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Li DY, Liu L, Liu DQ, Zhang LQ, Zhou YQ, Mei W. Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance. Int Immunopharmacol 2025; 158:114863. [PMID: 40359888 DOI: 10.1016/j.intimp.2025.114863] [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: 02/19/2025] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/15/2025]
Abstract
Neuropathic pain is a chronic and devastating clinical problem with few effective treatments. Mitochondrial dysfunction plays a critical role in the pathological process of neuropathic pain. Recently, mitochondrial calcium overload has been identified as the initial part of mitochondrial dysfunction, such as dynamic imbalance and excessive superoxide. Mitochondrial Ca2+ uniporter (MCU) serves as the primary channel for mitochondrial Ca2+ uptake, and Na+/Ca2+ exchanger (NCLX) is the dominant mechanism for mitochondrial calcium ion excretion. Herein, we investigated the role of mitochondrial calcium overload and its regulated channels in a rat model of neuropathic pain. Our results showed significant mitochondrial calcium overload in the spinal dorsal horn of SNI rats, accompanied by the upregulation of MCU and downregulation of NCLX. MCU inhibition or NCLX overexpression remarkably relieved mechanical allodynia and mitochondrial high calcium levels in SNI rats. Conversely, upregulation of MCU or downregulation of NCLX induced mitochondrial calcium overload and mechanical allodynia in naïve rats. We also observed excessive mitochondrial fission and reduced fusion in the spinal cord of SNI rats, which could be mitigated by MCU inhibition and NCLX overexpression, respectively. Notably, mitochondrial fission inhibitor or mitochondrial fusion promoter effectively reversed the MCU overexpression or NCLX knockdown-induced mechanical allodynia. Collectively, our data indicate that the MCU/NCLX-mediated mitochondrial calcium overload drives excessive mitochondrial fission, which promotes the progression of SNI.
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Affiliation(s)
- Dan-Yang Li
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Lin Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Long-Qing Zhang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China.
| | - Wei Mei
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China.
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Li J, Lei P, Jiang Y, Ji X, Meng F. PmRad23d Interacts With PmSRC2 and PmCAR4 to Mediate the Abscisic Acid-Dependent Drought Response in Prunus mira Koehne. PLANT, CELL & ENVIRONMENT 2025; 48:4178-4195. [PMID: 39924854 DOI: 10.1111/pce.15418] [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: 04/13/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 02/11/2025]
Abstract
Drought significantly restricts the growth and quality of fruit trees Prunus mira, an ancient wild peach species, exhibits strong drought tolerance; however, the detailed response mechanism remains unknown. The nucleic acid excision repair factor radiation sensitivity 23d (Rad23d) plays a crucial role in plant stress, growth, and development. However, its specific mechanism of action in P. mira is unclear. Here, we report that PmRad23d positively contributes to the abscisic acid (ABA)-dependent drought response in P. mira. Overexpression of PmRad23d enhanced drought tolerance and ABA sensitivity, whereas inhibiting PmRad23d expression reduced the plant's drought tolerance and ABA sensitivity. PmRad23d was found to interact with the C2 domain at the N-terminus of PmSRC2 and PmCAR4, respectively. Together, they regulate the expression of ABA- and drought-related genes, activate ABA signaling, and induce stomatal closure, ultimately enhancing drought resistance in plants. Our findings shed light on the ABA-dependent drought response mechanism of PmRad23d, providing a basis for further exploration of drought tolerance in P. mira. Additionally, this study identifies potential candidate genes for enhancing peach germplasm resources and breeding drought-tolerant cultivars.
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Affiliation(s)
- Jianxin Li
- College of Forestry and Grassland, Jilin Provincial Key Laboratory of Tree and Grass Genetics and Breeding, College of Horticulture, Jilin Agriculture University, Changchun, China
| | - Pei Lei
- College of Forestry and Grassland, Jilin Provincial Key Laboratory of Tree and Grass Genetics and Breeding, College of Horticulture, Jilin Agriculture University, Changchun, China
| | - Yaxuan Jiang
- College of Life Science, Northeast Forestry University, Harbin, China
| | - Ximei Ji
- College of Forestry and Grassland, Jilin Provincial Key Laboratory of Tree and Grass Genetics and Breeding, College of Horticulture, Jilin Agriculture University, Changchun, China
| | - Fanjuan Meng
- College of Forestry and Grassland, Jilin Provincial Key Laboratory of Tree and Grass Genetics and Breeding, College of Horticulture, Jilin Agriculture University, Changchun, China
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Fan H, Yang Z, Ying H, Zhao J, Wang X, Gong J, Li L, Liu X, Gong T, Ke Q, Zhuang L, Liang P. iPSC-derived cardiomyocytes and engineered heart tissues reveal suppressed JAK2/STAT3 signaling in LMNA-related emery-dreifuss muscular dystrophy. Redox Biol 2025; 83:103638. [PMID: 40286437 PMCID: PMC12059692 DOI: 10.1016/j.redox.2025.103638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
LMNA mutation related Emery-Dreifuss muscular dystrophy (LMNA-related EDMD), is a rare genetic disorder often involving life-threatening cardiac complications. However, the molecular links between LMNA mutations and their related EDMD cardiac phenotypes have remained unclear. Here, using EDMD patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we link the LMNA L204P mutation with the pathogenic phenotypes of arrhythmia and contractile dysfunction. Using multi-omics analysis, we then show that LMNA L204P results in decreased chromatin accessibility, leading to the downregulation of JAK2 in EDMD iPSC-CMs. Mechanistically, JAK2/STAT3 signaling pathway suppression in EDMD iPSC-CMs is shown to cause mitochondrial dysfunction and oxidative stress, ultimately resulting in the above phenotypes. Conversely, pharmacological or genetic activation of JAK2/STAT3 signaling effectively rescues both the arrhythmic and contractile dysfunction phenotypes in EDMD iPSC-CMs via improvements in mitochondrial function. In addition, whilst EDMD engineered heart tissues (EHTs) display dysfunctional contractile force generation, this can also be significantly alleviated by STAT3 activation. Taken together, we present chromatin compartment change-mediated JAK2/STAT3 suppression as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating the JAK2/STAT3 signaling pathway may hold the potential to serve as a novel therapeutic strategy for this condition.
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Affiliation(s)
- Hangping Fan
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Zongkuai Yang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Hangying Ying
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Jiuxiao Zhao
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xiaochen Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Junhao Gong
- Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518052, China
| | - Lingying Li
- Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518052, China
| | - Xujie Liu
- Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518052, China
| | - Tingyu Gong
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, China.
| | - Qing Ke
- Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lenan Zhuang
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Ping Liang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.
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Baka T, Moore J, Qin F, Yurista SR, Zhang A, He H, Chambers JM, Croteau D, Goel RK, Smith H, Wang MC, Chen CS, Hobai IA, Rombaldova M, Kuda O, Tardiff JC, Balschi JA, Pimentel DR, Seidman CE, Seidman JG, Emili A, Colucci WS, Luptak I. Empagliflozin enhances metabolic efficiency and improves left ventricular hypertrophy in a hypertrophic cardiomyopathy mouse model. Eur Heart J 2025:ehaf324. [PMID: 40396194 DOI: 10.1093/eurheartj/ehaf324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 11/30/2024] [Accepted: 04/29/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND AND AIMS Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation. METHODS Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes. RESULTS Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes. CONCLUSIONS Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.
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Affiliation(s)
- Tomas Baka
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Jarrod Moore
- Center for Network Systems Biology, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Fuzhong Qin
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Salva R Yurista
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Aifeng Zhang
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Huamei He
- Physiological NMR Core Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jordan M Chambers
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Dominique Croteau
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Raghuveera K Goel
- Center for Network Systems Biology, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Hunter Smith
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Miranda C Wang
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- Harvard-MIT Program in Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Christopher S Chen
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Ion A Hobai
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Martina Rombaldova
- Laboratory of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Ondrej Kuda
- Laboratory of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jil C Tardiff
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
- Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - James A Balschi
- Physiological NMR Core Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - David R Pimentel
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Christine E Seidman
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | | | - Andrew Emili
- Center for Network Systems Biology, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Wilson S Colucci
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
| | - Ivan Luptak
- Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA
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5
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Abdollahian P, Sui K, Li G, Berg RW, Meneghetti M, Markos C. Evaluating safe infrared neural stimulation parameters: Calcium dynamics and excitotoxicity thresholds in dorsal root ganglia neurons. J Neurosci Methods 2025; 421:110484. [PMID: 40383236 DOI: 10.1016/j.jneumeth.2025.110484] [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: 02/09/2025] [Revised: 04/29/2025] [Accepted: 05/15/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND As a promising neural stimulation technique, infrared neural stimulation (INS) has recently gained significant attention due to its ability to stimulate neuronal activities without needing exogenous agents. NIR light is absorbed by water of the tissue producing local thermal effects. Therefore, INS is a suitable candidate for localized and targeted neural stimulation. However, despite the wide variety of research studies on INS applications, limited studies have focused on identifying and optimizing the stimulation parameters to avoid potential excitotoxicity. This study evaluates the dorsal root ganglia (DRG) neurons' response under INS with varying intensities and illumination time. NEW METHOD Here, DRG neurons are cultured and labeled by the CamkII-GCaMP6s virus. The neurons were exposed to infrared laser pulses (2.01 µm wavelength, different powers of 2.5 mW, 5 mW, 7.5 mW, and 10 mW) for durations of 300 s and 400 s. The light was delivered through a silica optical fiber aligned and stabilized within a free-space optical setup. Simultaneous with INS, neuronal activity was evaluated by calcium imaging through a fluorescence microscope. This method allowed real-time monitoring of neuronal calcium dynamics under different stimulation conditions, preparing an overview of the safe thresholds for INS. RESULTS It was found that calcium saturation has happened for the neurons in exposure to light intensities (7.5 mW and 10 mW) for 300 s, representing potential excitotoxicity. In contrast, with the same exposure time, lower light intensities (2.5 mW and 5 mW) did not show significant signs of calcium saturation or neuronal damage. Moreover, in some neuronal networks, the peripheral neurons of the illuminated area revealed indirect activation, indicating inter-neuronal communication effects. COMPARISON WITH EXISTING METHODS Compared to previous studies that have explored the use of INS on DRG neurons, our work introduces a systematic approach to evaluate the light intensity-dependent INS, while addressing the critical issue of potential thermal injury. While earlier research has demonstrated the ability of INS to modulate neuronal activity and reduce electrical artifacts in electrophysiological recordings, concerns regarding excitotoxicity and neuronal damage remain insufficiently investigated. We examined a range of laser intensities (2.5 mW to 10 mW) to determine the safe exposure thresholds and optimize the photothermal impact. Furthermore, by utilizing CamKII-GCaMP6s virus-modified neurons, we enhance sensitivity in detecting calcium influx, providing a more precise evaluation of neuronal responses to INS. Therefore, here, we provide the knowledge for safe INS. CONCLUSIONS This work identifies the required laser stimulation parameters, particularly intensity and illumination time of the tissue for efficient and safe INS. We concluded that higher intensities (7.5 mW and 10 mW) can cause calcium saturation and potential neuronal injury, while lower intensities (2.5 mW and 5 mW) are safe for prolonged exposure. Moreover, the observed peripheral neuronal activation suggests indirect stimulation through inter-neuronal connections, offering further insights into the effects of INS on neural networks. These findings contribute valuable information towards safe neuromodulation methods with potential use in clinical settings.
