|
1
|
Carretero VJ, Álvarez-Merz I, Hernández-Campano J, Kirov SA, Hernández-Guijo JM. Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage. Neural Regen Res 2025; 20:2454-2463. [PMID: 39314160 PMCID: PMC11801293 DOI: 10.4103/nrr.nrr-d-24-00536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 07/16/2024] [Accepted: 08/14/2024] [Indexed: 09/25/2024] Open
Abstract
The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.
Collapse
Affiliation(s)
| | - Iris Álvarez-Merz
- Department of Pharmacology and Therapeutic, School of Medicine, Univ. Autónoma de Madrid, Madrid, Spain
- Ramón y Cajal Institute for Health Research (IRYCIS), Neurobiology-Research Service, Hospital Ramón y Cajal, Madrid, Spain
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Jorge Hernández-Campano
- Department of Pharmacology and Therapeutic, School of Medicine, Univ. Autónoma de Madrid, Madrid, Spain
| | - Sergei A. Kirov
- Department of Neuroscience and Regenerative Medicine & Department of Neurosurgery, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Jesús M. Hernández-Guijo
- Department of Pharmacology and Therapeutic, School of Medicine, Univ. Autónoma de Madrid, Madrid, Spain
- Ramón y Cajal Institute for Health Research (IRYCIS), Neurobiology-Research Service, Hospital Ramón y Cajal, Madrid, Spain
| |
Collapse
|
|
2
|
Cheng S, Zhou L, Wang WY, Zhang MJ, Yang QC, Da Wang W, Wang KH, Sun ZJ, Zhang L. Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss. Acta Biomater 2025; 195:225-239. [PMID: 39938705 DOI: 10.1016/j.actbio.2025.02.024] [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: 10/28/2024] [Revised: 01/21/2025] [Accepted: 02/09/2025] [Indexed: 02/14/2025]
Abstract
Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, the key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito-loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplies Mito as well as O2 to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation. STATEMENT OF SIGNIFICANCE: The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, we develop a method for encapsulating mitochondria within erythrocytes, termed mitochondria-loading erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O2 to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.
Collapse
Affiliation(s)
- Shi Cheng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Lu Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Wu-Yin Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Meng-Jie Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Qi-Chao Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Wen- Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Kong-Huai Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China.
| | - Lu Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, PR China.
| |
Collapse
|
|
3
|
Liu K, Ji Y, Xie Y, Wang C, Zhou J, Wei Z, Wang X, Zheng X, Cen Y, Zhang F, Xu B. Discovery of Isobenzofuran-1(3 H)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects. J Med Chem 2025; 68:5804-5823. [PMID: 40040241 DOI: 10.1021/acs.jmedchem.4c03146] [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: 03/06/2025]
Abstract
TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure-activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC50 values of a low micromolar level. Among them, Cpd8l potently and selectively inhibited TREK-1 (IC50 = 0.81 μM, selectivity >30 fold over other K+, Na+, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.
Collapse
Affiliation(s)
- Kaiyue Liu
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yunyun Ji
- The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Yiming Xie
- The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Chengyan Wang
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jie Zhou
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Ziyi Wei
- The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Xiaoyu Wang
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Xiaotong Zheng
- The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Yao Cen
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Fan Zhang
- The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Normal University, Guilin 541004, China
| | - Bailing Xu
- Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| |
Collapse
|
|
4
|
Chen R, Qian L, Zhang Q, Qin J, Chen X, Xu X. SMP30 alleviates cerebral ischemia/reperfusion-induced neuronal injury by inhibiting HDAC4/PSD-95 to preserve mitochondrial function. J Neuropathol Exp Neurol 2025; 84:59-73. [PMID: 39254519 DOI: 10.1093/jnen/nlae095] [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] [Indexed: 09/11/2024] Open
Abstract
Ischemic stroke is a major cause of global death and permanent disability. Major consequences of ischemic stroke include neuronal mitochondrial dysfunction. We investigated the effects of senescence marker protein 30 (SMP30) on mitochondria-mediated apoptosis and histone deacetylase 4 (HDAC4)/postsynaptic density-95 (PSD-95) signaling in stroke models in vivo and in vitro. Rats with middle cerebral artery occlusion/reperfusion (MCAO/R) were used to simulate cerebral ischemia/reperfusion (I/R) injury. SMP30 was downregulated in the brain tissues of rats after I/R induction. SMP30 overexpression decreased MCAO/R-induced infarct volumes and improved neurologic function and histopathological changes. Increasing SMP30 expression suppressed neuronal apoptosis and reduced mitochondrial dysfunction. SMP30 overexpression in SH-SY5Y and PC12 cells treated with oxygen-glucose deprivation/reoxygenation (OGD/R) decreased HDAC4 and PSD-95 expression; PSD-95 could bind to HDAC4. Furthermore, HDAC4 upregulation abolished the effects of SMP30 overexpression on OGD/R-induced apoptosis and mitochondrial dysfunction in SH-SY5Y cells. Together, these findings indicate that SMP30 alleviates cerebral I/R-induced neuronal injury by inhibiting HDAC4/PSD-95 to preserve mitochondrial function. These interactions might provide new treatment methods for patients with ischemic stroke.
Collapse
Affiliation(s)
- Rundong Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Lei Qian
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qian Zhang
- Gerontology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jiajun Qin
- Department of Neurosurgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xianzhen Chen
- Department of Neurosurgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaolong Xu
- Neurovascular Center, Changhai Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
|
5
|
Wang X, Hu J, Xie S, Li W, Zhang H, Huang L, Qian Z, Zhao C, Zhang L. Hidden role of microglia during neurodegenerative disorders and neurocritical care: A mitochondrial perspective. Int Immunopharmacol 2024; 142:113024. [PMID: 39217875 DOI: 10.1016/j.intimp.2024.113024] [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: 05/07/2024] [Revised: 08/04/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The incidence of aging-related neurodegenerative disorders and neurocritical care diseases is increasing worldwide. Microglia, the main inflammatory cells in the brain, could be potential viable therapeutic targets for treating neurological diseases. Interestingly, mitochondrial functions, including energy metabolism, mitophagy and transfer, fission and fusion, and mitochondrial DNA expression, also change in activated microglia. Notably, mitochondria play an active and important role in the pathophysiology of neurodegenerative disorders and neurocritical care diseases. This review briefly summarizes the current knowledge on mitochondrial dysfunction in microglia in neurodegenerative disorders and neurocritical care diseases and comprehensively discusses the prospects of the application of neurological injury prevention and treatment targets by mitochondria.
Collapse
Affiliation(s)
- Xinrun Wang
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Jiyun Hu
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Shucai Xie
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Wenchao Li
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Haisong Zhang
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Li Huang
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Zhaoxin Qian
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Chunguang Zhao
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
| | - Lina Zhang
- Department of Critical Care Medicine, Hunan Provincial Clinical Research Center for Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
| |
Collapse
|
|
6
|
Capobianco DL, De Zio R, Profico DC, Gelati M, Simone L, D'Erchia AM, Di Palma F, Mormone E, Bernardi P, Sbarbati A, Gerbino A, Pesole G, Vescovi AL, Svelto M, Pisani F. Human neural stem cells derived from fetal human brain communicate with each other and rescue ischemic neuronal cells through tunneling nanotubes. Cell Death Dis 2024; 15:639. [PMID: 39217148 PMCID: PMC11365985 DOI: 10.1038/s41419-024-07005-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y (dSH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to dSH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, dSH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R dSH-SY5Y became apoptotic with impaired electrical activity. When OGD/R dSH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R dSH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic dSH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.
