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Quan J, Liu Q, Li P, Yang Z, Zhang Y, Zhao F, Zhu G. Mesenchymal stem cell exosome therapy: current research status in the treatment of neurodegenerative diseases and the possibility of reversing normal brain aging. Stem Cell Res Ther 2025; 16:76. [PMID: 39985030 PMCID: PMC11846194 DOI: 10.1186/s13287-025-04160-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/21/2025] [Indexed: 02/23/2025] Open
Abstract
With the exacerbation of the aging population trend, a series of neurodegenerative diseases caused by brain aging have become increasingly common, significantly impacting the daily lives of the elderly and imposing heavier burdens on nations and societies. Brain aging is a complex process involving multiple mechanisms, including oxidative stress, apoptosis of damaged neuronal cells, chronic inflammation, and mitochondrial dysfunction, and research into new therapeutic strategies to delay brain aging has gradually become a research focus in recent years. Mesenchymal stem cells (MSCs) have been widely used in cell therapy due to their functions such as antioxidative stress, anti-inflammation, and tissue regeneration. However, accompanying safety issues such as immune rejection, tumor development, and pulmonary embolism cannot be avoided. Studies have shown that using exosome derived from mesenchymal stem cells (MSC-Exo) for the treatment of neurodegenerative diseases is a safe and effective method. It not only has the therapeutic effects of stem cells but also avoids the risks associated with cell therapy. Therefore, exploring new therapeutic strategies to delay normal brain aging from the mechanism of MSC-Exo in the treatment of neurodegenerative diseases is feasible. This review summarizes the characteristics of MSC-Exo and their clinical progress in the treatment of neurodegenerative diseases, aiming to explore the possibility and potential mechanisms of MSC-Exo in reversing brain aging.
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Affiliation(s)
- Jinglan Quan
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Qing Liu
- Department of Library, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Pinghui Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Zhiyu Yang
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Yaohui Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Fuxing Zhao
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China
| | - Gaohong Zhu
- Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650032, China.
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Liu X, Qian Z, Li Y, Wang Y, Zhang Y, Zhang Y, Enoch IVMV. Unveiling synergies: Integrating TCM herbal medicine and acupuncture with conventional approaches in stroke management. Neuroscience 2025; 567:109-122. [PMID: 39730019 DOI: 10.1016/j.neuroscience.2024.12.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/09/2024] [Accepted: 12/21/2024] [Indexed: 12/29/2024]
Abstract
This review explores the mechanisms and treatment strategies of ischemic stroke, a leading cause of morbidity and mortality worldwide. Ischemic stroke results from the obstruction of blood flow to the brain, leading to significant neurological impairment. The paper categorizes ischemic stroke into subtypes based on etiology, including cardioembolism and large artery atherosclerosis, and discusses the challenges of current therapeutic approaches. Conventional treatments like tissue plasminogen activator (tPA) and surgical interventions are limited by narrow windows and potential complications. The review highlights the promise of acupuncture, which offers neuroprotective benefits by promoting cerebral ischemic tolerance and neural regeneration. Integrating acupuncture with conventional treatments may enhance patient outcomes. Emphasis is placed on understanding the pathophysiology to develop targeted therapies that mitigate neuronal damage and enhance recovery.
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Affiliation(s)
- Xiliang Liu
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China
| | - Zhendong Qian
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China
| | - Yuxuan Li
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China
| | - Yanwei Wang
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China
| | - Yan Zhang
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China
| | - Yu Zhang
- Department of Rehabilitation Medicine, Dezhou Traditional Chinese Medicine Hospital, Dezhou 253000, China.