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Affiliation(s)
- Parinaz Abdollahian
- DTU Electro, Department of Electrical and Photonics Engineering, Technical University of Denmark, Lyngby, Denmark; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Kunyang Sui
- DTU Electro, Department of Electrical and Photonics Engineering, Technical University of Denmark, Lyngby, Denmark; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Guanghui Li
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Rune W Berg
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Marcello Meneghetti
- DTU Electro, Department of Electrical and Photonics Engineering, Technical University of Denmark, Lyngby, Denmark; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Christos Markos
- DTU Electro, Department of Electrical and Photonics Engineering, Technical University of Denmark, Lyngby, Denmark.
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6
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Wang X, Xiong X. Mitochondrial Reactive Oxygen Species (mROS) Generation and Cancer: Emerging Nanoparticle Therapeutic Approaches. Int J Nanomedicine 2025; 20:6085-6119. [PMID: 40385494 PMCID: PMC12085131 DOI: 10.2147/ijn.s510972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 04/24/2025] [Indexed: 05/20/2025] Open
Abstract
Mitochondrial reactive oxygen species (mROS) are generated as byproducts of mitochondrial oxidative phosphorylation. Changes in mROS levels are involved in tumorigenesis through their effects on cancer genome instability, sustained cancer cell survival, metabolic reprogramming, and tumor metastasis. Recent advances in nanotechnology offer a promising approach for precise regulation of mROS by either enhancing or depleting mROS generation. This review examines the association between dysregulated mROS levels and key cancer hallmarks. We also discuss the potential applications of mROS-targeted nanoparticles that artificially manipulate ROS levels in the mitochondria to achieve precise delivery of antitumor drugs.
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Affiliation(s)
- Xinyao Wang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Queen Mary School of Nanchang University, Nanchang, People’s Republic of China
| | - Xiangyang Xiong
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, People’s Republic of China
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7
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Pepin ME, Konrad PJM, Nazir S, Bazgir F, Maack C, Nickel A, Gorman J, Hohl M, Schreiter F, Dewenter M, de Britto Chaves Filho A, Schulze A, Karlstaedt A, Frey N, Seidman C, Seidman J, Backs J. Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF. Circ Res 2025. [PMID: 40340422 DOI: 10.1161/circresaha.125.326154] [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: 01/10/2025] [Revised: 04/14/2025] [Accepted: 04/21/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. METHODS Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6-10). RESULTS Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e' (42.8 versus 21.5, P=1.2×10-10), E/A (2.3 versus 1.4, P=4.1×10-2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10-3), and myocardial fibrosis (P=2.3×10-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10-3) and a 38.8% reduction in glutathione:GSSG (P=2.6×10-2) among Nnt+/+ mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis. CONCLUSIONS Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.
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Affiliation(s)
- Mark E Pepin
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
- Department of Genetics, Harvard Medical School, Boston, MA (M.E.P., J.G., C.S., J.S.)
- Broad Institute of Harvard and MIT, Boston, MA (M.E.P.)
- Division of Cardiovascular Medicine, Stanford University Hospital, CA (M.E.P.)
| | - Philipp J M Konrad
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine III, Heidelberg University Hospital, Germany. (P.J.M.K., N.F.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
| | - Sumra Nazir
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
| | - Farhad Bazgir
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
| | - Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg, Germany (C.M., A.N.)
- Medical Clinic I, University Clinic Würzburg, Germany (C.M.)
| | - Alexander Nickel
- Comprehensive Heart Failure Center, University Clinic Würzburg, Germany (C.M., A.N.)
| | - Joshua Gorman
- Department of Genetics, Harvard Medical School, Boston, MA (M.E.P., J.G., C.S., J.S.)
| | - Mathias Hohl
- Department of Internal Medicine III, Saarland University Hospital and Saarland University, Homburg/Saar, Germany (M.H.)
| | - Friederike Schreiter
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
| | - Matthias Dewenter
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), Germany and Heidelberg University, Germany (M.D., J.B.)
| | | | - Almut Schulze
- Division of Tumor Metabolism and Microenvironment, German Cancer Research Center, Heidelberg (A.d.B.C.F., A.S.)
| | - Anja Karlstaedt
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (A.K.)
| | - Norbert Frey
- Department of Internal Medicine III, Heidelberg University Hospital, Germany. (P.J.M.K., N.F.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
| | - Christine Seidman
- Department of Genetics, Harvard Medical School, Boston, MA (M.E.P., J.G., C.S., J.S.)
| | - Jonathan Seidman
- Department of Genetics, Harvard Medical School, Boston, MA (M.E.P., J.G., C.S., J.S.)
| | - Johannes Backs
- Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Heidelberg University, Germany. (J.B.)
- Department of Internal Medicine VIII, Heidelberg University Hospital, Germany. (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., J.B.)
- German Center for Cardiovascular Research (DZHK) (M.E.P., P.J.M.K., S.N., F.B., F.S., M.D., N.F., J.B.)
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), Germany and Heidelberg University, Germany (M.D., J.B.)
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8
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Kou P, Zhang YC, Wang H, Mo LL, Gu JJ, Yu F. NO Activates the Triterpenoid Biosynthetic Pathway in Inonotus obliquus Through Multilevel Signaling Regulation to Enhance Its Production. Int J Mol Sci 2025; 26:4561. [PMID: 40429706 DOI: 10.3390/ijms26104561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Triterpenoids are the bioactive components in Inonotus obliquus with extensive medicinal prospects, but their low content in fermentation production is the main limiting factor for their application. This study focuses on nitric oxide (NO), an important signaling molecule within organisms, aiming to explore its inducing effect on the synthesis of triterpenes in I. obliquus and the potential signaling transduction mechanisms involved. Compared with the control group, the content of representative triterpenoid betulin increased by 70.59% after adding the NO donor sodium nitroprusside. Gene expression level detection revealed that NO mainly promotes its biosynthesis by activating the transcription of key enzyme genes in the downstream pathway of betulin biosynthesis, thereby increasing its abundance. Tracing upstream, the NO signal was found to induce the upregulation of genes related to cellular antioxidant and calcium ion signaling pathways. Notably, IoCAMP responded strongly to the NO signal, participating in the regulation of cytoplasmic Ca2+ concentration by altering the Ca2+ concentration of mitochondria together with IoCATP and IoCALM. Additionally, the signaling of changes in Ca2+ concentrations is likely to crosstalk with the reactive oxygen species (ROS) signaling pathway. The increase in enzyme activity of IoNOX after NO induction confirmed the activation of the ROS signaling pathway. It works in synergy with IoSOD and IoCAT to reduce oxidative damage and promote downstream triterpenoid biosynthesis. This study not only contributes to clarify the signaling pathways regulating NO-mediated triterpenoid biosynthesis but also provides a theoretical basis for the efficient production of triterpenoid active components in I. obliquus.
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Affiliation(s)
- Ping Kou
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
| | - Yu-Chi Zhang
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
| | - He Wang
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
| | - Li-Li Mo
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
| | - Jun-Jiao Gu
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
| | - Fang Yu
- School of Biological Engineering, Dalian Polytechnic University, Dalian 116034, China
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9
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Gong G, Wan W, Zhang X, Chen X, Yin J. Management of ROS and Regulatory Cell Death in Myocardial Ischemia-Reperfusion Injury. Mol Biotechnol 2025; 67:1765-1783. [PMID: 38852121 DOI: 10.1007/s12033-024-01173-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: 12/13/2023] [Accepted: 04/02/2024] [Indexed: 06/10/2024]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.
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Affiliation(s)
- Ge Gong
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Wenhui Wan
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Xinghu Zhang
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 211002, China
| | - Xiangxuan Chen
- Department of Cardiology, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 211100, China.
| | - Jian Yin
- Department of Orthopedics, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, 211100, China.
- Department of Orthopedics, Jiangning Clinical Medical College of Jiangsu Medical Vocational College, Nanjing, 211100, China.
- Department of Orthopedics, Jiangning Clinical Medical College of Nanjing Medical University Kangda College, Nanjing, 211100, China.
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10
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Wu YJ, Yang YR, Yan YL, Yang HY, Du JR. Targeting mitochondrial dysfunction: an innovative strategy for treating renal fibrosis. Mol Cell Biochem 2025:10.1007/s11010-025-05297-w. [PMID: 40299265 DOI: 10.1007/s11010-025-05297-w] [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: 02/12/2025] [Accepted: 04/23/2025] [Indexed: 04/30/2025]
Abstract
The incidence and hospitalization rate of kidney disease, especially end-stage renal disease, have increased significantly, which seriously endangers the health of patients. Mitochondria are the core organelles of cellular energy metabolism, and their dysfunction can lead to kidney energy supply insufficiency and oxidative stress damage, which has become a global public health problem. Studies have shown that the disturbance of mitochondrial quality control mechanisms, including mitochondrial dynamics, autophagy, oxidative stress regulation and biosynthesis, is closely related to the occurrence and development of renal fibrosis (RF). As a multicellular pathological process, RF involves the injury and shedding of podocytes, the transdifferentiation of renal tubular epithelial cells, the activation of fibroblasts, and the infiltration of macrophages, among which the mitochondrial dysfunction plays an important role. This review systematically elaborates the molecular mechanisms of mitochondrial damage during RF progression, aiming to provide theoretical foundations for developing novel therapeutic strategies to delay RF advancement.
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Affiliation(s)
- Yi-Jin Wu
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Yan-Rong Yang
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Ya-Ling Yan
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Han-Yinan Yang
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Jun-Rong Du
- Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
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11
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Zhang JJ, Cheng L, Qiao Q, Xiao XL, Lin SJ, He YF, Sha RL, Sha J, Ma Y, Zhang HL, Ye XR. Adenosine triphosphate-induced cell death in heart failure: Is there a link? World J Cardiol 2025; 17:105021. [PMID: 40308621 PMCID: PMC12038699 DOI: 10.4330/wjc.v17.i4.105021] [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: 01/10/2025] [Revised: 02/22/2025] [Accepted: 04/02/2025] [Indexed: 04/21/2025] Open
Abstract
Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.
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Affiliation(s)
- Jing-Jing Zhang
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Lu Cheng
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Qian Qiao
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
| | - Xue-Liang Xiao
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Shao-Jun Lin
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yue-Fang He
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Ren-Luo Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Jun Sha
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Yin Ma
- Department of Critical Care Medicine, Ninglang Yi Autonomous County People's Hospital, Lijiang 674300, Yunnan Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia.
| | - Xue-Rui Ye
- Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy Medical Sciences, Kunming 650000, Yunnan Province, China
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12
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Sun L, Leng R, Liu M, Su M, He Q, Zhang Z, Liu Z, Wang Z, Jiang H, Wang L, Guo S, Xu Y, Huo Y, Miller CL, Banach M, Huang Y, Evans PC, Pelisek J, Camici GG, Berk BC, Offermanns S, Ge J, Xu S, Weng J. Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake. J Clin Invest 2025; 135:e181928. [PMID: 40166941 PMCID: PMC11957702 DOI: 10.1172/jci181928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 01/31/2025] [Indexed: 04/02/2025] Open
Abstract
Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca2+ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell-specific Micu1 knockout mice (Micu1ECKO) and attenuated in endothelial cell-specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated development of atherosclerosis, while Micu1ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca2+ influx, thereby decreasing the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.