Collapse
Affiliation(s)
- D L Capobianco
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - R De Zio
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - D C Profico
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Foggia, Italy
| | - M Gelati
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Foggia, Italy
| | - L Simone
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Foggia, Italy
| | - A M D'Erchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM) CNR, Bari, Italy
| | - F Di Palma
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - E Mormone
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Foggia, Italy
| | - P Bernardi
- Department of Neurosciences, Biomedicine and Movement Sciences. Unit of Human Anatomy, University of Verona, Verona, Italy
| | - A Sbarbati
- Department of Neurosciences, Biomedicine and Movement Sciences. Unit of Human Anatomy, University of Verona, Verona, Italy
| | - A Gerbino
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
| | - G Pesole
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM) CNR, Bari, Italy
| | - A L Vescovi
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Foggia, Italy
- Faculty of Medicine, Link Campus University, Rome, Italy
| | - M Svelto
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM) CNR, Bari, Italy
- National Institute of Biostructures and Biosystems (INBB), Rome, Italy
| | - F Pisani
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", Bari, Italy.
| |
Collapse
|
|
7
|
Sun L, Zhao Z, Guo J, Qin Y, Yu Q, Shi X, Guo F, Zhang H, Sun X, Gao C, Yang Q. Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis. Neural Regen Res 2024; 19:1325-1335. [PMID: 37905882 PMCID: PMC11467935 DOI: 10.4103/1673-5374.385313] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/04/2023] [Accepted: 07/28/2023] [Indexed: 11/02/2023] Open
Abstract
Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury. Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury. Thus, transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease. To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke, in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site (in situ ). Animal behavior tests, immunofluorescence staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, mRNA-seq, and western blotting were used to assess mouse anxiety and memory, cortical infarct area, pyroptosis, and neurogenesis, respectively. Using bioinformatics analysis, western blotting, co-immunoprecipitation, and mass spectroscopy, we identified S100 calcium binding protein A9 (S100A9) as a potential regulator of mitochondrial function and determined its possible interacting proteins. Interactions between exogenous and endogenous mitochondria, as well as the effect of exogenous mitochondria on recipient microglia, were assessed in vitro . Our data showed that: (1) mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function, as well as reducing infarct area, inhibiting pyroptosis, and promoting cortical neurogenesis; (2) microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function; (3) in vitro , exogenous mitochondria enhanced mitochondrial function, reduced redox stress, and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria; and (4) S100A9 promoted internalization of exogenous mitochondria by the microglia, thereby amplifying their pro-proliferation and anti-inflammatory effects. Taken together, our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis, and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.
Collapse
Affiliation(s)
- Li Sun
- Department of Experimental Surgery, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Zhaoyan Zhao
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jing Guo
- Department of Experimental Surgery, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Yuan Qin
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Qian Yu
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xiaolong Shi
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Fei Guo
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Haiqin Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xude Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Changjun Gao
- Department of Anesthesiology, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Qian Yang
- Department of Experimental Surgery, The Second Affiliated Hospital of Air Force Medical University, Xi’an, Shaanxi Province, China
| |
Collapse
|
|
8
|
Zhang J, Zhu Q, Wang J, Peng Z, Zhuang Z, Hang C, Li W. Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage. Neural Regen Res 2024; 19:825-832. [PMID: 37843218 PMCID: PMC10664111 DOI: 10.4103/1673-5374.381493] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/11/2023] [Accepted: 06/06/2023] [Indexed: 10/17/2023] Open
Abstract
The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.
Collapse
Affiliation(s)
- Jiatong Zhang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Qi Zhu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jie Wang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zheng Peng
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Zong Zhuang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chunhua Hang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wei Li
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China
| |
Collapse
|
|
9
|
Xu S, Zhong A, Zhang Y, Zhao L, Guo Y, Bai X, Yin P, Hua S. Bone marrow mesenchymal stem cells therapy regulates sphingolipid and glycerophospholipid metabolism to promote neurological recovery in stroke rats: A metabolomics analysis. Exp Neurol 2024; 372:114619. [PMID: 38029808 DOI: 10.1016/j.expneurol.2023.114619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/28/2023] [Accepted: 11/20/2023] [Indexed: 12/01/2023]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential in the subacute/chronic phase of acute ischemic stroke (AIS), but the underlying mechanisms are not yet fully elucidated. There is a knowledge gap in understanding the metabolic mechanisms of BMSCs in stroke therapy. In this study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). The treatment with BMSCs for 21 days significantly reduced the modified neurological severity score of MCAO rats (P < 0.01) and increased the number of surviving neurons in both the striatum and hippocampal dentate gyrus region (P < 0.01, respectively). Moreover, BMSCs treatment resulted in significant enhancements in various structural parameters of dendrites in layer V pyramidal neurons in the injured hemispheric motor cortex, including total length (P < 0.05), number of branches (P < 0.05), number of intersections (P < 0.01), and spine density (P < 0.05). Then, we performed plasma untargeted metabolomics analysis to study the metabolic changes of BMSCs on AIS. There were 65 differential metabolites identified in the BMSCs treatment group. Metabolic profiling analysis revealed that BMSCs modulate abnormal sphingolipid metabolism and glycerophospholipid metabolism, particularly affecting core members such as sphingomyelin (SM), ceramide (Cer) and sphingosine-1-phosphate (S1P). The metabolic network analysis and pathway-based compound-reaction-enzyme-gene network analysis showed that BMSCs inhibited the Cer-induced apoptotic pathway and promoted the S1P signaling pathway. These findings suggest that the enhanced effects of BMSCs on neuronal survival and synaptic plasticity after stroke may be mediated through these pathways. In conclusion, our study provides novel insight into the potential mechanisms of BMSCs treatment in stroke and sheds light on the possible clinical translation of BMSCs.
Collapse
Affiliation(s)
- Shixin Xu
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China.
| | - Aiqin Zhong
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Yunsha Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Linna Zhao
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Yuying Guo
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Xiaodan Bai
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Penglin Yin
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Shengyu Hua
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| |
Collapse
|
|
10
|
Carrillo Navarrete KA, Chapa González C. Hemiplegia in acute ischemic stroke: A comprehensive review of case studies and the role of intravenous thrombolysis and mechanical thrombectomy. IBRAIN 2024; 10:59-68. [PMID: 38682021 PMCID: PMC11045183 DOI: 10.1002/ibra.12146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 05/01/2024]
Abstract
Acute ischemic stroke is a significant health concern worldwide, often leading to long-term disability and decreased quality of life. Rapid and appropriate treatment is crucial for achieving optimal outcomes in these patients. Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are two commonly used interventions for acute ischemic stroke, but their effectiveness in improving neurological symptoms and functional outcomes in patients with hemiplegia remains uncertain. The aim of this work was to evaluate the impact of IVT and MT within a 4.5-h time frame on patients with acute ischemic stroke and hemiplegia. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies that assessed the impact of IVT and MT within 4.5-h on hemiplegia in patients with an acute ischemic stroke were included. Data were extracted and analyzed to determine the overall effects of these interventions. Most included case reports indicate positive outcomes in terms of neurological symptom improvement and functional recovery in patients with hemiplegia after receiving IVT and MT within the specified time frame. However, the heterogeneity among the patients and the limited use of IVT due to contraindications posed challenges in determining the most effective treatment option. The findings from the included studies demonstrate that both interventions led to a decrease in National Institutes of Health Stroke Scale scores, indicating an improvement in neurological symptoms. The results highlight the beneficial effects of early thrombolytic interventions and MT on the neurological status and functional outcomes of patients with an acute ischemic stroke.