| | - Israel V M V Enoch
- Centre for Nanoscience and Genomics, Karunya Institute of Technology and Sciences (Deemed University), Coimbatore 641114, Tamil Nadu, India
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Vadak N, Borkar MR, Bhatt LK. Deciphering neuroprotective mechanism of nitroxoline in cerebral ischemia: network pharmacology and molecular modeling-based investigations. Mol Divers 2024; 28:3993-4015. [PMID: 38233690 DOI: 10.1007/s11030-023-10791-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/05/2023] [Indexed: 01/19/2024]
Abstract
Cerebral ischemia is one of the major causes of death and disability worldwide. Currently, existing approved therapies are based on reperfusion and there is an unmet need to search for drugs with neuroprotective effects. The present study aims to investigate the neuroprotective mechanisms of nitroxoline, a nitro derivative of 8-Hydroxyquinoline, against cerebral ischemia using integrated network pharmacology and molecular docking approaches. Critical analytical tools used were SwissTarget, PharmMapper, BindingDB, DisGeNet, Cytoscape, GeneMANIA, ShinyGo, Metascape, GeneCodis, and Schrodinger GLIDE. Thirty-six overlapping drug and disease targets were identified and used for further analysis. Gene Ontology results showed that nitroxoline enriched the genes involved in biological processes of oxidative stress and apoptotic cell death that are highly implicated in hypoxic injury. KEGG enrichment analysis showed nitroxoline influenced a total of 159 biological pathways, out of which, top pathways involved in cerebral ischemia included longevity regulating pathway, VEGF signaling, EGFR tyrosine kinase inhibitor resistance, IL-17 and HIF-1 pathways, FoxO signaling, and AGE-RAGE pathway. Protein-protein interaction analysis using string database showed PARP1, EGFR, PTEN, BRD4, RAC1, NOS2, MTOR, MAPK3, BCL2, MAPK1, APP, METAP2, MAPK14, SIRT1, PRKAA1, and MCL1 as highly interactive proteins involved in pathogenesis of ischemic stroke regulated by nitroxoline. The highly interactive protein targets were validated by molecular docking studies and molecular dynamic simulations. Amongst all these targets, nitroxoline showed the highest binding affinity towards BRD4 followed by PARP1 and PTEN. Nitroxoline, through network pharmacology analysis, showed a role in regulating proteins, biological processes, and pathways crucial in cerebral ischemia. The current study thus provides a preliminary insight that nitroxoline might be used as a neuroprotectant against cerebral ischemia via modulating the epigenetic reader BRD4 and transcription factors such as RELA, NF-κβ1, and SP1. However, further in-vitro and preclinical studies need to be performed for concrete evidence.
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Affiliation(s)
- Namrata Vadak
- Department of Pharmacology, SVKM's Dr Bhanuben, Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Maheshkumar R Borkar
- Department of Pharmaceutical Chemistry, SVKM's Dr, Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr Bhanuben, Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
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Chai M, Su G, Chen W, Gao J, Wu Q, Song J, Zhang Z. Effects of Bone Marrow Mesenchymal Stem Cell-Derived Exosomes in Central Nervous System Diseases. Mol Neurobiol 2024; 61:7481-7499. [PMID: 38393450 DOI: 10.1007/s12035-024-04032-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 02/11/2024] [Indexed: 02/25/2024]
Abstract
Central nervous system (CNS) diseases are one of the diseases that threaten human health. The delivery of drugs targeting the CNS has always been a significant challenge; the blood-brain barrier (BBB) is the main obstacle that must be overcome. The rise of bone marrow mesenchymal stem cell (BMSC) therapy has brought hope for the treatment of CNS diseases. However, the problems of low homing rate, susceptibility differentiation into astrocytes, immune rejection, and formation of iatrogenic tumors of transplanted BMSCs limit their clinical application. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have become a hot research topic in the treatment of CNS diseases in recent years because of their excellent histocompatibility, low immunogenicity, ease of crossing the BBB, and their ability to serve as natural carriers for treatment. This article reviews the mechanisms of BMSC-Exos in CNS diseases and provides direction for further research.
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Affiliation(s)
- Miao Chai
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Gang Su
- Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Wei Chen
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Juan Gao
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Qionghui Wu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Jinyang Song
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Zhenchang Zhang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China.
