao Y, Zhu J, Lei M, Sun Y, Yang Q. Nicotinamide Riboside Supplementation Alleviates Testicular Aging Induced by Disruption of Qprt-Dependent NAD + De Novo Synthesis in Mice. Aging Cell 2025:e70004. [PMID: 39902575 DOI: 10.1111/acel.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/21/2024] [Accepted: 01/09/2025] [Indexed: 02/05/2025] Open
Abstract
Recent studies have shown that disruptions in the nicotinamide adenine dinucleotide (NAD+) de novo synthesis pathway accelerate ovarian aging, yet its role in spermatogenesis remains largely unknown. In this study, we investigated the impact of the NAD+ de novo synthesis pathway on spermatogenesis by generating Qprt-deficient mice using CRISPR-Cas9 to target quinolinate phosphoribosyl transferase (Qprt), a key enzyme predominantly expressed in spermatocytes. Our results revealed that the deletion of Qprt did not affect NAD+ levels or spermatogenesis in the testes of 3-month-old mice. However, from 6 months of age onward, Qprt-deficient mice exhibited significantly reduced NAD+ levels in the testes compared to wild-type (WT) controls, along with a notable decrease in germ cell numbers and increased apoptosis. Additionally, these mice demonstrated mitochondrial dysfunction in spermatocytes, impaired progression through prophase I of meiosis, defective double-strand break (DSB) repair, and abnormal meiotic sex chromosome inactivation. Importantly, supplementation with the NAD+ precursor nicotinamide riboside (NR) in Qprt-deficient mice restored NAD+ levels and rescued the spermatogenic defects. These findings underscore the critical role of NAD+ de novo synthesis in maintaining NAD+ homeostasis and highlight its importance in meiotic recombination and meiotic sex chromosome inactivation in spermatogenesis.
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Affiliation(s)
- Yining Xu
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huan Wang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Li
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenlu Wei
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenye Zhu
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanqing Zhao
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiajia Zhu
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Min Lei
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingpu Sun
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingling Yang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Obstetrical and Gynecological Diseases (Reproductive Medicine) Clinical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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49
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Sun S, Jiang M, Ma S, Ren J, Liu GH. Exploring the heterogeneous targets of metabolic aging at single-cell resolution. Trends Endocrinol Metab 2025; 36:133-146. [PMID: 39181730 DOI: 10.1016/j.tem.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 08/27/2024]
Abstract
Our limited understanding of metabolic aging poses major challenges to comprehending the diverse cellular alterations that contribute to age-related decline, and to devising targeted interventions. This review provides insights into the heterogeneous nature of cellular metabolism during aging and its response to interventions, with a specific focus on cellular heterogeneity and its implications. By synthesizing recent findings using single-cell approaches, we explored the vulnerabilities of distinct cell types and key metabolic pathways. Delving into the cell type-specific alterations underlying the efficacy of systemic interventions, we also discuss the complexity of integrating single-cell data and advocate for leveraging computational tools and artificial intelligence to harness the full potential of these data, develop effective strategies against metabolic aging, and promote healthy aging.
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Affiliation(s)
- Shuhui Sun
- Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China.
| | - Mengmeng Jiang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Shuai Ma
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium, Beijing 100101, China.
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium, Beijing 100101, China; Key Laboratory of RNA Innovation, Science and Engineering, China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
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50
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Burtscher J, Denti V, Gostner JM, Weiss AK, Strasser B, Hüfner K, Burtscher M, Paglia G, Kopp M, Dünnwald T. The interplay of NAD and hypoxic stress and its relevance for ageing. Ageing Res Rev 2025; 104:102646. [PMID: 39710071 DOI: 10.1016/j.arr.2024.102646] [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: 08/12/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 12/24/2024]
Abstract
Nicotinamide adenine dinucleotide (NAD) is an essential regulator of cellular metabolism and redox processes. NAD levels and the dynamics of NAD metabolism change with increasing age but can be modulated via the diet or medication. Because NAD metabolism is complex and its regulation still insufficiently understood, achieving specific outcomes without perturbing delicate balances through targeted pharmacological interventions remains challenging. NAD metabolism is also highly sensitive to environmental conditions and can be influenced behaviorally, e.g., by exercise. Changes in oxygen availability directly and indirectly affect NAD levels and may result from exposure to ambient hypoxia, increased oxygen demand during exercise, ageing or disease. Cellular responses to hypoxic stress involve rapid alterations in NAD metabolism and depend on many factors, including age, glucose status, the dose of the hypoxic stress and occurrence of reoxygenation phases, and exhibit complex time-courses. Here we summarize the known determinants of NAD-regulation by hypoxia and evaluate the role of NAD in hypoxic stress. We define the specific NAD responses to hypoxia and identify a great potential of the modulation of NAD metabolism regarding hypoxic injuries. In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and - conversely - controlled hypoxia is a potential tool to regulate NAD homeostasis.
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Affiliation(s)
- Johannes Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria.
| | - Vanna Denti
- School of Medicine and Surgery, University of Milano-Bicocca, Vedano al Lambro, MB, Italy
| | - Johanna M Gostner
- Medical University of Innsbruck, Biocenter, Institute of Medical Biochemistry, Innsbruck, Austria
| | - Alexander Kh Weiss
- Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Barbara Strasser
- Ludwig Boltzmann Institute for Rehabilitation Research, Vienna, Austria; Faculty of Medicine, Sigmund Freud Private University, Vienna, Austria
| | - Katharina Hüfner
- Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, University Hospital for Psychiatry II, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Giuseppe Paglia
- School of Medicine and Surgery, University of Milano-Bicocca, Vedano al Lambro, MB, Italy
| | - Martin Kopp
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Tobias Dünnwald
- Institute for Sports Medicine, Alpine Medicine and Health Tourism (ISAG), UMIT TIROL - Private University for Health Sciences and Health Technology, Hall in Tirol, Austria
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