Collapse
Affiliation(s)
- Karen Adriana Carrillo Navarrete
- Instituto de Ingeniería y TecnologíaUniversidad Autónoma de Ciudad JuárezCiudad Juárez, ChihuahuaMéxico
- Grupo de Nanomedicina, Laboratorio de Integración de Datos y Evidencia en Revisiones de Salud y Ciencia, LIDERSCUniversidad Autónoma de Ciudad JuárezCiudad Juárez, ChihuahuaMéxico
| | - Christian Chapa González
- Instituto de Ingeniería y TecnologíaUniversidad Autónoma de Ciudad JuárezCiudad Juárez, ChihuahuaMéxico
- Grupo de Nanomedicina, Laboratorio de Integración de Datos y Evidencia en Revisiones de Salud y Ciencia, LIDERSCUniversidad Autónoma de Ciudad JuárezCiudad Juárez, ChihuahuaMéxico
| |
Collapse
|
|
11
|
Jia Y, Xiao H, Wang X, Liu Y, Wang J, Xie H, Shang H, Sun G, Tian Y. Design, synthesis, and evaluation of n-butylphthalide and ligustrazine hybrids as potent neuroprotective agents for the treatment of ischemic stroke in vitro and in vivo. Bioorg Chem 2024; 142:106961. [PMID: 37956636 DOI: 10.1016/j.bioorg.2023.106961] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/28/2023] [Accepted: 11/05/2023] [Indexed: 11/15/2023]
Abstract
A series of novel NBP-TMP hybrids with neuroprotective effects were designed and synthesized for the treatment of ischemic stroke. The anti-cerebral ischemic activity of these compounds was screened by evaluating their neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell injury model in vitro. Nine compounds 7e, 7h-7i, 7k, 7m-7p and 7r showed better activities on cell viability and LDH levels compared to NBP at the concentration of 6.25 μM. Among them, compound 7m showed the best potency with a percentage of protection 90.2 % compared to NBP (69.2 %) and other compounds. Preliminary structure-activity analysis revealed that the introduction of iodine and N-methylpiperazine groups could significantly improve the neuroprotective effect. Further mechanism research showed that compound 7m could reduce the damage to neuronal mitochondria caused by OGD/R by reducing ROS and increasing mitochondrial membrane potential (MMP), and reduce the apoptosis and necrosis of neurons to play a neuroprotective role. In addition, 7m could regulate the levels of mitochondrial apoptosis pathway-related proteins Bcl-2, Bax, and caspase 3. Finally, in vivo experiments showed that the compound 7m significantly inhibited ischemia-reperfusion injury and cerebral blood flow in rats, and showed a more significant neuroprotective effect than the positive drug NBP at a dose concentration of 20 mg/kg. In conclusion, our results suggest that 7m may be used as a novel lead compound for the future development of anti-cerebral ischemic agents.
Collapse
Affiliation(s)
- Yi Jia
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Haiyan Xiao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Xiaolin Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Ying Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jiaxin Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Haochen Xie
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Hai Shang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Guibo Sun
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
| | - Yu Tian
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
| |
Collapse
|
|
12
|
Zhang Y, Zhang G, Chen X. Elevated Calcium after Acute Ischemic Stroke Predicts Severity and Prognosis. Mol Neurobiol 2024; 61:266-275. [PMID: 37605095 DOI: 10.1007/s12035-023-03581-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/14/2023] [Indexed: 08/23/2023]
Abstract
The aim of this study is to investigate whether there is a correlation between serum calcium levels and clinical severity or functional outcome at discharge in Chinese patients with acute ischemic stroke. Data from 339 patients admitted to our hospital between July 2020 and July 2021 were analyzed. Baseline demographic and clinical information was collected within 24 h of admission, including serum calcium levels, stroke severity (measured by the National Institutes of Health Stroke Scale [NIHSS] score), and lesion volumes. The modified Rankin Scale [mRS] assessed functional outcomes at discharge. Our analysis showed that the median age of patients included in the study was 65 years (interquartile range [IQR], 60-70), and 60.8% were men. We found a positive correlation between serum calcium levels and stroke severity (r[spearman] = 0.266, P < 0.001), with calcium levels increasing as stroke severity increased. In a subgroup of 188 patients with available MRI data, serum calcium concentrations positively correlated with infarct size. Furthermore, in multivariate analysis, a calcium serum level in the highest quartile was associated with a higher risk of unfavorable outcome (odds ratios [OR] = 3.27; 95% confidence intervals [CI] = 1.91-5.59; P < 0.001). In conclusion, our study indicates that higher calcium serum levels are associated with stroke severity and early neurologic outcome after acute ischemic stroke, indicating that calcium may serve as a prognostic biomarker for stroke in Chinese patients.
Collapse
Affiliation(s)
- Yueqi Zhang
- Department of Neurology, Weifang People's Hospital, No.151 Guangwen Street, Weifang, Shandong Province, 26100, China
| | - Guangjian Zhang
- Department of Neurology, Weifang People's Hospital, No.151 Guangwen Street, Weifang, Shandong Province, 26100, China
| | - Xuecong Chen
- Department of Neurology, Weifang People's Hospital, No.151 Guangwen Street, Weifang, Shandong Province, 26100, China.
| |
Collapse
|
|
13
|
Zeng J, Liu J, Ni H, Zhang L, Wang J, Li Y, Jiang W, Wu Z, Zhou M. Mitochondrial transplantation reduces lower limb ischemia-reperfusion injury by increasing skeletal muscle energy and adipocyte browning. Mol Ther Methods Clin Dev 2023; 31:101152. [PMID: 38027061 PMCID: PMC10667789 DOI: 10.1016/j.omtm.2023.101152] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/03/2023] [Indexed: 12/01/2023]
Abstract
Recent studies have shown that mitochondrial transplantation can repair lower limb IRI, but the underlying mechanism of the repair effect remains unclear. In this study, we found that in addition to being taken up by skeletal muscle cells, human umbilical cord mesenchymal stem cells (hMSCs)-derived mitochondria were also taken up by adipocytes, which was accompanied by an increase in optic atrophy 1 (OPA1) and uncoupling protein 1. Transplantation of hMSCs-derived mitochondria could not only supplement the original damaged mitochondrial function of skeletal muscle, but also promote adipocyte browning by increasing the expression of OPA1. In this process, mitochondrial transplantation can reduce cell apoptosis and repair muscle tissue, which promotes the recovery of motor function in vivo. To the best of our knowledge, there is no study on the therapeutic mechanism of mitochondrial transplantation from this perspective, which could provide a theoretical basis.
Collapse
Affiliation(s)
- Jiaqi Zeng
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
- Department of Vascular Surgery, Kunshan Traditional Chinese Medicine Hospital, Kunshan 215300, China
| | - Jianing Liu
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Haiya Ni
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Ling Zhang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Jun Wang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Yazhou Li
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Wentao Jiang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Ziyu Wu
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Min Zhou
- Department of Vascular Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| |
Collapse
|
|
14
|
Onieva A, Martin J, R Cuesta-Aguirre D, Planells V, Coronado-Zamora M, Beyer K, Vega T, Lozano JE, Santos C, Aluja MP. Complete mitochondrial DNA profile in stroke: A geographical matched case-control study in Spanish population. Mitochondrion 2023; 73:51-61. [PMID: 37793469 DOI: 10.1016/j.mito.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 08/28/2023] [Accepted: 10/01/2023] [Indexed: 10/06/2023]
Abstract
INTRODUCTION Stroke, the second leading cause of death worldwide, is a complex disease influenced by many risk factors among which we can find reactive oxygen species (ROS). Since mitochondria are the main producers of cellular ROS, nowadays studies are trying to elucidate the role of these organelles and its DNA (mtDNA) variation in stroke risk. The aim of the present study was to perform a comprehensive evaluation of the association between mtDNA mutations and mtDNA content and stroke risk. MATERIAL AND METHODS Homoplasmic and heteroplasmic mutations of the mtDNA were analysed in a case-controls study using 110 S cases and their corresponding control individuals. Mitochondrial DNA copy number (mtDNA-CN) was analysed in 73 of those case-control pairs. RESULTS Our results suggest that haplogroup V, specifically variants m.72C > T, m.4580G > A, m.15904C > T and m.16298 T > C have a protective role in relation to stroke risk. On the contrary, variants m.73A > G, m.11719G > A and m.14766C > T appear to be genetic risk factors for stroke. In this study, we found no statistically significant association between stroke risk and mitochondrial DNA copy number. CONCLUSIONS These results demonstrate the possible role of mtDNA genetics on the pathogenesis of stroke, probably through alterations in mitochondrial ROS production.