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Ryou MG, Burton S. Intermittent hypoxic training - derived exosomes in stroke rehabilitation. Front Integr Neurosci 2024; 18:1475234. [PMID: 39323911 PMCID: PMC11422222 DOI: 10.3389/fnint.2024.1475234] [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: 08/03/2024] [Accepted: 08/19/2024] [Indexed: 09/27/2024] Open
Abstract
Ischemic stroke is the fourth leading cause of adult disability in the US, and it is a huge social burden all over the world. However, the efficient treatment of ischemic stroke is not available. An apparent reason for failing to find or develop an intervention for ischemic stroke is contributed to the tight blood-brain barrier (BBB). The unique characteristics of exosomes that can traverse BBB have been highlighted among researchers investigating interventions for ischemic stroke conditions. Additionally, intermittent hypoxic training has been considered a potential intervention in the treatment or rehabilitation process of ischemic stroke patients. In this mini-review, we are going to review the possibility of applying exosomes produced by a subject who does intermittent hypoxic conditioning in a treatment program for ischemic stroke.
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Affiliation(s)
- Myoung-Gwi Ryou
- Department of Medical Laboratory Sciences, Public Health, and Nutrition Science, College of Health Science, Tarleton State University, Fort Worth, TX, United States
| | - Summer Burton
- Department of Medical Laboratory Sciences, Public Health, and Nutrition Science, College of Health Science, Tarleton State University, Fort Worth, TX, United States
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Fang X, Zhou D, Wang X, Ma Y, Zhong G, Jing S, Huang S, Wang Q. Exosomes: A Cellular Communication Medium That Has Multiple Effects On Brain Diseases. Mol Neurobiol 2024; 61:6864-6892. [PMID: 38356095 DOI: 10.1007/s12035-024-03957-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Exosomes, as membranous vesicles generated by multiple cell types and secreted to extracellular space, play a crucial role in a range of brain injury-related brain disorders by transporting diverse proteins, RNA, DNA fragments, and other functional substances. The nervous system's pathogenic mechanisms are complicated, involving pathological processes like as inflammation, apoptosis, oxidative stress, and autophagy, all of which result in blood-brain barrier damage, cognitive impairment, and even loss of normal motor function. Exosomes have been linked to the incidence and progression of brain disorders in recent research. As a result, a thorough knowledge of the interaction between exosomes and brain diseases may lead to the development of more effective therapeutic techniques that may be implemented in the clinic. The potential role of exosomes in brain diseases and the crosstalk between exosomes and other pathogenic processes were discussed in this paper. Simultaneously, we noted the delicate events in which exosomes as a media allow the brain to communicate with other tissues and organs in physiology and disease, and compiled a list of natural compounds that modulate exosomes, in order to further improve our understanding of exosomes and propose new ideas for treating brain disorders.
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Affiliation(s)
- Xiaoling Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Dishu Zhou
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Xinyue Wang
- Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510405, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 510405, Guangzhou, China
| | - Yujie Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shangwen Jing
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shuiqing Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
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García-Domínguez M. Enkephalins and Pain Modulation: Mechanisms of Action and Therapeutic Perspectives. Biomolecules 2024; 14:926. [PMID: 39199314 PMCID: PMC11353043 DOI: 10.3390/biom14080926] [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: 07/14/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 09/01/2024] Open
Abstract
Enkephalins, a subclass of endogenous opioid peptides, play a pivotal role in pain modulation. Enkephalins primarily exert their effects through opioid receptors located widely throughout both the central and peripheral nervous systems. This review will explore the mechanisms by which enkephalins produce analgesia, emotional regulation, neuroprotection, and other physiological effects. Furthermore, this review will analyze the involvement of enkephalins in the modulation of different pathologies characterized by severe pain. Understanding the complex role of enkephalins in pain processing provides valuable insight into potential therapeutic strategies for managing pain disorders.
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Affiliation(s)
- Mario García-Domínguez
- Faculty of Education and Psychology, Universidad Francisco de Vitoria, 28223 Pozuelo de Alarcón, Spain
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Song J, Zhou D, Cui L, Wu C, Jia L, Wang M, Li J, Ya J, Ji X, Meng R. Advancing stroke therapy: innovative approaches with stem cell-derived extracellular vesicles. Cell Commun Signal 2024; 22:369. [PMID: 39039539 PMCID: PMC11265156 DOI: 10.1186/s12964-024-01752-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues.