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Affiliation(s)
- Lu Sun
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Ruixue Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Monan Liu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Meiming Su
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Qingze He
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhidan Zhang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhenghong Liu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhihua Wang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Hui Jiang
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Shuai Guo
- School of Basic Medical Sciences, State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yiming Xu
- School of Basic Medical Sciences, State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuqing Huo
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Clint L. Miller
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Paul C. Evans
- Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Jaroslav Pelisek
- Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Giovanni G. Camici
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Bradford C. Berk
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, Anhui, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, Anhui, China
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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13
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El-Shiekh RA, Atwa AM, Elgindy AM, Ibrahim KM, Senna MM, Ebid N, Mustafa AM. Current Perspective and Mechanistic Insights on α-Hederin for the Prevention and Treatment of Several Noncommunicable Diseases. Chem Biodivers 2025; 22:e202402289. [PMID: 39607970 DOI: 10.1002/cbdv.202402289] [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: 09/13/2024] [Revised: 11/12/2024] [Accepted: 11/28/2024] [Indexed: 11/30/2024]
Abstract
α-Hederin, a naturally occurring compound found in various plant sources, has remarkable properties and therapeutic potential for human health. One notable attribute is its potent anti-inflammatory activity, such as in arthritis, asthma, and inflammatory bowel disease. In addition, it exhibits notable antioxidant effects implicated in the development of chronic diseases, including cardiovascular disorders and certain types of cancer. According to research, it may limit the growth and proliferation of cancer cells, making it a possible candidate for future cancer treatments. Moreover, it is a promising neuroprotective agent and enhances cognitive function, suggesting its potential in the treatment of neurodegenerative illnesses like Alzheimer's and Parkinson's disease. The multifaceted benefits of α-hederin make it an intriguing compound with significant therapeutic implications. As research progresses, exploring its mechanisms of action and clinical applications is warranted. Harnessing the potential of α-hederin may pave the way for innovative treatment strategies and improved outcomes in the battle against various chronic diseases.
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Affiliation(s)
- Riham A El-Shiekh
- Faculty of Pharmacy, Department of Pharmacognosy, Cairo University, Cairo, Egypt
| | - Ahmed M Atwa
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Ayen Iraqi University, Thi-Qar, Iraq
| | - Ali M Elgindy
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Kawther Magdy Ibrahim
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Mohamed Magdy Senna
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Nouran Ebid
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
| | - Aya M Mustafa
- Faculty of Pharmacy, Department of Pharmacology and Toxicology, Egyptian Russian University, Cairo, Egypt
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14
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Zaglia T, Campo A, Moro N, Di Mauro V, Borile G, Menabò R, Antonucci S, Poli L, Campesan M, Carullo P, Martinazzi S, Luciani GB, Hammer K, Pesce P, Bariani R, Faggian G, Maier L, Ventura L, De Stefani D, Mammucari C, Rizzuto R, Catalucci D, Di Lisa F, Mongillo M. Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning Akt. Proc Natl Acad Sci U S A 2025; 122:e2402639122. [PMID: 40067892 PMCID: PMC11929399 DOI: 10.1073/pnas.2402639122] [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: 02/11/2024] [Accepted: 01/27/2025] [Indexed: 03/25/2025] Open
Abstract
Regulation of mitochondrial Ca2+ uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca2+ handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca2+ uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca2+ uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca2+ uptake in cardiomyocytes entails "mitochondrion-to-cytoplasm" signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca2+ uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca2+/ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.
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Affiliation(s)
- Tania Zaglia
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
- Interdepartmental Research Center of Myology, Padova35131, Italy
| | - Antonio Campo
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
| | - Nicola Moro
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
| | - Vittoria Di Mauro
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
| | - Giulia Borile
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
| | - Roberta Menabò
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | | | - Laura Poli
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
| | - Marika Campesan
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | - Pierluigi Carullo
- Istituti di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan20089, Italy
- National Research Council, Institute of Genetics and Biomedical Research, Milan Unit, Milan20138, Italy
| | - Sara Martinazzi
- Division of Cardiac Surgery, University of Verona, Verona37126, Italy
| | | | - Karin Hammer
- Internal Medicine II, University Hospital Regensburg, Regensburg93053, Germany
| | - Paola Pesce
- Department of Medicine, University of Padova, Padova35128, Italy
| | - Riccardo Bariani
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova35131, Italy
| | - Giuseppe Faggian
- Division of Cardiac Surgery, University of Verona, Verona37126, Italy
| | - Lars Maier
- Internal Medicine II, University Hospital Regensburg, Regensburg93053, Germany
| | - Laura Ventura
- Department of Statistical Sciences, University of Padova, Padova35121, Italy
| | - Diego De Stefani
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | - Cristina Mammucari
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | - Daniele Catalucci
- Istituti di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan20089, Italy
- National Research Council, Institute of Genetics and Biomedical Research, Milan Unit, Milan20138, Italy
| | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
| | - Marco Mongillo
- Department of Biomedical Sciences, University of Padova, Padova35131, Italy
- Veneto Institute of Molecular Medicine, Padova35129, Italy
- Interdepartmental Research Center of Myology, Padova35131, Italy
- National Research Council Institute of Neuroscience, Padova35121, Italy
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15
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Nawaz S, Kulyar MF, Mo Q, Zhang Z, Quan C, Iqbal M, Imad EF, Li J. Thiram-induced ER stress promotes mitochondrial calcium signaling and NLRP3 inflammasome activation in a tissue specific manner. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 293:118026. [PMID: 40080941 DOI: 10.1016/j.ecoenv.2025.118026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/18/2025] [Accepted: 03/06/2025] [Indexed: 03/15/2025]
Abstract
Thiram, a broadly used dithiocarbamate fungicide, exaggerates endoplasmic reticulum (ER) stress and interferes with mitochondrial function, thus disrupting cellular homeostasis. Here, we intend to identify the molecular actions of thiram at the mitochondrial-associated ER membranes (MAMs) that lead to the induction of ER stress and mitochondrial calcium overload in both liver and bone tissues. Taken together, we show that thiram-induced remodelling of MAMs leads to huge ER stress and calcium dysregulation. Histological and immunohistochemical examinations revealed that thiram-induced hyperactivation of IP3R1 mediated the release of endoplasmic reticulum calcium, but mitochondrial calcium uptake was mediated by voltage-dependent anion channels VDAC1. This stress response was characterized by increased glucose regulated protein 78 (GRP78) expression in the liver and tibial growth plates (GP). In this respect, a new liver-bone axis was delineated for thiram-induced ER stress. More interestingly, the activation of NLRP3 inflammasome was very striking in tibial growth plates but not in liver tissues. Hence, the results highlight the systemic effects of thiram by identifying a critical metabolic junction that might play a role in metabolic disorders such as tibial dyschondroplasia and related bone disorders, e.g., osteoarthritis and osteoporosis.
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Affiliation(s)
- Shah Nawaz
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Md F Kulyar
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
| | - Quan Mo
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
| | - Zhao Zhang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Chuxian Quan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Mudassar Iqbal
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - El Fatihi Imad
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Jiakui Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
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16
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Chen Y, Zhang X, Liu M, Zhang Y, Li S, Zhou L, Yang X, Chen X, Yue M, Qu Q, Qiu Y, Shi J. The association between basal metabolic rate and ischemic stroke: a Mendelian randomization study. Front Neurol 2025; 16:1434740. [PMID: 40098688 PMCID: PMC11912940 DOI: 10.3389/fneur.2025.1434740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 01/16/2025] [Indexed: 03/19/2025] Open
Abstract
Objective This study aims to elucidate the potential impact of basal metabolic rate on ischemic stroke at the genetic prediction level through a two-sample Mendelian randomization analysis. Methods Using summary data from genome-wide association studies, we obtained information on basal metabolic rate and ischemic stroke from a large-scale genome-wide association study. MR analysis used inverse variance weighting, weighted median, MR-Egger, simple mode, and weighted estimation. Sensitivity analyses, including the MR-Egger method, MR-PRESSO, Cochran's Q-test, and leave-one-out assessment, were performed to assess the reliability of the results. Results Genetic susceptibility to basal metabolic rate was significantly associated with ischemic stroke in multiple models, including the inverse variance weighting model (OR, 1.108 [95% CI: 1.005-1.221]; p = 0.0392), the weighted median method (OR, 1.179 [95% CI: 1.020-1.363]; p = 0.0263), and MR-Egger (OR, 1.291 [95% CI: 1.002-1.663]; p = 0.0491). These results indicate a positive causal relationship between basal metabolic rate and ischemic stroke. The MR-Egger intercept and Cochran's Q-test indicated the absence of heterogeneity and horizontal pleiotropy in the analyses of basal metabolic rate and ischemic stroke. Conclusion The MR analysis suggests a positive correlation between basal metabolic rate and ischemic stroke.
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Affiliation(s)
- Yizhou Chen
- Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Xiahui Zhang
- Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Meifang Liu
- Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Yi Zhang
- Qingdao Central Hospital, Qingdao, China
| | - Song Li
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Li Zhou
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Xiaolin Yang
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Xu Chen
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Mengqi Yue
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Qi Qu
- Department of Medicine, Hubei Minzu University, Enshi, China
| | - Yong Qiu
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Jing Shi
- Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, China
- Department of Acupuncture and Moxibustion, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
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17
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Jin S, Wu J, Wang C, He Y, Tang Y, Huang L, Zhou H, Liu D, Wu Z, Feng Y, Chen H, He X, Yang G, Peng C, Qiu J, Li T, Yin Y, He L. Aspartate Metabolism-Driven Gut Microbiota Dynamics and RIP-Dependent Mitochondrial Function Counteract Oxidative Stress. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2404697. [PMID: 39874197 PMCID: PMC11923965 DOI: 10.1002/advs.202404697] [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: 05/01/2024] [Revised: 12/18/2024] [Indexed: 01/30/2025]
Abstract
Aspartate (Asp) metabolism-mediated antioxidant functions have important implications for neonatal growth and intestinal health; however, the antioxidant mechanisms through which Asp regulates the gut microbiota and influences RIP activation remain elusive. This study reports that chronic oxidative stress disrupts gut microbiota and metabolite balance and that such imbalance is intricately tied to the perturbation of Asp metabolism. Under normal conditions, in vivo and in vitro studies reveal that exogenous Asp improves intestinal health by regulating epithelial cell proliferation, nutrient uptake, and apoptosis. During oxidative stress, Asp reduces Megasphaera abundance while increasing Ruminococcaceae. This reversal effect depends on the enhanced production of the antioxidant eicosapentaenoic acid mediated through Asp metabolism and microbiota. Mechanistically, the application of exogenous Asp orchestrates the antioxidant responses in enterocytes via the modulation of the RIP3-MLKL and RIP1-Nrf2-NF-κB pathways to eliminate excessive reactive oxygen species and maintain mitochondrial functionality and cellular survival. These results demonstrate that Asp signaling alleviates oxidative stress by dynamically modulating the gut microbiota and RIP-dependent mitochondrial function, providing a potential therapeutic strategy for oxidative stress disease treatment.