Collapse
Affiliation(s)
- Ana Onieva
- Unitat d'Antropologia Biològica, Departament BAVE, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
| | - Joan Martin
- Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Daniel R Cuesta-Aguirre
- Unitat d'Antropologia Biològica, Departament BAVE, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Violeta Planells
- Unitat d'Antropologia Biològica, Departament BAVE, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Marta Coronado-Zamora
- Institut de Biotecnologia i Biomedicina; Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Katrin Beyer
- Department of Pathology, Germans Trias i Pujol Research Institute, Badalona 08916 Barcelona, Spain
| | - Tomás Vega
- Dirección General de Salud Pública. Consejería de Sanidad. Junta de Castilla y León, 47007 Valladolid, Spain
| | - José Eugenio Lozano
- Dirección General de Salud Pública. Consejería de Sanidad. Junta de Castilla y León, 47007 Valladolid, Spain
| | - Cristina Santos
- Unitat d'Antropologia Biològica, Departament BAVE, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain
| | - Maria Pilar Aluja
- Unitat d'Antropologia Biològica, Departament BAVE, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
| |
Collapse
|
|
15
|
Farzaei MH, Ramezani-Aliakbari F, Ramezani-Aliakbari M, Zarei M, Komaki A, Shahidi S, Sarihi A, Salehi I. Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1633-1646. [PMID: 36971866 DOI: 10.1007/s00210-023-02469-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/19/2023] [Indexed: 03/29/2023]
Abstract
Ischemia/reperfusion (I/R) injury is a tissue damage during reperfusion after an ischemic condition. I/R injury is induced by pathological cases including stroke, myocardial infarction, circulatory arrest, sickle cell disease, acute kidney injury, trauma, and sleep apnea. It can lead to increased morbidity and mortality in the context of these processes. Mitochondrial dysfunction is one of the hallmarks of I/R insult, which is induced via reactive oxygen species (ROS) production, apoptosis, and autophagy. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play a main regulatory role in gene expression. Recently, there are evidence, which miRNAs are the major modulators of cardiovascular diseases, especially myocardial I/R injury. Cardiovascular miRNAs, specifically miR-21, and probably miR-24 and miR-126 have protective effects on myocardial I/R injury. Trimetazidine (TMZ) is a new class of metabolic agents with an anti-ischemic activity. It has beneficial effects on chronic stable angina by suppressing mitochondrial permeability transition pore (mPTP) opening. The present review study addressed the different mechanistic effects of TMZ on cardiac I/R injury. Online databases including Scopus, PubMed, Web of Science, and Cochrane library were assessed for published studies between 1986 and 2021. TMZ, an antioxidant and metabolic agent, prevents the cardiac reperfusion injury by regulating AMP-activated protein kinase (AMPK), cystathionine-γ-lyase enzyme (CSE)/hydrogen sulfide (H2S), and miR-21. Therefore, TMZ protects the heart against I/R injury by inducing key regulators such as AMPK, CSE/H2S, and miR-21.
Collapse
Affiliation(s)
- Mohammad Hosein Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Maryam Ramezani-Aliakbari
- Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Siamak Shahidi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Abdolrahman Sarihi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Salehi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
16
|
Ragni M, Fenaroli F, Ruocco C, Segala A, D’Antona G, Nisoli E, Valerio A. A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult. Front Neurosci 2023; 17:1197208. [PMID: 37397466 PMCID: PMC10308218 DOI: 10.3389/fnins.2023.1197208] [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: 03/30/2023] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Mitochondrial dysfunction plays a key role in the aging process, and aging is a strong risk factor for neurodegenerative diseases or brain injury characterized by impairment of mitochondrial function. Among these, ischemic stroke is one of the leading causes of death and permanent disability worldwide. Pharmacological approaches for its prevention and therapy are limited. Although non-pharmacological interventions such as physical exercise, which promotes brain mitochondrial biogenesis, have been shown to exert preventive effects against ischemic stroke, regular feasibility is complex in older people, and nutraceutical strategies could be valuable alternatives. We show here that dietary supplementation with a balanced essential amino acid mixture (BCAAem) increased mitochondrial biogenesis and the endogenous antioxidant response in the hippocampus of middle-aged mice to an extent comparable to those elicited by treadmill exercise training, suggesting BCAAem as an effective exercise mimetic on brain mitochondrial health and disease prevention. In vitro BCAAem treatment directly exerted mitochondrial biogenic effects and induced antioxidant enzyme expression in primary mouse cortical neurons. Further, exposure to BCAAem protected cortical neurons from the ischemic damage induced by an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD). BCAAem-mediated protection against OGD was abolished in the presence of rapamycin, Torin-1, or L-NAME, indicating the requirement of both mTOR and eNOS signaling pathways in the BCAAem effects. We propose BCAAem supplementation as an alternative to physical exercise to prevent brain mitochondrial derangements leading to neurodegeneration and as a nutraceutical intervention aiding recovery after cerebral ischemia in conjunction with conventional drugs.
Collapse
Affiliation(s)
- Maurizio Ragni
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Francesca Fenaroli
- Department of Molecular and Translational Medicine, Brescia University, Brescia, Italy
| | - Chiara Ruocco
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Agnese Segala
- Department of Molecular and Translational Medicine, Brescia University, Brescia, Italy
| | - Giuseppe D’Antona
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Alessandra Valerio
- Department of Molecular and Translational Medicine, Brescia University, Brescia, Italy
| |
Collapse
|
|
17
|
Sun M, Jiang W, Mu N, Zhang Z, Yu L, Ma H. Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases. J Transl Med 2023; 21:347. [PMID: 37231493 DOI: 10.1186/s12967-023-04203-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/13/2023] [Indexed: 05/27/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of noncommunicable disease-related death worldwide, and effective therapeutic strategies against CVD are urgently needed. Mitochondria dysfunction involves in the onset and development of CVD. Nowadays, mitochondrial transplantation, an alternative treatment aimed at increasing mitochondrial number and improving mitochondrial function, has been emerged with great therapeutic potential. Substantial evidence indicates that mitochondrial transplantation improves cardiac function and outcomes in patients with CVD. Therefore, mitochondrial transplantation has profound implications in the prevention and treatment of CVD. Here, we review the mitochondrial abnormalities that occur in CVD and summarize the therapeutic strategies of mitochondrial transplantation for CVD.
Collapse
Affiliation(s)
- Mingchu Sun
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, P.R. China
| | - Wenhua Jiang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, P.R. China
| | - Nan Mu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an, 710032, China
| | - Zihui Zhang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, P.R. China.
| | - Lu Yu
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Heng Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an, 710032, China.
| |
Collapse
|
|
18
|
Mishra Y, Kumar Kaundal R. Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders. Drug Discov Today 2023; 28:103583. [PMID: 37028501 DOI: 10.1016/j.drudis.2023.103583] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/19/2023] [Accepted: 03/31/2023] [Indexed: 04/09/2023]
Abstract
Sirtuin 3 (SIRT3), a mitochondrial deacetylase expressed preferentially in high-metabolic-demand tissues including the brain, requires NAD+ as a cofactor for catalytic activity. It regulates various processes such as energy homeostasis, redox balance, mitochondrial quality control, mitochondrial unfolded protein response (UPRmt), biogenesis, dynamics and mitophagy by altering protein acetylation status. Reduced SIRT3 expression or activity causes hyperacetylation of hundreds of mitochondrial proteins, which has been linked with neurological abnormalities, neuro-excitotoxicity and neuronal cell death. A body of evidence has suggested, SIRT3 activation as a potential therapeutic modality for age-related brain abnormalities and neurodegenerative disorders.
Collapse
Affiliation(s)
- Yogesh Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)-226002, India
| | - Ravinder Kumar Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)-226002, India.
| |
Collapse
|
|
19
|
Huang H, Oo TT, Apaijai N, Chattipakorn N, Chattipakorn SC. An Updated Review of Mitochondrial Transplantation as a Potential Therapeutic Strategy Against Cerebral Ischemia and Cerebral Ischemia/Reperfusion Injury. Mol Neurobiol 2023; 60:1865-1883. [PMID: 36595193 DOI: 10.1007/s12035-022-03200-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023]
Abstract
Regardless of the progress made in the pathogenesis of ischemic stroke, it remains a leading cause of adult disability and death. To date, the most effective treatment for ischemic stroke is the timely recanalization of the occluded artery. However, the short time window and reperfusion injury have greatly limited its application and efficacy. Mitochondrial dysfunction and ATP depletion have become regarded as being hallmarks of neuropathophysiology following ischemic stroke. Mitochondrial transplantation is a novel potential therapeutic intervention for ischemic stroke that has sparked widespread concern during the past few years. This review summarizes and discusses the effects of mitochondrial transplantation in in vitro and in vivo ischemic stroke models. In addition, pharmacological interventions promoting mitochondrial transplantation are reviewed and discussed. We also discuss the potential challenges to the clinical application of mitochondrial transplantation in the treatment of ischemic stroke.