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Affiliation(s)
- Jiahao Song
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Lili Cui
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Chuanjie Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Lina Jia
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Mengqi Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingrun Li
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, England
| | - Xunming Ji
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China.
- National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
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Larson A, Natera-Rodriguez DE, Crane A, Larocca D, Low WC, Grande AW, Lee J. Emerging Roles of Exosomes in Stroke Therapy. Int J Mol Sci 2024; 25:6507. [PMID: 38928214 PMCID: PMC11203879 DOI: 10.3390/ijms25126507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/04/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Stroke is the number one cause of morbidity in the United States and number two cause of death worldwide. There is a critical unmet medical need for more effective treatments of ischemic stroke, and this need is increasing with the shift in demographics to an older population. Recently, several studies have reported the therapeutic potential of stem cell-derived exosomes as new candidates for cell-free treatment in stoke. This review focuses on the use of stem cell-derived exosomes as a potential treatment tool for stroke patients. Therapy using exosomes can have a clear clinical advantage over stem cell transplantation in terms of safety, cost, and convenience, as well as reducing bench-to-bed latency due to fewer regulatory milestones. In this review article, we focus on (1) the therapeutic potential of exosomes in stroke treatment, (2) the optimization process of upstream and downstream production, and (3) preclinical application in a stroke animal model. Finally, we discuss the limitations and challenges faced by exosome therapy in future clinical applications.
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Affiliation(s)
- Anthony Larson
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; (A.L.); (D.E.N.-R.); (A.C.); (W.C.L.); (A.W.G.)
| | - Dilmareth E. Natera-Rodriguez
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; (A.L.); (D.E.N.-R.); (A.C.); (W.C.L.); (A.W.G.)
| | - Andrew Crane
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; (A.L.); (D.E.N.-R.); (A.C.); (W.C.L.); (A.W.G.)
| | - Dana Larocca
- DC Biotechnology Consulting, Alameda, CA 94501, USA;
| | - Walter C. Low
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; (A.L.); (D.E.N.-R.); (A.C.); (W.C.L.); (A.W.G.)
| | - Andrew W. Grande
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; (A.L.); (D.E.N.-R.); (A.C.); (W.C.L.); (A.W.G.)
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jieun Lee
- UniverXome Bioengineering, Inc. (Formerly Known as AgeX Therapeutics Inc.), Alameda, CA 94501, USA
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He Z, Yin BK, Wang K, Zhao B, Chen Y, Li ZC, Chen J. The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats. Metab Brain Dis 2024; 39:741-752. [PMID: 38833094 DOI: 10.1007/s11011-024-01354-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 05/06/2024] [Indexed: 06/06/2024]
Abstract
Apoptosis is the crucial pathological mechanism following cerebral ischemic injury. Our previous studies demonstrated that clonidine, one agonist of alpha2-adrenergic receptor (α2-AR), could attenuate cerebral ischemic injury in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). However, it's unclear whether clonidine exerts neuroprotective effects by regulating neuronal apoptosis. In this study, we elucidated whether clonidine can exert anti-apoptotic effects in cerebral ischemic injury, and further explored the possible mechanisms. Neurological deficit score was measured to evaluate the neurological function. TTC staining was used for the measurement of brain infarct size. Hematoxylin-Eosin (HE) staining was applied to examine the cell morphology. TUNEL and DAPI fluorescent staining methods were used to analyze the cell apoptosis in brain tissue. Fluorescence quantitative real-time PCR was performed to assess the gene expression of Caspase-3 and P53. Western blotting assay was applied to detect the protein expression of Caspase-3 and P53. The results showed that clonidine improved neurological function, reduced brain infarct size, alleviated neuronal damage, and reduced the ratio of cell apoptosis in the brain with MCAO/R injury. moreover, clonidine down-regulated the gene and protein expression of Caspase-3 and P53 which were over-expressed after MCAO/R injury. Whereas, yohimbine (one selective α2-AR antagonist) mitigated the anti-apoptosis effects of clonidine, accompanied by reversed gene and protein expression changes. The results indicated that clonidine attenuated cerebral MCAO/R injury via suppressing neuronal apoptosis, which may be mediated, at least in part, by activating α2-AR.