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Affiliation(s)
- Shunshun Jin
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Department of Animal ScienceUniversity of ManitobaWinnipegManitobaR3T2N2Canada
| | - Jian Wu
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Chenyu Wang
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Yiwen He
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Yulong Tang
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Le Huang
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Hui Zhou
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Di Liu
- Heilongjiang Academy of Agricultural SciencesHarbin150086China
| | - Ziping Wu
- Agricultural and Food EconomicsQueen's University BelfastNorthern IrelandBT95PXUK
| | - Yanzhong Feng
- Heilongjiang Academy of Agricultural SciencesHarbin150086China
| | - Heshu Chen
- Heilongjiang Academy of Agricultural SciencesHarbin150086China
| | - Xinmiao He
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Heilongjiang Academy of Agricultural SciencesHarbin150086China
| | - Guan Yang
- Department of Infectious Diseases and Public HealthCity University of Hong KongKowloonHong Kong SAR999077China
| | - Can Peng
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Jiazhang Qiu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infections DiseaseKey Laboratory for Zoonosis Research of the Ministry of EducationCollege of Veterinary MedicineJilin UniversityChangchun130025China
| | - Tiejun Li
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
| | - Yulong Yin
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
- Yuelushan LaboratoryNo. 246 Hongqi Road, Furong DistrictChangsha410128China
| | - Liuqin He
- Hunan Provincial Key Laboratory of Animal Intestinal Function and RegulationHunan international joint laboratory of Animal Intestinal Ecology and HealthLaboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangsha410081China
- Key Laboratory of Agro‐ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessChangsha410125China
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18
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Chang Y, Zou Q. Mitochondrial calcium homeostasis and atrial fibrillation: Mechanisms and therapeutic strategies review. Curr Probl Cardiol 2025; 50:102988. [PMID: 39828107 DOI: 10.1016/j.cpcardiol.2025.102988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Atrial fibrillation (AF) is tightly linked to mitochondrial dysfunction, calcium (Ca²⁺) imbalance, and oxidative stress. Mitochondrial Ca²⁺ is essential for regulating metabolic enzymes, maintaining the tricarboxylic acid (TCA) cycle, supporting the electron transport chain (ETC), and producing ATP. Additionally, Ca²⁺ modulates oxidative balance by regulating antioxidant enzymes and reactive oxygen species (ROS) clearance. However, Ca²⁺ homeostasis disruptions, particularly overload, result in excessive ROS production, mitochondrial permeability transition pore (mPTP) opening, and oxidative stress-induced damage. These changes lead to mitochondrial dysfunction, Ca²⁺ leakage, and cardiomyocyte apoptosis, driving AF progression and atrial remodeling. Therapeutically, targeting mitochondrial Ca²⁺ homeostasis shows promise in mitigating AF. Moderate Ca²⁺ regulation enhances energy metabolism, stabilizes mitochondrial membrane potential, and bolsters antioxidant defenses by upregulating enzymes like superoxide dismutase and glutathione peroxidase. This reduces ROS generation and facilitates clearance. Proper Ca²⁺ levels also prevent electron leakage and promote mitophagy, aiding in damaged mitochondria removal and reducing ROS accumulation. Future strategies include modulating Ryanodine receptor 2 (RyR2), mitochondrial calcium uniporter (MCU), and sodium-calcium exchanger (NCLX) to control Ca²⁺ overload and oxidative damage. Addressing mitochondrial Ca²⁺ dynamics offers a compelling approach to breaking the cycle of Ca²⁺ overload, oxidative stress, and AF progression. Further research is needed to clarify the mechanisms of mitochondrial Ca²⁺ regulation and its role in AF pathogenesis. This knowledge will guide the development of innovative treatments to improve outcomes and quality of life for AF patients.
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Affiliation(s)
- Yixuan Chang
- School of Health Management, Binzhou Medical University, BinZhou, 256600, PR China
| | - Qi Zou
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou, 730030, PR China.
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19
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Liu Y, Tang Q, Tao Q, Dong H, Shi Z, Zhou L. Low-frequency magnetic field therapy for glioblastoma: Current advances, mechanisms, challenges and future perspectives. J Adv Res 2025; 69:531-543. [PMID: 38565404 PMCID: PMC11954840 DOI: 10.1016/j.jare.2024.03.024] [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: 12/28/2023] [Revised: 03/10/2024] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common malignant tumour of the central nervous system. Despite recent advances in multimodal GBM therapy incorporating surgery, radiotherapy, systemic therapy (chemotherapy, targeted therapy), and supportive care, the overall survival (OS) remains poor, and long-term survival is rare. Currently, the primary obstacles hindering the effectiveness of GBM treatment are still the blood-brain barrier and tumor heterogeneity. In light of its substantial advantages over conventional therapies, such as strong penetrative ability and minimal side effects, low-frequency magnetic fields (LF-MFs) therapy has gradually caught the attention of scientists. AIM OF REVIEW In this review, we shed the light on the current status of applying LF-MFs in the treatment of GBM. We specifically emphasize our current understanding of the mechanisms by which LF-MFs mediate anticancer effects and the challenges faced by LF-MFs in treating GBM cells. Furthermore, we discuss the prospective applications of magnetic field therapy in the future treatment of GBM. Key scientific concepts of review: The review explores the current progress on the use of LF-MFs in the treatment of GBM with a special focus on the potential underlying mechanisms of LF-MFs in anticancer effects. Additionally, we also discussed the complex magnetic field features and biological characteristics related to magnetic bioeffects. Finally, we proposed a promising magnetic field treatment strategy for future applications in GBM therapy.
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Affiliation(s)
- Yinlong Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, China
| | - Qisheng Tang
- Department of Neurosurgery, Huashan Hospital, Fudan University, China; National Center for Neurological Disorders, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, China
| | - Quan Tao
- Shanghai Institute of Microsystem and Information Technology, China
| | - Hui Dong
- Shanghai Institute of Microsystem and Information Technology, China
| | - Zhifeng Shi
- Department of Neurosurgery, Huashan Hospital, Fudan University, China; National Center for Neurological Disorders, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, China.
| | - Liangfu Zhou
- Department of Neurosurgery, Huashan Hospital, Fudan University, China; National Center for Neurological Disorders, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, China.
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20
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Shao F, Wieland J, Wang Y, Keles M, Meng Z, Lomada S, Qin M, Leiss V, Martin-Garrido A, Fuhrmann M, Qiu Y, Trogisch FA, Vettel C, Heineke J, Feng Y. Deficiency in nucleoside diphosphate kinase B leads to endothelial activation of the hexosamine biosynthesis pathway and cardiac dysfunction. Cardiovasc Diabetol 2025; 24:84. [PMID: 39985023 PMCID: PMC11846329 DOI: 10.1186/s12933-025-02633-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/05/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart. METHODS NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs). RESULTS NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E' wave, and in the ratios of E/A and E'/A' in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB-/- mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation. CONCLUSIONS Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.
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MESH Headings
- Animals
- Hexosamines/biosynthesis
- Mice, Knockout
- Endothelial Cells/enzymology
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/pathology
- NM23 Nucleoside Diphosphate Kinases/deficiency
- NM23 Nucleoside Diphosphate Kinases/genetics
- Ventricular Function, Left
- Ventricular Dysfunction, Left/enzymology
- Ventricular Dysfunction, Left/physiopathology
- Ventricular Dysfunction, Left/genetics
- Ventricular Dysfunction, Left/diagnostic imaging
- Cells, Cultured
- Myocardial Contraction
- Disease Models, Animal
- Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
- Male
- Phosphorylation
- Mice, Inbred C57BL
- Signal Transduction
- Hypertrophy, Left Ventricular/enzymology
- Hypertrophy, Left Ventricular/physiopathology
- Hypertrophy, Left Ventricular/genetics
- Calcium-Binding Proteins/metabolism
- Mice
- Ventricular Remodeling
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Affiliation(s)
- Feng Shao
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Johanna Wieland
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Yixin Wang
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Merve Keles
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Zenghui Meng
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
- First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, 68167 Mannheim, Germany
| | - Santosh Lomada
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Miao Qin
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Veronika Leiss
- Department of Pharmacology, Experimental Therapy and Toxicology, University of Tübingen, 72074 Tübingen, Germany
| | - Abel Martin-Garrido
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Manuela Fuhrmann
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Yi Qiu
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Felix A Trogisch
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Christiane Vettel
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Joerg Heineke
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- DZHK (German Center of Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Yuxi Feng
- Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany.
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Jiang P, Huang F, Chen L, Zhou H, Deng Y, Li L, Chen M, Huang Y. Intercellular NETwork-facilitated sarcoplasmic reticulum targeting for myocardial ischemia-reperfusion injury treatment. SCIENCE ADVANCES 2025; 11:eadr4333. [PMID: 39937916 PMCID: PMC11818016 DOI: 10.1126/sciadv.adr4333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 01/10/2025] [Indexed: 02/14/2025]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca2+-ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell "NETwork" of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.
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Affiliation(s)
- Peihang Jiang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fangyang Huang
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases and Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liqiang Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Hao Zhou
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases and Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yudi Deng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Lian Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Mao Chen
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases and Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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22
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Chang R, Fang W, Yang X, Jin J, Han X, Ma L, Li Y, Chen X. Sodium Alginate Attenuates H 2O 2-Induced Myocardial DNA Damage via VSNL1 Regulating the CNP/NPR-B Signaling Pathway. Mol Biotechnol 2025:10.1007/s12033-024-01340-1. [PMID: 39924636 DOI: 10.1007/s12033-024-01340-1] [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: 07/28/2024] [Accepted: 11/25/2024] [Indexed: 02/11/2025]
Abstract
Myocardial DNA damage plays a critical role in the pathogenesis of cardiovascular diseases, frequently leading to adverse outcomes such as myocardial infarction and heart failure. This study elucidated the protective effects of sodium alginate (SA) against myocardial DNA damage and explored the underlying molecular mechanisms involved. Hydrogen peroxide (H₂O₂) -stimulated AC16 cells were employed as an in vitro model to induce myocardial DNA damage, and CCK-8 assays established that SA exhibited no cytotoxicity at concentrations up to 800 µM. The protective effects of SA on myocardial DNA damage were shown to be mediated by VSNL1 using immunofluorescence, western blotting and qPCR analyses. To further substantiate this mechanism, lentiviral transduction was utilized to achieve VSNL1 overexpression, whereas targeted siRNA silencing was employed for VSNL1 knockdown. Following VSNL1 overexpression, a reduction in γ-H2AX protein expression was observed, accompanied by increased levels of CNP and NPR-B proteins on the cell membrane, as well as a decrease in intracellular calcium ion concentrations. Conversely, knockdown of VSNL1 reduced the protective effects of SA, highlighting its critical role in the mediation of cardioprotective mechanisms. Taken together, these findings suggest that SA exerts a potential protective effect against myocardial DNA damage through upregulating VSNL1, activating the CNP/NPR-B signaling pathway, and decreasing intracellular calcium ion accumulation. These results underscore that SA is a promising therapeutic candidate for the attenuation of myocardial injury.