Collapse
Affiliation(s)
- Huatuo Huang
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Thura Tun Oo
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nattayaporn Apaijai
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 50200, Chiang Mai, Thailand. .,Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
| |
Collapse
|
|
20
|
Moradi Vastegani S, Nasrolahi A, Ghaderi S, Belali R, Rashno M, Farzaneh M, Khoshnam SE. Mitochondrial Dysfunction and Parkinson's Disease: Pathogenesis and Therapeutic Strategies. Neurochem Res 2023:10.1007/s11064-023-03904-0. [PMID: 36943668 DOI: 10.1007/s11064-023-03904-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/21/2023] [Accepted: 02/28/2023] [Indexed: 03/23/2023]
Abstract
Parkinson's disease (PD) is a common age-related neurodegenerative disorder whose pathogenesis is not completely understood. Mitochondrial dysfunction and increased oxidative stress have been considered as major causes and central events responsible for the progressive degeneration of dopaminergic (DA) neurons in PD. Therefore, investigating mitochondrial disorders plays a role in understanding the pathogenesis of PD and can be an important therapeutic target for this disease. This study discusses the effect of environmental, genetic and biological factors on mitochondrial dysfunction and also focuses on the mitochondrial molecular mechanisms underlying neurodegeneration, and its possible therapeutic targets in PD, including reactive oxygen species generation, calcium overload, inflammasome activation, apoptosis, mitophagy, mitochondrial biogenesis, and mitochondrial dynamics. Other potential therapeutic strategies such as mitochondrial transfer/transplantation, targeting microRNAs, using stem cells, photobiomodulation, diet, and exercise were also discussed in this review, which may provide valuable insights into clinical aspects. A better understanding of the roles of mitochondria in the pathophysiology of PD may provide a rationale for designing novel therapeutic interventions in our fight against PD.
Collapse
Affiliation(s)
- Sadegh Moradi Vastegani
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahab Ghaderi
- Department of Neuroscience, School of Science and Advanced Technologies in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rafie Belali
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masome Rashno
- Asadabad School of Medical Sciences, Asadabad, Iran
- Student Research Committee, Asadabad School of Medical Sciences, Asadabad, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
|
21
|
Vastegani SM, Hajipour S, Sarkaki A, Basir Z, Farbood Y, Bavarsad K, Khoshnam SE. Curcumin Ameliorates Neurobehavioral Deficits in Ambient Dusty Particulate Matter-Exposure Rats: The Role of Oxidative Stress. Neurochem Res 2023; 48:1798-1810. [PMID: 36708454 DOI: 10.1007/s11064-023-03877-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/29/2023]
Abstract
It has been consistently found that exposure to ambient air pollution, such as particulate matter (PM), results in cognitive impairments and mental disorders. This study aimed to investigate the possible neuroprotective effects of curcumin, a polyphenol compound, on the neurobehavioral deficits and to identify the role of oxidative stress in dusty PM exposure rats. Rats received curcumin (50 mg/kg, daily, gavage, 2 weeks) 30 min before placing animals in a clean air chamber (≤ 150 µg/m3, 60 min daily, 2 weeks) or ambient dusty PM chamber (2000-8000 µg/m3, 60 min daily, 2 weeks). Subsequently, the cognitive and non-cognitive functions of the animals were evaluated using standard behavioral tests. Moreover, blood-brain barrier (BBB) permeability, brain water content (BWC), oxidative-antioxidative status, and histological changes were determined in the cerebral cortex and hippocampal areas of the rats. Our results showed that curcumin administration in dusty PM exposure rats attenuates memory impairment, decreases anxiety-/depression-like behaviors, and improves locomotor/exploratory activities. These findings were accompanied by reduced BBB permeability and BWC, decreasing oxidative stress, and lessening neuronal loss in the cerebral cortex and different hippocampal areas. The results of this study suggest that curcumin's antioxidant properties may contribute to its efficacy in improving neurobehavioral deficits and preventing neuronal loss associated with dusty PM exposure.
Collapse
Affiliation(s)
- Sadegh Moradi Vastegani
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Somayeh Hajipour
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Alireza Sarkaki
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zahra Basir
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Yaghoob Farbood
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kowsar Bavarsad
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
|
22
|
Monsour M, Gordon J, Lockard G, Alayli A, Elsayed B, Connolly J, Borlongan CV. Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke. Int J Mol Sci 2022; 23:13106. [PMID: 36361891 PMCID: PMC9656972 DOI: 10.3390/ijms232113106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 08/16/2024] Open
Abstract
Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.
Collapse
Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jonah Gordon
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Gavin Lockard
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Adam Alayli
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Bassel Elsayed
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jacob Connolly
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| |
Collapse
|
|
23
|
Zhao T, Zhu T, Xie L, Li Y, Xie R, Xu F, Tang H, Zhu J. Neural Stem Cells Therapy for Ischemic Stroke: Progress and Challenges. Transl Stroke Res 2022; 13:665-675. [PMID: 35032307 DOI: 10.1007/s12975-022-00984-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/07/2023]
Abstract
Ischemic stroke, with its high morbidity and mortality, is the most common cerebrovascular accident and results in severe neurological deficits. Despite advances in medical and surgical intervention, post-stroke therapies remain scarce, which seriously affects the quality of life of patients. Over the past decades, stem cell transplantation has been recognized as very promising therapy for neurological diseases. Neural stem cell (NSC) transplantation is the optimal choice for ischemic stroke as NSCs inherently reside in the brain and can potentially differentiate into a variety of cell types within the central nervous system. Recent research has demonstrated that NSC transplantation can facilitate neural recovery after ischemic stroke, but the mechanisms still remain unclear, and basic/clinical studies of NSC transplantation for ischemic stroke have not yet been thoroughly elucidated. We thus, in this review, provide a futher understanding of the therapeutic role of NSCs for ischemic stroke, and evaluate their prospects for future application in clinical patients of ischemic stroke.
Collapse
Affiliation(s)
- Tong Zhao
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Tongming Zhu
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Liqian Xie
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Yao Li
- Med-X Research Institute, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Rong Xie
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Feng Xu
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China.
| | - Hailiang Tang
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China.
| | - Jianhong Zhu
- Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Shanghai Key Laboratory of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College-Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China.
| |
Collapse
|
|
24
|
Hu Q, Lu J, Zhang X, Liu R, Yang SH. Mitochondria transplantation/transfer between single cells. J Cereb Blood Flow Metab 2022; 42:1748-1750. [PMID: 35726581 PMCID: PMC9441722 DOI: 10.1177/0271678x221109685] [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] [Indexed: 11/16/2022]
Abstract
Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al. reported a novel method for single cells mitochondria transplantation using "nanosyringe". This technique combines atomic force microscopy, optical microscopy, and nanofluidics that enable intra- and intercellular organelle micromanipulation and cell-to-cell mitochondria transplantation with up to 95% success rate. The transferred mitochondria fuse to the host mitochondrial network and donor mtDNA incorporate into the recipient mitochondrial genome. The nanosyringe technique provides a novel tool for future mitochondrial research to offer insight into mitochondrial replacement therapy for stroke and fundamental mitochondrial biology.