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Affiliation(s)
- Zhi He
- Department of Pharmacology, College of Medicine, Jiaxing University, 314001, Jiaxing, People's Republic of China.
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China.
- College of Basic Medical Sciences, China Three Gorges University, 443002, Yichang, People's Republic of China.
| | - Bo-Kai Yin
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China
- Yichang Yiling Hospital, 443000, Yichang, People's Republic of China
- Zhongnan Hospital of Wuhan University, 430071, Wuhan, People's Republic of China
| | - Ke Wang
- Department of Pharmacology, College of Medicine, Jiaxing University, 314001, Jiaxing, People's Republic of China
| | - Bo Zhao
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China
- College of Basic Medical Sciences, China Three Gorges University, 443002, Yichang, People's Republic of China
| | - Yue Chen
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China
- College of Basic Medical Sciences, China Three Gorges University, 443002, Yichang, People's Republic of China
| | - Zi-Cheng Li
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China.
- College of Basic Medical Sciences, China Three Gorges University, 443002, Yichang, People's Republic of China.
| | - Jing Chen
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, 443002, Yichang, People's Republic of China.
- College of Medicine and Health Sciences, China Three Gorges University, No.8 Daxue Road, 443002, Yichang, People's Republic of China.
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11
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Li H, Yuan Y, Xie Q, Dong Z. Exosomes: potential targets for the diagnosis and treatment of neuropsychiatric disorders. J Transl Med 2024; 22:115. [PMID: 38287384 PMCID: PMC10826005 DOI: 10.1186/s12967-024-04893-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/14/2024] [Indexed: 01/31/2024] Open
Abstract
The field of neuropsychiatry is considered a middle ground between neurological and psychiatric disorders, thereby bridging the conventional boundaries between matter and mind, consciousness, and function. Neuropsychiatry aims to evaluate and treat cognitive, behavioral, and emotional disorders in individuals with neurological conditions. However, the pathophysiology of these disorders is not yet fully understood, and objective biological indicators for these conditions are currently lacking. Treatment options are also limited due to the blood-brain barrier, which results in poor treatment effects. Additionally, many drugs, particularly antipsychotic drugs, have adverse reactions, which make them difficult to tolerate for patients. As a result, patients often abandon treatment owing to these adverse reactions. Since the discovery of exosomes in 1983, they have been extensively studied in various diseases owing to their potential as nanocellulators for information exchange between cells. Because exosomes can freely travel between the center and periphery, brain-derived exosomes can reflect the state of the brain, which has considerable advantages in diagnosis and treatment. In addition, administration of engineered exosomes can improve therapeutic efficacy, allow lesion targeting, ensure drug stability, and prevent systemic adverse effects. Therefore, this article reviews the source and biological function of exosomes, relationship between exosomes and the blood-brain barrier, relationship between exosomes and the pathological mechanism of neuropsychiatric disorders, exosomes in the diagnosis and treatment of neuropsychiatric disorders, and application of engineered exosomes in neuropsychiatric disorders.