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Affiliation(s)
- Rui Chang
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Wenjuan Fang
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
| | - Xing Yang
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Jiahui Jin
- The College of Medical Technology, Shanghai University of Medicine and Health Sciences, No. 279 Zhouzhu Road, Pudong New Area, Shanghai, 201318, China
| | - Xijun Han
- The College of Medical Technology, Shanghai University of Medicine and Health Sciences, No. 279 Zhouzhu Road, Pudong New Area, Shanghai, 201318, China
| | - Linlin Ma
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Yanfei Li
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China.
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
| | - Xiaoyan Chen
- The College of Medical Technology, Shanghai University of Medicine and Health Sciences, No. 279 Zhouzhu Road, Pudong New Area, Shanghai, 201318, China.
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Cheng Z, Gan W, Xiang Q, Zhao K, Gao H, Chen Y, Shi P, Zhang A, Li G, Song Y, Feng X, Yang C, Zhang Y. Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration. Autophagy 2025; 21:352-373. [PMID: 39212196 PMCID: PMC11759519 DOI: 10.1080/15548627.2024.2395797] [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: 09/07/2023] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value.Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Zhangrong Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Weikang Gan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Xiang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Kangcheng Zhao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haiyang Gao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuhang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Pengzhi Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Anran Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Gaocai Li
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Song
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaobo Feng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cao Yang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Qi X, Xiong F, Xiao J, Muthukumarasamy KM, Altuntas Y, Zhong Y, Abu-Taha I, Bruns F, Tekook M, Kamler M, Villeneuve L, Nozza A, Sirois M, Karch J, Pasdois P, Bers DM, Dobrev D, Nattel S. Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.29.635508. [PMID: 39975327 PMCID: PMC11838346 DOI: 10.1101/2025.01.29.635508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BACKGROUND Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model. METHODS AND RESULTS Atrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca 2+ -concentration ([Ca 2+ ] Mito ), reactive oxygen species (mtROS) production, membrane potential (ΔΨ m ), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca 2+ ] Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca 2+ -current (I CaL )-downregulation in canine and human AF ACMs in vitro . Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca 2+ -overload, mtROS-overproduction, structural damage and abnormalities in ΔΨ m and respiration. Functionally, mitoquinone reduced AF-induced Ca 2+ -current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability. CONCLUSIONS Mitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.
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25
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Monaghan RM. The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan. Open Biol 2025; 15:240287. [PMID: 39933574 PMCID: PMC11813573 DOI: 10.1098/rsob.240287] [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: 10/02/2024] [Revised: 12/20/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.
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Affiliation(s)
- Richard M. Monaghan
- British Heart Foundation Centre of Research Excellence Manchester, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, The AV Hill Building, ManchesterM13 9PT, UK
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26
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Jaiswal A, Yadav P, Rawat PS, Kaur M, Babu SS, Khurana A, Bhatti JS, Navik U. Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions. Mol Biol Rep 2025; 52:158. [PMID: 39853512 DOI: 10.1007/s11033-025-10260-5] [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: 11/07/2024] [Accepted: 01/13/2025] [Indexed: 01/26/2025]
Abstract
Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.
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Affiliation(s)
- Aiswarya Jaiswal
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Pushkar Singh Rawat
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Maninder Kaur
- Department of Human Anatomy, Bhojia Dental College and Hospital, Budh, Baddi, Himachal Pradesh, 173205, India
| | | | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, 151401, India.
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27
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Yin L, Yuan X, Yu J, Ren X, Zhang H, Ye Y, Wang Z, Chen X. β-asarone relieves Parkinson's disease through reducing intracellular Ca 2+ in PINK1 mutant Drosophila melanogaster. Eur J Pharmacol 2025; 987:177155. [PMID: 39622404 DOI: 10.1016/j.ejphar.2024.177155] [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: 06/18/2024] [Revised: 10/20/2024] [Accepted: 11/27/2024] [Indexed: 12/06/2024]
Abstract
β-asarone, an effective volatile oil component of Acorus chinensis, has been found to hold beneficial effects on Parkinson's disease (PD), but its mechanism remains incompletely understood. Drosophila melanogaster with PTEN induced kinase 1 (PINK1) mutations, a prototype PD model, was used in this study. We found that calcium chelation profoundly alleviated a spectrum of PD symptoms. Whereas, calcium supplementation made the case worse, suggesting accumulated calcium contributes to progression of PD. β-asarone administration decreased Ca2+ level in PD flies, accompanied by alleviated behavioral and neural defects. Further study demonstrated that β-asarone downregulated L-type Ca2+ channels (Dmca1D), which was increased in PD flies. Besides, β-asarone decreased expression of 1,4,5 - trisphosphate receptor (Itpr), which is responsible for calcium release from endoplasmic reticulum (ER). Knockdown of either Dmca1D or Itpr specifically in dopaminergic neurons alleviated behavioral and neural defects in PD flies. While overexpression of Itpr aggravated PD symptoms. The results indicated that increased intracellular calcium influx and release triggers dysregulation of calcium homeostasis in PD flies. And β-asarone prevents PD by restoring Ca2+ homeostasis. Overall, the study demonstrated that β-asarone can serve as a new prospective medication against PD or other diseases associated with dysregulation of Ca2+ homeostasis.
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Affiliation(s)
- Lanxiang Yin
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xintong Yuan
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jiahui Yu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xuemin Ren
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Hongqin Zhang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yunyan Ye
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230601, Anhui, China
| | - Zixuan Wang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiangtao Chen
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China.
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28
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Lin P, Shi J, Liu L, Wang J, Yang Z, Sun X, Hong M, Zhang Y. Spatial confinement growth of high-performance persistent luminescence nanoparticles for image-guided sonodynamic therapy. Acta Biomater 2025; 192:279-289. [PMID: 39644942 DOI: 10.1016/j.actbio.2024.12.011] [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: 09/11/2024] [Revised: 11/15/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) have significant potential in diagnostic and therapeutic applications owing to their unique persistent luminescence (PersL). However, obtaining high-performance NIR PLNPs remains challenging because of the limitations of current synthesis methods. Herein, we introduce a spatial confinement growth strategy for synthesizing high-performance NIR PLNPs using hollow mesoporous silica (hmSiO2). By calcining precursor ions in the hollow cavity, the yolk size of NIR PLNPs was regulated, yielding well-dispersed Zn1.3Ga1.4Sn0.3O4: Cr0.005, Y0.003@hmSiO2 (ZS) with a yolk-shell structure. Compared to the conventional template method, ZS synthesized via the spatial confinement growth strategy exhibited a 7.7-fold increase in PersL intensity and a threefold increase in specific surface area. As a proof of concept, ZS@PpIX@CaP-AMD (ZPSC-AMD) nanoparticles, with potential for sonodynamic therapy (SDT), were synthesized by loading the sonosensitizer protoporphyrin IX (PpIX) into ZS, coating it with a calcium phosphate (CaP) shell, and modifying it with a tumor-targeting molecule plerixafor (AMD-3100). The tumor enrichment behavior of ZPSC-AMD was monitored by sensitive NIR PersL to guide SDT. Simultaneously, ZPSC-AMD enabled the precise monitoring of tumor accumulation, thereby guiding effective SDT. In addition, Ca2+ released from CaP degradation increased the level of reactive oxygen species during SDT, promoting tumor cell apoptosis. This study outlines a reliable design and synthesis approach for high-performance NIR PLNPs and promotes their development in biomedical applications. STATEMENT OF SIGNIFICANCE: The potential of near infrared (NIR) persistent luminescence nanoparticles (PLNPs) in bio applications is hindered by limitations in the synthesis method. In this article, we proposed a spatial confinement growth strategy of high-performance NIR PLNPs. The obtained PLNPs with yolk-shell structure showed a 7.7-fold increase in PersL intensity and a threefold increase in specific surface area, compared with the commonly used template method. Due to the advantages, sonodynamic therapeutic nanoparticles were constructed based on the above PLNPs, where persistent luminescence was used for ultrasensitive imaging to determine the optimal timing in sonodynamic therapy. In addition, the multifunctional calcium phosphate shell elevated the intracellular reactive oxygen species level to promote tumor cell apoptosis.
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Affiliation(s)
- Peng Lin
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Junpeng Shi
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China.
| | - Lin Liu
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Jinyuan Wang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Zhengxia Yang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Xia Sun
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China; Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, PR China
| | - Maochun Hong
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China
| | - Yun Zhang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, PR China; Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, PR China.
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Shi J, Liu M, Zhu H, Jiang C. SIRT3 mitigates high glucose-induced damage in retinal microvascular endothelial cells via OPA1-mediated mitochondrial dynamics. Exp Cell Res 2025; 444:114320. [PMID: 39491778 DOI: 10.1016/j.yexcr.2024.114320] [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: 09/21/2024] [Revised: 10/29/2024] [Accepted: 11/02/2024] [Indexed: 11/05/2024]
Abstract
Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway.
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Affiliation(s)
- Jiemei Shi
- Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Fudan University, Shanghai, China; Key Laboratory of Myopia of State Health Ministry, and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China
| | - Min Liu
- Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Fudan University, Shanghai, China; Key Laboratory of Myopia of State Health Ministry, and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China
| | - Haohao Zhu
- Department of Ophthalmology, People's Hospital of Shanghai No. 5, Shanghai, 200240, China.
| | - Chunhui Jiang
- Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Fudan University, Shanghai, China; Key Laboratory of Myopia of State Health Ministry, and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China.
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30
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Chen Z, Zhao X, Lin L, Cui Y, Cao D, Chen XL, Wang X. CaGA nanozymes with multienzyme activity realize multifunctional repair of acute wounds by alleviating oxidative stress and inhibiting cell apoptosis. Biomater Sci 2025; 13:422-433. [PMID: 39412895 DOI: 10.1039/d4bm01155d] [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: 10/18/2024]
Abstract
Acute wounds result from damage to the skin barrier, exposing underlying tissues and increasing susceptibility to bacterial and other pathogen infections. Improper wound care increases the risk of exposure and infection, often leading to chronic nonhealing wounds, which cause significant patient suffering. Early wound repair can effectively prevent the development of chronic nonhealing wounds. In this study, Ca-Gallic Acid (CaGA) nanozymes with multienzyme catalytic activity were constructed for treating acute wounds by coordinating Ca ions with gallic acid. CaGA nanozymes exhibit high superoxide dismutase/catalase (SOD/CAT) catalytic activity and good antioxidant performance in vitro. In vitro experiments demonstrated that CaGA nanozymes can effectively promote cell migration, efficiently scavenge ROS, maintain mitochondrial homeostasis, reduce inflammation, and decrease cell apoptosis. In vivo, CaGA nanozymes promoted granulation tissue formation, accelerated collagen fiber deposition, and reconstructed skin appendages, thereby accelerating acute wound healing. CaGA nanozymes have potential clinical application value in wound healing treatment.
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Affiliation(s)
- Zenghong Chen
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P. R. China.
| | - Xinyu Zhao
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, P. R. China.
| | - Liting Lin
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, 230032, P. R. China
| | - Yuyu Cui
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P. R. China.
| | - Dongsheng Cao
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P. R. China.