Collapse
Affiliation(s)
- Qin Hu
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Jianfei Lu
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Xiaohua Zhang
- Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Ran Liu
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Shao-Hua Yang
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
| |
Collapse
|
|
25
|
Li Z, Yu H, Li J. Identification of Key Endoplasmic Reticulum Stress-Related Genes in Non-Alcoholic Fatty Liver Disease. BIOMEDINFORMATICS 2022; 2:424-433. [DOI: 10.3390/biomedinformatics2030027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Background: Endoplasmic reticulum stress (ERS) is involved in the etiology of non-alcoholic fatty liver disease (NAFLD). Thus, the current study was designed to identify key ERS-associated genes in NAFLD. Methods: RNA-Seq data of NAFLD and controls were sourced from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in NAFLD and controls were identified by limma. By overlapping DEGs and ERS-related genes, ERS-related DEGs were identified. The function of ERS-related DEGs was characterized by clusterProfiler. Next, the protein–protein interaction (PPI) network was created using the Cytoscape software and the STRING database to identify key ERS-related genes in NAFLD. Furthermore, the correlations among key ERS-related genes were calculated. Results: A total of 8965 DEGs were identified between NAFLD and controls in the GSE126848 dataset. After overlapping these DEGs and ERS-related genes, 20 genes were identified as ERS-related DEGs in NAFLD. Functional analysis revealed that the genes mainly participated in ER-related functions, such as the ER–nucleus signaling pathway, regulation of ERS response, and protein processing in ER. The PPI network revealed the interactions among 17 ERS-related DEGs, including ERN1, ATF6, and EIF2S1 as the key genes. The expressions of ERN1, ATF6, and EIF2S1 were significantly down-regulated in NAFLD and were strongly positively correlated with each other. Further, the expression of ERN1 and ATFA6 was also similar in the GSE89632 datasets. Conclusion: The present study identified ERN1, ATF6, and EIF2S1 as key ERS-related genes in NAFLD. These findings may provide a molecular basis for the role of ERS in NAFLD.
Collapse
Affiliation(s)
- Zhuang Li
- School of Basic Medical Sciences, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Haozhen Yu
- School of Basic Medical Sciences, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Jun Li
- School of Basic Medical Sciences, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| |
Collapse
|
|
26
|
Zhang Z, Zhang A, Liu Y, Hu X, Fang Y, Wang X, Luo Y, Lenahan C, Chen S. New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria. Curr Neuropharmacol 2022; 20:1278-1296. [PMID: 34720082 PMCID: PMC9881073 DOI: 10.2174/1570159x19666211101103646] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/06/2021] [Accepted: 10/28/2021] [Indexed: 11/22/2022] Open
Abstract
Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (Δψm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets and summarize the promising therapeutic strategies targeting mitochondria for SAH.
Collapse
Affiliation(s)
- Zeyu Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Anke Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Yibo Liu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Xiaoming Hu
- Department of Neurosurgery, Taizhou Hospital, Taizhou, Zhejiang Province, China;
| | - Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;
| | - Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;
| | - Yujie Luo
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;
| | - Cameron Lenahan
- Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,Address correspondence to this author at the Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Tel: +86-571-87784815; Fax: +86-571-87784755; E-mail:
| |
Collapse
|
|
27
|
Eugenin E, Camporesi E, Peracchia C. Direct Cell-Cell Communication via Membrane Pores, Gap Junction Channels, and Tunneling Nanotubes: Medical Relevance of Mitochondrial Exchange. Int J Mol Sci 2022; 23:6133. [PMID: 35682809 PMCID: PMC9181466 DOI: 10.3390/ijms23116133] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/28/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
The history of direct cell-cell communication has evolved in several small steps. First discovered in the 1930s in invertebrate nervous systems, it was thought at first to be an exception to the "cell theory", restricted to invertebrates. Surprisingly, however, in the 1950s, electrical cell-cell communication was also reported in vertebrates. Once more, it was thought to be an exception restricted to excitable cells. In contrast, in the mid-1960s, two startling publications proved that virtually all cells freely exchange small neutral and charged molecules. Soon after, cell-cell communication by gap junction channels was reported. While gap junctions are the major means of cell-cell communication, in the early 1980s, evidence surfaced that some cells might also communicate via membrane pores. Questions were raised about the possible artifactual nature of the pores. However, early in this century, we learned that communication via membrane pores exists and plays a major role in medicine, as the structures involved, "tunneling nanotubes", can rescue diseased cells by directly transferring healthy mitochondria into compromised cells and tissues. On the other hand, pathogens/cancer could also use these communication systems to amplify pathogenesis. Here, we describe the evolution of the discovery of these new communication systems and the potential therapeutic impact on several uncurable diseases.
Collapse
Affiliation(s)
- Eliseo Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch (UTMB), 105 11th Street, Galveston, TX 77555, USA
| | - Enrico Camporesi
- Department of Surgery and TEAM Health Anesthesia, University of South Florida, 2 Tampa General Circle, Tampa, FL 33606, USA;
| | - Camillo Peracchia
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA;
| |
Collapse
|
|
28
|
Yang YD, Li ZX, Hu XM, Wan H, Zhang Q, Xiao R, Xiong K. Insight into Crosstalk Between Mitophagy and Apoptosis/Necroptosis: Mechanisms and Clinical Applications in Ischemic Stroke. Curr Med Sci 2022; 42:237-248. [PMID: 35391618 DOI: 10.1007/s11596-022-2579-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/14/2022] [Indexed: 12/14/2022]
Abstract
Ischemic stroke is a serious cerebrovascular disease with high morbidity and mortality. As a result of ischemia-reperfusion, a cascade of pathophysiological responses is triggered by the imbalance in metabolic supply and demand, resulting in cell loss. These cellular injuries follow various molecular mechanisms solely or in combination with this disorder. Mitochondria play a driving role in the pathophysiological processes of ischemic stroke. Once ischemic stroke occurs, damaged cells would respond to such stress through mitophagy. Mitophagy is known as a conservatively selective autophagy, contributing to the removal of excessive protein aggregates and damaged intracellular components, as well as aging mitochondria. Moderate mitophagy may exert neuroprotection against stroke. Several pathways associated with the mitochondrial network collectively contribute to recovering the homeostasis of the neurovascular unit. However, excessive mitophagy would also promote ischemia-reperfusion injury. Therefore, mitophagy is a double-edged sword, which suggests that maximizing the benefits of mitophagy is one of the direction of future efforts. This review emphasized the role of mitophagy in ischemic stroke, and highlighted the crosstalk between mitophagy and apoptosis/necroptosis.
Collapse
Affiliation(s)
- Yan-di Yang
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, 410013, China
| | - Zi-Xin Li
- Clinical Medicine Eight-year Program, 03 Class, 18 Grade, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Xi-Min Hu
- Clinical Medicine Eight-Year Program, 02 Class, 17 Grade, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Hao Wan
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, 410013, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, 410013, China
| | - Rui Xiao
- Administrative Office, the Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, 410013, China.
- Hunan Key Laboratory of Ophthalmology, Changsha, 410008, China.
- Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, China.
| |
Collapse
|
|
29
|
Li X, Chen G. Mitochondrial-Based Therapeutic Strategies for Intracerebral Hemorrhage. Transl Stroke Res 2022; 13:214-215. [PMID: 34743289 DOI: 10.1007/s12975-021-00966-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 02/03/2023]
Affiliation(s)
- Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China.
| |
Collapse
|
|
30
|
Yan F, Tang H, Wang L, Huang L, Zhang J. Editorial: Mitochondrial Dysfunction in Stroke. Front Aging Neurosci 2022; 14:888952. [PMID: 35431902 PMCID: PMC9007590 DOI: 10.3389/fnagi.2022.888952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 03/07/2022] [Indexed: 11/15/2022] Open
Affiliation(s)
- Feng Yan
- Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hailiang Tang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lin Wang
- Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lei Huang
- Department of Neurosurgery, Loma Linda University, Loma Linda, CA, United States
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, United States
- *Correspondence: Lei Huang
| | - John Zhang
- Department of Neurosurgery, Loma Linda University, Loma Linda, CA, United States
- Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, United States
- John Zhang
| |
Collapse
|
|
31
|
Gao L, Liu F, Hou PP, Manaenko A, Xiao ZP, Wang F, Xu TL, Hu Q. Neurons Release Injured Mitochondria as “Help-Me” Signaling After Ischemic Stroke. Front Aging Neurosci 2022; 14:785761. [PMID: 35309888 PMCID: PMC8926840 DOI: 10.3389/fnagi.2022.785761] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a “help-me” signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.