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Affiliation(s)
- Haorao Li
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Yanling Yuan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Qinglian Xie
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Zaiquan Dong
- Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
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12
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Markowska A, Koziorowski D, Szlufik S. Microglia and Stem Cells for Ischemic Stroke Treatment-Mechanisms, Current Status, and Therapeutic Challenges. FRONT BIOSCI-LANDMRK 2023; 28:269. [PMID: 37919085 DOI: 10.31083/j.fbl2810269] [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: 07/28/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/04/2023]
Abstract
Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing research is focusing on the neuroprotective effects of microglia and stem cells. By exerting the bystander effect, secreting exosomes and forming biobridges, mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and multilineage-differentiating stress-enduring cells (Muse cells) have been shown to stimulate neurogenesis, angiogenesis, cell migration, and reduce neuroinflammation. Exosome-based therapy is now being extensively researched due to its many advantageous properties over cell therapy, such as lower immunogenicity, no risk of blood vessel occlusion, and ease of storage and modification. However, although preclinical studies have shown promising therapeutic outcomes, clinical trials have been associated with several translational challenges. This review explores the therapeutic effects of preconditioned microglia as well as various factors secreted in stem cell-derived extracellular vesicles with their mechanisms of action explained. Furthermore, an overview of preclinical and clinical studies is presented, explaining the main challenges of microglia and stem cell therapies, and providing potential solutions. In particular, a highlight is the use of novel stem cell therapy of Muse cells, which bypasses many of the conventional stem cell limitations. The paper concludes with suggestions for directions in future neuroprotective research.
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Affiliation(s)
- Aleksandra Markowska
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Dariusz Koziorowski
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Stanisław Szlufik
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
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13
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Kumari R, Kareem ZY, McLaughlin PJ. Acute Low Dose Naltrexone Increases β-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice. Neurochem Res 2023:10.1007/s11064-023-03938-4. [PMID: 37166576 DOI: 10.1007/s11064-023-03938-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/05/2023] [Accepted: 04/08/2023] [Indexed: 05/12/2023]
Abstract
Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10 week old male db/db and db/ + mice, collected tissue at 24 and 72 h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1 mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48 h post HI, and collected brain tissue and blood at 72 h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.
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Affiliation(s)
- Rashmi Kumari
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive H109, Hershey, PA, 17033, USA.
| | - Zainab Y Kareem
- Kent State University College of Podiatric Medicine, 6000 Rockside Woods Boulevard North, Independence, OH, 44131, USA
| | - Patricia J McLaughlin
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive H109, Hershey, PA, 17033, USA
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14
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Zhao N, Gao Y, Jia H, Jiang X. Anti-apoptosis effect of traditional Chinese medicine in the treatment of cerebral ischemia-reperfusion injury. Apoptosis 2023; 28:702-729. [PMID: 36892639 DOI: 10.1007/s10495-023-01824-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2023] [Indexed: 03/10/2023]
Abstract
Cerebral ischemia, one of the leading causes of neurological dysfunction of brain cells, muscle dysfunction, and death, brings great harm and challenges to individual health, families, and society. Blood flow disruption causes decreased glucose and oxygen, insufficient to maintain normal brain tissue metabolism, resulting in intracellular calcium overload, oxidative stress, neurotoxicity of excitatory amino acids, and inflammation, ultimately leading to neuronal cell necrosis, apoptosis, or neurological abnormalities. This paper summarizes the specific mechanism of cell injury that apoptosis triggered by reperfusion after cerebral ischemia, the related proteins involved in apoptosis, and the experimental progress of herbal medicine treatment through searching, analyzing, and summarizing the PubMed and Web Of Science databases, which includes active ingredients of herbal medicine, prescriptions, Chinese patent medicines, and herbal extracts, providing a new target or new strategy for drug treatment, and providing a reference for future experimental directions and using them to develop suitable small molecule drugs for clinical application. With the research of anti-apoptosis as the core, it is important to find highly effective, low toxicity, safe and cheap compounds from natural plants and animals with abundant resources to prevent and treat Cerebral ischemia/reperfusion (I/R) injury (CIR) and solve human suffering. In addition, understanding and summarizing the apoptotic mechanism of cerebral ischemia-reperfusion injury, the microscopic mechanism of CIR treatment, and the cellular pathways involved will help to develop new drugs.
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Affiliation(s)
- Nan Zhao
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Yuhe Gao
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Hongtao Jia
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Xicheng Jiang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China.