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, P. R. China.
| | - Xianwen Wang
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P. R. China.
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, 230032, P. R. China
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Wen H, Deng H, Li B, Chen J, Zhu J, Zhang X, Yoshida S, Zhou Y. Mitochondrial diseases: from molecular mechanisms to therapeutic advances. Signal Transduct Target Ther 2025; 10:9. [PMID: 39788934 PMCID: PMC11724432 DOI: 10.1038/s41392-024-02044-3] [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: 07/02/2024] [Revised: 09/28/2024] [Accepted: 10/31/2024] [Indexed: 01/12/2025] Open
Abstract
Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.
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Affiliation(s)
- Haipeng Wen
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China
| | - Hui Deng
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China
| | - Bingyan Li
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China
| | - Junyu Chen
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China
| | - Junye Zhu
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China
| | - Xian Zhang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China
| | - Shigeo Yoshida
- Department of Ophthalmology, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan
| | - Yedi Zhou
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, 410011, China.
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Camargo LL, Rios FJ, Montezano AC, Touyz RM. Reactive oxygen species in hypertension. Nat Rev Cardiol 2025; 22:20-37. [PMID: 39048744 DOI: 10.1038/s41569-024-01062-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/26/2024] [Indexed: 07/27/2024]
Abstract
Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin-angiotensin-aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension.
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Affiliation(s)
- Livia L Camargo
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada.
| | - Francisco J Rios
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada
| | - Augusto C Montezano
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada
| | - Rhian M Touyz
- Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada.
- Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
- Department of Family Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
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Yuan C, Yu B, Li L, Chen J, Qin W, Zhou Z, Su M, Wang D, Zhang Y, Wu Q, He C, Wei D. SUCNR 1 promotes atherosclerosis by inducing endoplasmic reticulum stress mediated ER-mito crosstalk. Int Immunopharmacol 2024; 143:113510. [PMID: 39486175 DOI: 10.1016/j.intimp.2024.113510] [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: 08/30/2024] [Revised: 10/19/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024]
Abstract
Atherosclerosis is a progressive inflammatory disease within the large and medium arteries. SUCNR1(Succinate receptor 1) has been reported to regulate the inflammatory response in cardiovascular diseases, but how it works in atherosclerosis remains unclear. In this study, we observed that SUCNR1 is upregulated in endothelial cells within human atherosclerotic lesions. The deletion of SUCNR1 in vascular endothelial cells can mitigate the progression of atherosclerotic lesions in high-fat diet ApoE-/- mice. The overexpression or activation of SUCNR1 intensified endoplasmic reticulum stress and mitochondria-endoplasmic reticulum interactions. Moreover, SUCNR1 exacerbated mitochondrial injury, mtDNA leakage, and the activation of cGAS-STING signaling. Elevated mitochondrial damage, ER-mitochondrial interactions, and inflammation induced by SUCNR1 activation were blocked by the endoplasmic reticulum stress inhibitor. Collectively, these findings suggest that SUCNR1 promotes atherosclerosis through endoplasmic reticulum stress signaling mediated ER-mitochondrial crosstalk and its downstream cGAS-STING pathway. Our results provide new insights into the mechanism of SUCNR1 in atherosclerosis and inhibiting endoplasmic reticulum stress signaling may provide a promising strategy to prevent and treat atherosclerosis.
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Affiliation(s)
- Chuchu Yuan
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Bo Yu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Lu Li
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College), Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518020, China
| | - Jinna Chen
- Department of Pathology & Pathophysiology, Hunan University of Medicine, Huaihua, Hunan 418000, China
| | - Wenhua Qin
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhixiang Zhou
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Ming Su
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Die Wang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yile Zhang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Qian Wu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Chao He
- Department of Pediatrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China.
| | - Dangheng Wei
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Casagrande Raffi G, Chen J, Feng X, Chen Z, Lieftink C, Deng S, Mo J, Zeng C, Steur M, Wang J, Bleijerveld OB, Hoekman L, van der Wel N, Wang F, Beijersbergen R, Zheng J, Bernards R, Wang L. An antibiotic that mediates immune destruction of senescent cancer cells. Proc Natl Acad Sci U S A 2024; 121:e2417724121. [PMID: 39693343 DOI: 10.1073/pnas.2417724121] [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: 08/30/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).
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Affiliation(s)
- Gabriele Casagrande Raffi
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Jian Chen
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Xuezhao Feng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhen Chen
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Cor Lieftink
- Division of Molecular Carcinogenesis, The Netherlands Cancer Institute Robotic and Screening Center, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Shuang Deng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jinzhe Mo
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chuting Zeng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Marit Steur
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Jing Wang
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Onno B Bleijerveld
- Division of Biochemistry, Proteomics facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Liesbeth Hoekman
- Division of Biochemistry, Proteomics facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Nicole van der Wel
- Amsterdam Faculty of Medicine Location University of Amsterdam, Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam 1105 AZ, The Netherlands
| | - Feng Wang
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Roderick Beijersbergen
- Division of Molecular Carcinogenesis, The Netherlands Cancer Institute Robotic and Screening Center, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Jian Zheng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Rene Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
| | - Liqin Wang
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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Qin L, Huang T, Zhang D, Wei L, Li G, Zhu Q, Tong Q, Ding G, Liu J. The mitochondrial function of peripheral blood cells in cognitive frailty patients. Front Aging Neurosci 2024; 16:1503246. [PMID: 39723155 PMCID: PMC11669044 DOI: 10.3389/fnagi.2024.1503246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Background Cognitive frailty (CF), characterized by the coexistence of physical frailty and cognitive impairment, is linked to increased morbidity and mortality in older adults. While CF has been linked to multiple physiological and lifestyle factors, the underlying biological mechanisms remain poorly understood. This study investigated the risk factors for CF and explored the relationship between mitochondrial function and CF in hospitalized patients. Methods A total of 279 hospitalized individuals were recruited from December 2020 to August 2022, conducted comprehensive clinical assessments, and collected peripheral blood samples. CF was evaluated using the Physical Frailty Phenotype and Montreal Cognitive Assessment scales. Nutritional status was assessed with the Mini Nutritional Assessment, and depression was measured using the Geriatric Depression Scale. DNA was obtained from the peripheral blood and interrogated for mitochondrial DNA copy number (mtDNAcn). Peripheral blood mononuclear cells isolated from peripheral blood were examined for respiratory function and reactive oxygen species (ROS) levels. Additionally, plasma samples were analyzed for inflammatory markers and Carnitine Palmitoyltransferase II (CPT2). Results Among the participants, 90 were classified as CF and 46 as non-CF. Logistic regression analysis revealed that increased age (OR 1.156, 95% CI 1.064-1.255), lower educational attainment (OR 0.115, 95% CI 0.024-0.550), malnutrition (OR 0.713, 95% CI 0.522-0.973), and higher depression scores (OR 1.345, 95% CI 1.065-1.699) were significantly associated with CF. The independent t tests and Mann-Whitney U tests showed the CF group exhibited impaired mitochondrial function, characterized by reduced mtDNAcn and respiratory activity, coupled with elevated ROS, interleukin-6, and CPT2 levels compared with the non-CF group. After adjusted for age, sex, and BMI, compared with non-CF group, the OR values for the CF group of mtDNAcn and ROS were 0.234 (95% CI = 0.065-0.849) (p = 0.027) and 1.203 (95% CI = 1.075-1.347) (p = 0.001), respectively. The Sensitive analysis showed that the area under curve values for mtDNAcn and ROS were 0.653 and 0.925. Conclusion Age, lower educational attainment, malnutrition, and depression are significant risk factors for CF. Moreover, mitochondrial dysfunction, characterized by decreased mtDNAcn, impaired respiratory function and increased ROS levels appears to be a critical phenotype of CF.
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Affiliation(s)
| | | | | | | | | | | | | | - Guoxian Ding
- Division of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Juan Liu
- Division of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Chen YR, Zhu FY, Zhou R. SGLT2 inhibitors for alleviating heart failure through non-hypoglycemic mechanisms. Front Cardiovasc Med 2024; 11:1494882. [PMID: 39717441 PMCID: PMC11663900 DOI: 10.3389/fcvm.2024.1494882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/12/2024] [Indexed: 12/25/2024] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors afford significant cardiovascular benefits to patients with diabetes mellitus and heart failure. Three large randomized clinical trials (EMPAREG-Outcomes, DECLARE-TIMI58, and DAPA-HF) have shown that SGLT2 inhibitors prevent cardiovascular events and reduce the risk of death and hospital admission resulting from heart failure. Patients without type 2 diabetes mellitus (T2DM) also experience a similar degree of cardiovascular benefit as those with T2DM do. SGLT2 inhibitors could improve cardiac function through potential non-hypoglycemic mechanisms, including the reduction of the circulatory volume load, regulation of energy metabolism, maintenance of ion homeostasis, alleviation of inflammation and oxidative stress, and direct inhibition of cardiac SGLT1 receptors and antimyocardial fibrosis. This article reviews the mechanism through which SGLT2 inhibitors prevent/alleviate heart failure through non-hypoglycemic pathways, to support their use for the treatment of heart failure in non-T2DM patients.
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Affiliation(s)
| | | | - Rong Zhou
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Zinkevich NS, Drachuk K, Zhang DX. Prolonged L-NAME exposure changes the vasodilator factor from NO to H 2O 2 in human arterioles in response to A23187. Vascul Pharmacol 2024; 157:107440. [PMID: 39537001 PMCID: PMC11624973 DOI: 10.1016/j.vph.2024.107440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/05/2024] [Accepted: 11/09/2024] [Indexed: 11/16/2024]
Abstract
The Ca2+ ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (n = 25) and CAD (n = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H2O2 scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H2O2 contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H2O2 switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible.
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Affiliation(s)
- Natalya S Zinkevich
- College of Health, Science and Technology, School of Integrated Sciences, Sustainability, and Public Health, Biology, University of Illinois Springfield, Springfield, IL 62703-5407, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Kostiantyn Drachuk
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - David X Zhang
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Luo Y, He X, Du Q, Xu L, Xu J, Wang J, Zhang W, Zhong Y, Guo D, Liu Y, Chen X. Metal-based smart nanosystems in cancer immunotherapy. EXPLORATION (BEIJING, CHINA) 2024; 4:20230134. [PMID: 39713201 PMCID: PMC11655314 DOI: 10.1002/exp.20230134] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 01/12/2024] [Indexed: 12/24/2024]
Abstract
Metals are an emerging topic in cancer immunotherapy that have shown great potential in modulating cancer immunity cycle and promoting antitumor immunity by activating the intrinsic immunostimulatory mechanisms which have been identified in recent years. The main challenge of metal-assisted immunotherapy lies in the fact that the free metals as ion forms are easily cleared during circulation, and even cause systemic metal toxicity due to the off-target effects. With the rapid development of nanomedicine, metal-based smart nanosystems (MSNs) with unique controllable structure become one of the most promising delivery carriers to solve the issue, owing to their various endogenous/external stimuli-responsiveness to release free metal ions for metalloimmunotherapy. In this review, the state-of-the-art research progress in metal-related immunotherapy is comprehensively summarized. First, the mainstream mechanisms of MSNs-assisted immunotherapy will be delineated. The immunological effects of certain metals and categorization of MSNs with different characters and compositions are then provided, followed by the representative exemplar applications of MSNs in cancer treatment, and synergistic combination immunotherapy. Finally, we conclude this review with a summary of the remaining challenges associated with MSNs and provide the authors' perspective on their further advances.