Collapse
Affiliation(s)
- Li Gao
- Central Laboratory, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Cerebrovascular Disease Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Liu
- Department of Anatomy and Physiology, Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pin-Pin Hou
- Central Laboratory, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Anatol Manaenko
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Peng Xiao
- Cerebrovascular Disease Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Wang
- Cerebrovascular Disease Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian-Le Xu
- Department of Anatomy and Physiology, Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Tian-Le Xu,
| | - Qin Hu
- Central Laboratory, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Qin Hu,
| |
Collapse
|
|
32
|
Parvez S, Kaushik M, Ali M, Alam MM, Ali J, Tabassum H, Kaushik P. Dodging blood brain barrier with "nano" warriors: Novel strategy against ischemic stroke. Theranostics 2022; 12:689-719. [PMID: 34976208 PMCID: PMC8692911 DOI: 10.7150/thno.64806] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022] Open
Abstract
Ischemic stroke (IS) is one of the leading causes of death and disability resulting in inevitable burden globally. Ischemic injury initiates cascade of pathological events comprising energy dwindling, failure of ionic gradients, failure of blood brain barrier (BBB), vasogenic edema, calcium over accumulation, excitotoxicity, increased oxidative stress, mitochondrial dysfunction, inflammation and eventually cell death. In spite of such complexity of the disease, the only treatment approved by US Food and Drug Administration (FDA) is tissue plasminogen activator (t-PA). This therapy overcome blood deficiency in the brain along with side effects of reperfusion which are responsible for considerable tissue injury. Therefore, there is urgent need of novel therapeutic perspectives that can protect the integrity of BBB and salvageable brain tissue. Advancement in nanomedicine is empowering new approaches that are potent to improve the understanding and treatment of the IS. Herein, we focus nanomaterial mediated drug delivery systems (DDSs) and their role to bypass and cross BBB especially via intranasal drug delivery. The various nanocarriers used in DDSs are also discussed. In a nut shell, the objective is to provide an overview of use of nanomedicine in the diagnosis and treatment of IS to facilitate the research from benchtop to bedside.
Collapse
Affiliation(s)
- Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Medha Kaushik
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Mubashshir Ali
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Mumtaz Alam
- Drug Design & Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi - 110062, India
| | - Heena Tabassum
- Division of Basic Medical Sciences, Indian Council of Medical Research, Ministry of Health and Family Welfare, Govt. of India, V. Ramalingaswami Bhawan, P.O. Box No. 4911, New Delhi 110029, India
| | - Pooja Kaushik
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi 110062, India
| |
Collapse
|
|
33
|
Chen Y. Disturbed cerebral circulation and metabolism matters: A preface to the special issue "Stroke and Energy Metabolism": A preface to the special issue "Stroke and Energy Metabolism". J Neurochem 2021; 160:10-12. [PMID: 34894153 DOI: 10.1111/jnc.15552] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/21/2021] [Accepted: 11/28/2021] [Indexed: 11/30/2022]
Abstract
Stroke is a serious neurological disorder caused by blockage or rupture of cerebral blood vessels. Two main aims in acute stroke therapy include the restoration of cerebral blood flow in order to preserve energy supply to neurons and other brain cells, and minimizing neuronal loss. Maintenance of energy homeostasis in the brain drives neural network dynamics, which preserves normal brain function under physiological conditions. As such, cerebral energy homeostasis is a key target in stroke therapy. The various articles in this special issue highlight energy metabolism changes following stroke, including disturbed cerebral blood circulation, mitochondrial dysfunction, programmed neuronal cell death and cell-cell communication in brain metabolism. Collectively, this series of articles provides insight and presents new avenues for further research to improve the clinical management of stroke patients.
Collapse
Affiliation(s)
- Yujie Chen
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| |
Collapse
|
|
34
|
Park JH, Lo EH, Hayakawa K. Endoplasmic Reticulum Interaction Supports Energy Production and Redox Homeostasis in Mitochondria Released from Astrocytes. Transl Stroke Res 2021; 12:1045-1054. [PMID: 33479917 PMCID: PMC8324082 DOI: 10.1007/s12975-021-00892-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 12/18/2020] [Accepted: 01/17/2021] [Indexed: 01/09/2023]
Abstract
Mitochondria can be released by astrocytes as part of a help-me signaling process in stroke. In this study, we investigated the molecular mechanisms that underlie mitochondria secretion, redox status, and functional regulation in the extracellular environment. Exposure of rat primary astrocytes to NAD or cADPR elicited an increase in mitochondrial calcium through ryanodine receptor (RyR) in the endoplasmic reticulum (ER). Importantly, CD38 stimulation with NAD accelerated ATP production along with increasing glutathione reductase (GR) and dipicolinic acid (DPA) in intracellular mitochondria. When RyR was blocked by Dantrolene, all effects were clearly diminished. Mitochondrial functional assay showed that these activated mitochondria appeared to be resistant to H2O2 exposure and sustained mitochondrial membrane potential, while inhibition of RyR resulted in disrupted membrane potential under oxidative stress. Finally, a gain- or loss-of-function assay demonstrated that treatment with DPA in control mitochondria preserved GR contents and increased mitochondrial membrane potential, whereas inhibiting GR with carmustine decreased membrane potentials in extracellular mitochondria released from astrocytes. Collectively, these data suggest that ER-mitochondrial interaction mediated by CD38 stimulation may support mitochondrial energy production and redox homeostasis during the mode of mitochondrial transfer from astrocytes.
Collapse
Affiliation(s)
- Ji-Hyun Park
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149-2401, Charlestown, MA, 02129, USA
| | - Eng H Lo
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149-2401, Charlestown, MA, 02129, USA
| | - Kazuhide Hayakawa
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149-2401, Charlestown, MA, 02129, USA.
| |
Collapse
|
|
35
|
Mu Q, Zhang Y, Gu L, Gerner ST, Qiu X, Tao Q, Pang J, Dipritu G, Zhang L, Yin S, Jiang Y, Peng J. Transcriptomic Profiling Reveals the Antiapoptosis and Antioxidant Stress Effects of Fos in Ischemic Stroke. Front Neurol 2021; 12:728984. [PMID: 34744970 PMCID: PMC8566985 DOI: 10.3389/fneur.2021.728984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/09/2021] [Indexed: 12/02/2022] Open
Abstract
Arterial hypertension is considered the most prevalent risk factor for stroke. Both pathophysiologic and clinical data previously acquired suggest a strong correlation between the hemodynamic nature of arterial hypertension and an increase in the risk of ischemic insult to tissues. However, the knowledge of specific molecular interactions between hypertension and ischemic stroke (IS) is limited. In this study, we performed systematic bioinformatics analysis of stroke-prone spontaneous hypertensive brain tissue samples of rats (GSE41452), middle cerebral artery occlusion of brain tissue samples of rats (GSE97537), and peripheral blood array data of IS patients (GSE22255). We identified that Fos, an immediate-early gene (IEG) that responds to alterations in arterial blood pressure, has a strong correlation with the occurrence and prognosis of IS. To further evaluate the potential function of Fos, the oxygen–glucose deprivation model and RNA sequencing of HT22 neuronal cells were performed. Consistent with the sequencing results, real-time quantitative PCR and Western blot indicate that Fos was elevated at 3 h and returned to normal levels at 6 h after oxygen–glucose deprivation. Knock-down of Fos by lentivirus significantly increased the oxidative stress level, neuronal apoptosis, and inhibited the mitochondrial function. In conclusion, Fos acts as an important link between hypertension and IS. Furthermore, Fos can be used as a potential biomarker for target therapy in the prevention of stroke among hypertensive patients and also potential treatment targeting apoptosis and oxidative stress after its onset.