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Affiliation(s)
- Ying Luo
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Xiaojing He
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Qianying Du
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Lian Xu
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Jie Xu
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Junrui Wang
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Wenli Zhang
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Yixin Zhong
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Dajing Guo
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Yun Liu
- Department of RadiologySecond Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Xiaoyuan Chen
- Department of Diagnostic Radiology Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Department of SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingaporeSingapore
- Institute of Molecular and Cell BiologyAgency for Science, Technology, and Research (A*STAR)SingaporeSingapore
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Watson WD, Arvidsson PM, Miller JJJ, Lewis AJ, Rider OJ. A Mitochondrial Basis for Heart Failure Progression. Cardiovasc Drugs Ther 2024; 38:1161-1171. [PMID: 38878138 PMCID: PMC11680631 DOI: 10.1007/s10557-024-07582-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2024] [Indexed: 12/29/2024]
Abstract
In health, the human heart is able to match ATP supply and demand perfectly. It requires 6 kg of ATP per day to satisfy demands of external work (mechanical force generation) and internal work (ion movements and basal metabolism). The heart is able to link supply with demand via direct responses to ADP and AMP concentrations but calcium concentrations within myocytes play a key role, signalling both inotropy, chronotropy and matched increases in ATP production. Calcium/calmodulin-dependent protein kinase (CaMKII) is a key adapter to increased workload, facilitating a greater and more rapid calcium concentration change. In the failing heart, this is dysfunctional and ATP supply is impaired. This review aims to examine the mechanisms and pathologies that link increased energy demand to this disrupted situation. We examine the roles of calcium loading, oxidative stress, mitochondrial structural abnormalities and damage-associated molecular patterns.
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Affiliation(s)
- William D Watson
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
- Oxford Centre for Magnetic Resonance Research, University of Oxford, Oxford, UK.
| | - Per M Arvidsson
- Oxford Centre for Magnetic Resonance Research, University of Oxford, Oxford, UK
- Clinical Physiology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Department of Clinical Physiology, Skåne University Hospital, Lund, Sweden
| | - Jack J J Miller
- Oxford Centre for Magnetic Resonance Research, University of Oxford, Oxford, UK
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Andrew J Lewis
- Oxford Centre for Magnetic Resonance Research, University of Oxford, Oxford, UK
| | - Oliver J Rider
- Oxford Centre for Magnetic Resonance Research, University of Oxford, Oxford, UK
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40
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Li JR, Li LY, Zhang HX, Zhong MQ, Zou ZM. Atramacronoid A induces the PANoptosis-like cell death of human breast cancer cells through the CASP-3/PARP-GSDMD-MLKL pathways. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:1475-1488. [PMID: 38958645 DOI: 10.1080/10286020.2024.2368841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 07/04/2024]
Abstract
Breast cancer is the most common malignant tumor and a major cause of mortality among women worldwide. Atramacronoid A (AM-A) is a unique natural sesquiterpene lactone isolated from the rhizome of Atractylodes macrocephala Koidz (known as Baizhu in Chinese). Our study demonstrated that AM-A triggers a specific form of cell death resembling PANoptosis-like cell death. Further analysis indicated that AM-A-induced PANoptosis-like cell death is associated with the CASP-3/PARP-GSDMD-MLKL pathways, which are mediated by mitochondrial dysfunction. These results suggest the potential of AM-A as a lead compound and offer insights for the development of therapeutic agents for breast cancer from natural products.
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Affiliation(s)
- Jing-Rong Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Ling-Yu Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Hai-Xin Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Ming-Qin Zhong
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Zhong-Mei Zou
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China
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41
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Mesmar F, Muhsen M, Mirchandani R, Tourigny JP, Tennessen JM, Bondesson M. The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase activity. Toxicol Sci 2024; 202:302-313. [PMID: 39240656 PMCID: PMC11589103 DOI: 10.1093/toxsci/kfae113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024] Open
Abstract
Metabolic syndrome is increasing worldwide, particularly in rural communities, where residents have a higher risk of exposure to pesticides. We investigated whether six commonly used agricultural pesticides on corn and soy fields possess adipogenic and metabolic disruption activity. Exposure to two of these pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure induced morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 µM and LC50 of 12 µM. Acetochlor exposure at 10 nM resulted in lipid accumulation in zebrafish larvae when simultaneously fed a high-cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we performed transcriptomic and lipidomic analyses of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consistent with this prediction, Gpx activity was efficiently repressed by acetochlor in zebrafish, whereas lipid peroxidation was increased. We propose that acetochlor disrupts lipid homeostasis by inhibiting GPX activity, resulting in the accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contains the chloroacetamide group, inhibition of GPX activity may represent a novel, common molecular initiating event of metabolic disruption.
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Affiliation(s)
- Fahmi Mesmar
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, United States
| | - Maram Muhsen
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, United States
| | - Rachna Mirchandani
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, United States
| | - Jason P Tourigny
- Department of Biology, Indiana University, Bloomington, IN 47405, United States
| | - Jason M Tennessen
- Department of Biology, Indiana University, Bloomington, IN 47405, United States
| | - Maria Bondesson
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47408, United States
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Panday N, Sigdel D, Adam I, Ramirez J, Verma A, Eranki AN, Wang W, Wang D, Ping P. Data-Driven Insights into the Association Between Oxidative Stress and Calcium-Regulating Proteins in Cardiovascular Disease. Antioxidants (Basel) 2024; 13:1420. [PMID: 39594561 PMCID: PMC11590986 DOI: 10.3390/antiox13111420] [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: 10/04/2024] [Revised: 11/10/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
A growing body of biomedical literature suggests a bidirectional regulatory relationship between cardiac calcium (Ca2+)-regulating proteins and reactive oxygen species (ROS) that is integral to the pathogenesis of various cardiac disorders via oxidative stress (OS) signaling. To address the challenge of finding hidden connections within the growing volume of biomedical research, we developed a data science pipeline for efficient data extraction, transformation, and loading. Employing the CaseOLAP (Context-Aware Semantic Analytic Processing) algorithm, our pipeline quantifies interactions between 128 human cardiomyocyte Ca2+-regulating proteins and eight cardiovascular disease (CVD) categories. Our machine-learning analysis of CaseOLAP scores reveals that the molecular interfaces of Ca2+-regulating proteins uniquely associate with cardiac arrhythmias and diseases of the cardiac conduction system, distinguishing them from other CVDs. Additionally, a knowledge graph analysis identified 59 of the 128 Ca2+-regulating proteins as involved in OS-related cardiac diseases, with cardiomyopathy emerging as the predominant category. By leveraging a link prediction algorithm, our research illuminates the interactions between Ca2+-regulating proteins, OS, and CVDs. The insights gained from our study provide a deeper understanding of the molecular interplay between cardiac ROS and Ca2+-regulating proteins in the context of CVDs. Such an understanding is essential for the innovation and development of targeted therapeutic strategies.
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Affiliation(s)
- Namuna Panday
- Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90095, USA; (N.P.); (D.S.)
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Dibakar Sigdel
- Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90095, USA; (N.P.); (D.S.)
| | - Irsyad Adam
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Joseph Ramirez
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Aarushi Verma
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Anirudh N. Eranki
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Wei Wang
- Department of Computer Science, University of California, Los Angeles, CA 90095, USA;
- Department of Computational Medicine, University of California, Los Angeles, CA 90095, USA
- Scalable Analytics Institute (ScAi), University of California, Los Angeles, CA 90095, USA
- Department of Bioinformatics and Biomedical Informatics, University of California, Los Angeles, CA 90095, USA
| | - Ding Wang
- Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90095, USA; (N.P.); (D.S.)
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
| | - Peipei Ping
- Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90095, USA; (N.P.); (D.S.)
- NHLBI Integrated Cardiovascular Data Science Training Program (iDISCOVER), University of California, Los Angeles, CA 90095, USA; (I.A.); (J.R.); (A.V.); (A.N.E.)
- Scalable Analytics Institute (ScAi), University of California, Los Angeles, CA 90095, USA
- Department of Bioinformatics and Biomedical Informatics, University of California, Los Angeles, CA 90095, USA
- Department of Medicine/Cardiology, University of California, Los Angeles, CA 90095, USA
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43
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Toro-Urrego N, Luaces JP, Kobiec T, Udovin L, Bordet S, Otero-Losada M, Capani F. Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury. Int J Mol Sci 2024; 25:12121. [PMID: 39596189 PMCID: PMC11594051 DOI: 10.3390/ijms252212121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/11/2024] [Accepted: 08/23/2024] [Indexed: 11/28/2024] Open
Abstract
Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5-10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen-glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival-65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen-glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen-glucose-deprived astrocyte cells, used to mimic hypoxic-ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.
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Affiliation(s)
- Nicolás Toro-Urrego
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Juan P. Luaces
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Tamara Kobiec
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Centro de Investigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina (UCA), Buenos Aires C1107AFB, Argentina
| | - Lucas Udovin
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Sofía Bordet
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Centro de Investigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina (UCA), Buenos Aires C1107AFB, Argentina
| | - Matilde Otero-Losada
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Francisco Capani
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago 7500912, Chile
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Tagashira H, Abe F, Sakai A, Numata T. Shakuyaku-Kanzo-To Prevents Angiotensin Ⅱ-Induced Cardiac Hypertrophy in Neonatal Rat Ventricular Myocytes. Cureus 2024; 16:e74064. [PMID: 39712736 PMCID: PMC11659909 DOI: 10.7759/cureus.74064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2024] [Indexed: 12/24/2024] Open
Abstract
The global incidence of mortality due to heart failure (HF) is on the rise, presenting a significant challenge in various regions, including Japan. There is an urgent need for innovative prevention and treatment strategies to address this issue. Traditional medicine, particularly Japanese Kampo medicine (JKM), has been proposed as a potential therapeutic approach and has undergone examination in clinical trials related to HF. However, the deficiency of robust scientific evidence underscores the necessity for further exploration into the cardioprotective mechanisms of JKM. This study systematically examines the cardioprotective effects of Shakuyaku-kanzo-to (SKT), a specific JKM with limited application in cardiac care. Utilizing neonatal rat ventricular myocytes, we assessed the direct effects of SKT on myocardial hypertrophy. Methodologies included immunohistochemistry for cell size and a plate reader for quantifying cell survival, intracellular calcium levels ([Ca2+]i), and reactive oxygen species (ROS) production. In addition, quantitative reverse transcription polymerase chain reaction (RT-PCR) was employed for gene expression analysis. The findings reveal that SKT significantly mitigates angiotensin Ⅱ (AngⅡ)-induced cardiomyocyte hypertrophy and cell death, while also reducing elevated [Ca2+]i and ROS production associated with this condition. Furthermore, co-administration of nifedipine, an L-type Ca2+ channel (L-Ca2+) blocker, demonstrated that SKT antagonizes L-Ca2+ actions. These results indicate that SKT offers protection against AngⅡ-induced cardiomyocyte hypertrophy by inhibiting L-Ca2+-mediated pathways. Consequently, this research highlights the potential of SKT as a promising therapeutic agent for cardiac applications, paving the way for new preventive and treatment strategies for HF.
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Affiliation(s)
- Hideaki Tagashira
- Department of Integrative Physiology, Akita University Graduate School of Medicine, Akita, JPN
| | - Fumiha Abe
- Department of Integrative Physiology, Graduate School of Medicine, Akita University, Akita, JPN
| | - Ayako Sakai
- Department of Integrative Physiology, Graduate School of Medicine, Akita University, Akita, JPN
| | - Tomohiro Numata
- Department of Integrative Physiology, Akita University Graduate School of Medicine, Akita, JPN
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45
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Lu X, Wang Y, Geng N, Zou Z, Feng X, Wang Y, Xu Z, Zhang N, Pu J. Dysregulated Mitochondrial Calcium Causes Spiral Artery Remodeling Failure in Preeclampsia. Hypertension 2024; 81:2368-2382. [PMID: 39291377 DOI: 10.1161/hypertensionaha.124.23046] [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: 03/25/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]m in preeclampsia development remains largely unknown. METHODS To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester-induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca2+]m to improve the outcome for preeclamptic mothers or their infants. RESULTS Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca2+]m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na+/Ca2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na+/Ca2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia-derived VSMCs and the preeclampsia rat model. CONCLUSIONS This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca2+]m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia.
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Affiliation(s)
- Xiyuan Lu
- Department of Cardiology (X.L., Yifan Wang, N.G., Z.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Yifan Wang
- Department of Cardiology (X.L., Yifan Wang, N.G., Z.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Na Geng
- Department of Cardiology (X.L., Yifan Wang, N.G., Z.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Zhiguo Zou
- Department of Cardiology (X.L., Yifan Wang, N.G., Z.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Xueqing Feng
- Department of Obstetrics Affiliated Hospital of Jining Medical University, China (X.F.)
| | - Yuehong Wang
- State Key Laboratory of Systems Medicine for Cancer (Yuehong Wang), School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, China
| | - Zhice Xu
- Wuxi Maternity and Child Health Care Hospital, China (Z.X.)
| | - Ning Zhang
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology (N.Z.), Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Jun Pu
- Department of Cardiology, Renji Hospital State Key Laboratory of Systems Medicine for Cancer (J.P.), School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, China
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Xie Y, Zhang W, Peng T, Wang X, Lian X, He J, Wang C, Xie N. TBC1D15-regulated mitochondria-lysosome membrane contact exerts neuroprotective effects by alleviating mitochondrial calcium overload in seizure. Sci Rep 2024; 14:23782. [PMID: 39390030 PMCID: PMC11467349 DOI: 10.1038/s41598-024-74388-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Mitochondrial calcium overload plays an important role in the neurological insults in seizure. The Rab7 GTPase-activating protein, Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15), is involved in the regulation of mitochondrial calcium dynamics by mediating mitochondria-lysosome membrane contact. However, whether TBC1D15-regulated mitochondria-lysosome membrane contact and mitochondrial calcium participate in neuronal injury in seizure is unclear. We aimed to investigate the effect of TBC1D15-regulated mitochondria-lysosome membrane contact on epileptiform discharge-induced neuronal damage and further explore the underlying mechanism. Lentiviral vectors (Lv) infection and stereotaxic adeno-associated virus (AAV) injection were used to regulate TBC1D15 expression before establishing in vitro epileptiform discharge and in vivo status epilepticus (SE) models. TBC1D15's effect on inter-organellar interactions, mitochondrial calcium levels and neuronal injury in seizure was evaluated. The results showed that abnormalities in mitochondria-lysosome membrane contact, mitochondrial calcium overload, mitochondrial dysfunction, increased levels of reactive oxygen species, and prominent neuronal damage were partly relieved by TBC1D15 overexpression, whereas TBC1D15 knockdown markedly deteriorated these phenomena. Further examination revealed that epileptiform discharge-induced mitochondrial calcium overload in primary hippocampal neurons was closely associated with abnormal mitochondria-lysosome membrane contact. This study highlights the crucial role played by TBC1D15-regulated mitochondria-lysosome membrane contact in epileptiform discharge-induced neuronal injury by alleviating mitochondrial calcium overload.
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Affiliation(s)
- Yinyin Xie
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wanwan Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Tingting Peng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiaoyi Wang
- Institutes of Biological and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, 215123, China
| | - Xiaolei Lian
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jiao He
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Cui Wang
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Nanchang Xie
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Wang F, Huynh PM, An YA. Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications. Compr Physiol 2024; 14:5581-5640. [PMID: 39382163 DOI: 10.1002/cphy.c230009] [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: 10/10/2024]
Abstract
For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.
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Affiliation(s)
- Fenfen Wang
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Phu M Huynh
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
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Sorge M, Savoré G, Gallo A, Acquarone D, Sbroggiò M, Velasco S, Zamporlini F, Femminò S, Moiso E, Morciano G, Balmas E, Raimondi A, Nattenberg G, Stefania R, Tacchetti C, Rizzo AM, Corsetto P, Ghigo A, Turco E, Altruda F, Silengo L, Pinton P, Raffaelli N, Sniadecki NJ, Penna C, Pagliaro P, Hirsch E, Riganti C, Tarone G, Bertero A, Brancaccio M. An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress. EMBO Mol Med 2024; 16:2450-2484. [PMID: 39271959 PMCID: PMC11473679 DOI: 10.1038/s44321-024-00132-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/15/2024] Open
Abstract
Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.
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Affiliation(s)
- Matteo Sorge
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy.
| | - Giulia Savoré
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Andrea Gallo
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Davide Acquarone
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Mauro Sbroggiò
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Silvia Velasco
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Federica Zamporlini
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60121, Italy
| | - Saveria Femminò
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy
| | - Enrico Moiso
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Giampaolo Morciano
- Department of Medical Sciences, University of Ferrara, Ferrara, 44121, Italy
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Elisa Balmas
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Andrea Raimondi
- Experimental Imaging Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Gabrielle Nattenberg
- Departments of Mechanical Engineering, Bioengineering, and Laboratory Medicine and Pathology, Institute for Stem Cell and Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA
| | - Rachele Stefania
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Carlo Tacchetti
- Experimental Imaging Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Angela Maria Rizzo
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, 20133, Italy
| | - Paola Corsetto
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, 20133, Italy
| | - Alessandra Ghigo
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Emilia Turco
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Fiorella Altruda
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Lorenzo Silengo
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, 44121, Italy
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Nadia Raffaelli
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, 60121, Italy
| | - Nathan J Sniadecki
- Departments of Mechanical Engineering, Bioengineering, and Laboratory Medicine and Pathology, Institute for Stem Cell and Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle, WA, 98109, USA
| | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043, Italy
| | - Emilio Hirsch
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Chiara Riganti
- Department of Oncology, University of Turin, Torino, 10126, Italy
| | - Guido Tarone
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Alessandro Bertero
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy
| | - Mara Brancaccio
- Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, 10126, Italy.
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Li M, Kong D, Meng L, Wang Z, Bai Z, Wu G. Discovery of novel SS-31 (d-Arg-dimethylTyr-Lys-Phe-NH 2) derivatives as potent agents to ameliorate inflammation and increase mitochondrial ATP synthesis. RSC Adv 2024; 14:29789-29799. [PMID: 39301232 PMCID: PMC11409442 DOI: 10.1039/d4ra05517a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024] Open
Abstract
Neuroinflammation and mitochondrial function are crucial for neuronal function and survival. SS-31 is a novel mitochondria-targeted peptide antioxidant that reduces mitochondrial reactive oxygen species production, increases ATP generation, protects the integrity of mitochondrial cristae and the mitochondrial respiratory chain, and reduces inflammatory responses. Exploring novel SS-31 derivatives is important for the treatment of neurodegenerative diseases. In this study, nineteen SS-31 derived peptides (5a-5s) were synthesized. Through cellular activity screening, we discovered that 5f and 5g exhibited significantly greater anti-inflammatory activity compared to SS-31, reducing LPS-induced TNF-α levels by 43% and 45%, respectively, at a concentration of 10 μM. Furthermore, treatment with 50 nM of 5f and 5g increased ATP synthesis by 42% and 41% in rotenone-induced HT22 cells and attenuated mitochondrial ROS production by preserving mitochondrial integrity. These findings demonstrate their direct protective effects on neuronal mitochondria. This work highlights the potential of 5f and 5g in the treatment of neurodegenerative diseases associated with inflammation and mitochondrial damage, offering a promising therapeutic avenue for mitochondrial-related conditions such as Alzheimer's disease.
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Affiliation(s)
- Mei Li
- Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan 250012 Shandong China
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
| | - Deyuan Kong
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
| | - Liying Meng
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Shandong University Qingdao 266035 Shandong China
| | - Zheyi Wang
- Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan 250012 Shandong China
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
| | - Zetai Bai
- Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan 250012 Shandong China
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
| | - Guanzhao Wu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan 250012 Shandong China
- Qingdao Key Lab of Mitochondrial Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University Qingdao 266103 China
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Shandong University Qingdao 266035 Shandong China
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50
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Di Carlo E, Sorrentino C. Oxidative Stress and Age-Related Tumors. Antioxidants (Basel) 2024; 13:1109. [PMID: 39334768 PMCID: PMC11428699 DOI: 10.3390/antiox13091109] [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: 07/19/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Oxidative stress is the result of the imbalance between reactive oxygen and nitrogen species (RONS), which are produced by several endogenous and exogenous processes, and antioxidant defenses consisting of exogenous and endogenous molecules that protect biological systems from free radical toxicity. Oxidative stress is a major factor in the aging process, contributing to the accumulation of cellular damage over time. Oxidative damage to cellular biomolecules, leads to DNA alterations, lipid peroxidation, protein oxidation, and mitochondrial dysfunction resulting in cellular senescence, immune system and tissue dysfunctions, and increased susceptibility to age-related pathologies, such as inflammatory disorders, cardiovascular and neurodegenerative diseases, diabetes, and cancer. Oxidative stress-driven DNA damage and mutations, or methylation and histone modification, which alter gene expression, are key determinants of tumor initiation, angiogenesis, metastasis, and therapy resistance. Accumulation of genetic and epigenetic damage, to which oxidative stress contributes, eventually leads to unrestrained cell proliferation, the inhibition of cell differentiation, and the evasion of cell death, providing favorable conditions for tumorigenesis. Colorectal, breast, lung, prostate, and skin cancers are the most frequent aging-associated malignancies, and oxidative stress is implicated in their pathogenesis and biological behavior. Our aim is to shed light on the molecular and cellular mechanisms that link oxidative stress, aging, and cancers, highlighting the impact of both RONS and antioxidants, provided by diet and exercise, on cellular senescence, immunity, and development of an antitumor response. The dual role of ROS as physiological regulators of cell signaling responsible for cell damage and diseases, as well as its use for anti-tumor therapeutic purposes, will also be discussed. Managing oxidative stress is crucial for promoting healthy aging and reducing the risk of age-related tumors.
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Affiliation(s)
- Emma Di Carlo
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Carlo Sorrentino
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
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