Collapse
Affiliation(s)
- Qiancheng Mu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yuxuan Zhang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Long Gu
- Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Stefan T Gerner
- Department of Neurology, University Hospital Erlangen-Nuremberg, Erlangen, Germany
| | - Xiancheng Qiu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qianke Tao
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jinwei Pang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Ghosh Dipritu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lifang Zhang
- Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shigang Yin
- Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.,Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
|
36
|
Pang J, Wu Y, Peng J, Yang P, Chen L, Jiang Y. Association of Pericyte Loss With Microthrombosis After Subarachnoid Hemorrhage in ApoE-Deficient Mice. Front Neurol 2021; 12:726520. [PMID: 34566870 PMCID: PMC8460864 DOI: 10.3389/fneur.2021.726520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/19/2021] [Indexed: 11/23/2022] Open
Abstract
Background: The occurrence of microthrombosis contributes to not only delayed cerebral ischemia (DCI), but also early brain injury (EBI) after SAH. However, the underlying mechanism is not completely investigated. In the current study, we explored the underlying mechanism of microthrombosis in EBI stage after SAH in ApoE-deficient mice. Methods: Experimental SAH was established by endovascular perforation in apolipoprotein E (ApoE)-deficient mice and wild type (WT) mice. Neurobehavioral, molecular biological and histopathological methods were used to assess the relationship between pericytes loss, neurobehavioral performance, and microthrombosis. Results: We found that the number of microthrombi was significantly increased and peaked 48 h after SAH in WT mice. The increased microthrombosis was related to the decreased effective microcirculation perfusion area and EBI severity. ApoE-deficient mice showed more extensive microthrombosis than that of WT mice 48 h after SAH, which was thereby associated with greater neurobehavioral deficits. Immunohistochemical staining showed that microthrombi were predominantly located in microvessels where pericytes coverage was absent. Mechanistically, ApoE deficiency caused more extensive CypA-NF-κB-MMP-9 pathway activation than that observed in WT mice, which thereby led to more degradation of N-cadherin, and subsequently more pericytes loss. Thereafter, the major adhesion molecule that promoting microthrombi formation in microvessels, P-selectin, was considerably increased in WT mice and increased to a greater extent in the ApoE-deficient mice. Conclusion: Taken together, these data suggest that pericytes loss is associated with EBI after SAH through promoting microthrombosis. Therapies that target ApoE to reduce microthrombosis may be a promising strategy for SAH treatment.
Collapse
Affiliation(s)
- Jinwei Pang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yue Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ping Yang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ligang Chen
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Sichuan Clinical Research Center for Neurosurgery, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Sichuan Clinical Research Center for Neurosurgery, Luzhou, China.,Luzhou Key Laboratory of Neurological Diseases and Brain Function, Luzhou, China
| |
Collapse
|
|
37
|
Nasoni MG, Carloni S, Canonico B, Burattini S, Cesarini E, Papa S, Pagliarini M, Ambrogini P, Balduini W, Luchetti F. Melatonin reshapes the mitochondrial network and promotes intercellular mitochondrial transfer via tunneling nanotubes after ischemic-like injury in hippocampal HT22 cells. J Pineal Res 2021; 71:e12747. [PMID: 34085316 PMCID: PMC8365755 DOI: 10.1111/jpi.12747] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/21/2021] [Accepted: 05/31/2021] [Indexed: 12/17/2022]
Abstract
Mitochondrial dysfunction is considered one of the hallmarks of ischemia/reperfusion injury. Mitochondria are plastic organelles that undergo continuous biogenesis, fusion, and fission. They can be transferred between cells through tunneling nanotubes (TNTs), dynamic structures that allow the exchange of proteins, soluble molecules, and organelles. Maintaining mitochondrial dynamics is crucial to cell function and survival. The present study aimed to assess the effects of melatonin on mitochondrial dynamics, TNT formation, and mitochondria transfer in HT22 cells exposed to oxygen/glucose deprivation followed by reoxygenation (OGD/R). The results showed that melatonin treatment during the reoxygenation phase reduced mitochondrial reactive oxygen species (ROS) production, improved cell viability, and increased the expression of PGC1α and SIRT3. Melatonin also preserved the expression of the membrane translocase proteins TOM20 and TIM23, and of the matrix protein HSP60, which are involved in mitochondrial biogenesis. Moreover, it promoted mitochondrial fusion and enhanced the expression of MFN2 and OPA1. Remarkably, melatonin also fostered mitochondrial transfer between injured HT22 cells through TNT connections. These results provide new insights into the effect of melatonin on mitochondrial network reshaping and cell survival. Fostering TNTs formation represents a novel mechanism mediating the protective effect of melatonin in ischemia/reperfusion injury.
Collapse
Affiliation(s)
- Maria Gemma Nasoni
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Silvia Carloni
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Barbara Canonico
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Sabrina Burattini
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Erica Cesarini
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Stefano Papa
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Marica Pagliarini
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Patrizia Ambrogini
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Walter Balduini
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| | - Francesca Luchetti
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly
| |
Collapse
|
|
38
|
Park JH, Nakamura Y, Li W, Hamanaka G, Arai K, Lo EH, Hayakawa K. Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab 2021; 41:1523-1535. [PMID: 33153373 PMCID: PMC8221762 DOI: 10.1177/0271678x20969588] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mitochondria may be transferred from cell to cell in the central nervous system and this process may help defend neurons against injury and disease. But how mitochondria maintain their functionality during the process of release into extracellular space remains unknown. Here, we report that mitochondrial protein O-GlcNAcylation is a critical process to support extracellular mitochondrial functionality. Activation of CD38-cADPR signaling in astrocytes robustly induced protein O-GlcNAcylation in mitochondria, while oxygen-glucose deprivation and reoxygenation showed transient and mild protein modification. Blocking the endoplasmic reticulum - Golgi trafficking with Brefeldin A or slc35B4 siRNA reduced O-GlcNAcylation, and resulted in the secretion of mitochondria with decreased membrane potential and mtDNA. Finally, loss-of-function studies verified that O-GlcNAc-modified mitochondria demonstrated higher levels of neuroprotection after astrocyte-to-neuron mitochondrial transfer. Collectively, these findings suggest that post-translational modification by O-GlcNAc may be required for supporting the functionality and neuroprotective properties of mitochondria released from astrocytes.
Collapse
Affiliation(s)
- Ji-Hyun Park
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Yoshihiko Nakamura
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Wenlu Li
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Gen Hamanaka
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Ken Arai
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Eng H Lo
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Kazuhide Hayakawa
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| |
Collapse
|
|
39
|
Zhao L, Li H, Gao Q, Xu J, Zhu Y, Zhai M, Zhang P, Shen N, Di Y, Wang J, Chen T, Huang M, Sun J, Liu C. Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway. Front Pharmacol 2021; 12:609693. [PMID: 33995012 PMCID: PMC8113774 DOI: 10.3389/fphar.2021.609693] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 03/31/2021] [Indexed: 12/15/2022] Open
Abstract
Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.
Collapse
Affiliation(s)
- Lina Zhao
- Department of Anaesthesiology, Tianjin Hospital, Tianjin, China
| | - Huanming Li
- Department of Cardiology, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin, China
| | - Qian Gao
- Department of Emergency Medicine, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China
| | - Jin Xu
- Department of Anaesthesiology, Tianjin Hospital, Tianjin, China
| | - Yongjie Zhu
- Department of Pathology, First People's Hospital of Aksu, Xinjiang, China
| | - Meili Zhai
- Department of Anaesthesiology, Tianjin Central Hospital of Gynecology Obstetrics, Gynecology Obstetrics Hospital of Nankai University, Tianjin, China
| | - Peijun Zhang
- Department of Anaesthesiology, Tianjin Central Hospital of Gynecology Obstetrics, Gynecology Obstetrics Hospital of Nankai University, Tianjin, China
| | - Na Shen
- Department of Central Laboratory, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China
| | - Yanbo Di
- Department of Central Laboratory, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China
| | - Jinhui Wang
- Department of Anaesthesiology, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin, China
| | - Tie Chen
- Department of Anaesthesiology, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin, China
| | - Meina Huang
- Department of Anaesthesiology, Wuqing People's Hospital, Tianjin, China
| | - Jinglai Sun
- Department of Biomedical Engineering, Tianjin Key Laboratory of Biomedical Detecting Techniques and Instruments, Tianjin University, Tianjin, China
| | - Chong Liu
- Department of Central Laboratory, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China.,Department of Anaesthesiology, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin, China
| |
Collapse
|