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15
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Sen S, Xavier J, Kumar N, Ahmad MZ, Ranjan OP. Exosomes as natural nanocarrier-based drug delivery system: recent insights and future perspectives. 3 Biotech 2023; 13:101. [PMID: 36860361 PMCID: PMC9970142 DOI: 10.1007/s13205-023-03521-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/13/2023] [Indexed: 03/03/2023] Open
Abstract
Exosomes are nanosized (size ~ 30-150 nm) natural vesicular structures released from cells by physiological processes or pathological circumstances. Exosomes are growing in popularity as a result of their many benefits over conventional nanovehicles, including their ability to escape homing in the liver or metabolic destruction and their lack of undesired accumulation before reaching their intended targets. Various therapeutic molecules, including nucleic acids, have been incorporated into exosomes by different techniques, many of which have shown satisfactory performance in various diseases. Surface-modified exosomes are a potentially effective strategy, and it increases the circulation time and produces the specific drug target vehicle. In this comprehensive review, we describe composition exosomes biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. In addition, we discuss the role of exosomes as diagnostic markers, and their therapeutic and clinical implications. Furthermore, we addressed the challenges and outstanding developments in exosome research and discuss future perspectives. In addition to the current status of exosomes as a therapeutic carrier, the lacuna in the clinical development lifecycles along with the possible strategies to fill the lacuna have been addressed.
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Affiliation(s)
- Srijita Sen
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam 781101 India
| | - Joyal Xavier
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur, Bihar 844102 India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur, Bihar 844102 India
| | - Mohammad Zaki Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, 11001 Kingdom of Saudi Arabia
| | - Om Prakash Ranjan
- Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam 781101 India
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16
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Stem Cell-derived Extracellular Vesicles: A Promising Nano Delivery Platform to the Brain? Stem Cell Rev Rep 2023; 19:285-308. [PMID: 36173500 DOI: 10.1007/s12015-022-10455-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2022] [Indexed: 02/07/2023]
Abstract
A very important cause of the frustration with drug therapy for central nervous system (CNS) diseases is the failure of drug delivery. The blood-brain barrier (BBB) prevents most therapeutic molecules from entering the brain while maintaining CNS homeostasis. Scientists are keen to develop new brain drug delivery systems to solve this dilemma. Extracellular vesicles (EVs), as a class of naturally derived nanoscale vesicles, have been extensively studied in drug delivery due to their superior properties. This review will briefly present current brain drug delivery strategies, including invasive and non-invasive techniques that target the brain, and the application of nanocarriers developed for brain drug delivery in recent years, especially EVs. The cellular origin of EVs affects the surface protein, size, yield, luminal composition, and other properties of EVs, which are also crucial in determining whether EVs are useful as drug carriers. Stem cell-derived EVs, which inherit the properties of parental cells and avoid the drawbacks of cell therapy, have always been favored by researchers. Thus, in this review, we will focus on the application of stem cell-derived EVs for drug delivery in the CNS. Various nucleic acids, proteins, and small-molecule drugs are loaded into EVs with or without modification and undergo targeted delivery to the brain to achieve their therapeutic effects. In addition, the challenges facing the clinical application of EVs as drug carriers will also be discussed. The directions of future efforts may be to improve drug loading efficiency and precise targeting.
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17
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Jin M, Zhang S, Wang M, Li Q, Ren J, Luo Y, Sun X. Exosomes in pathogenesis, diagnosis, and therapy of ischemic stroke. Front Bioeng Biotechnol 2022; 10:980548. [PMID: 36588958 PMCID: PMC9800834 DOI: 10.3389/fbioe.2022.980548] [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: 06/28/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Ischemic stroke is one of the major contributors to death and disability worldwide. Thus, there is an urgent need to develop early brain tissue perfusion therapies following acute stroke and to enhance functional recovery in stroke survivors. The morbidity, therapy, and recovery processes are highly orchestrated interactions involving the brain with other tissues. Exosomes are natural and ideal mediators of intercellular information transfer and recognized as biomarkers for disease diagnosis and prognosis. Changes in exosome contents express throughout the physiological process. Accumulating evidence demonstrates the use of exosomes in exploring unknown cellular and molecular mechanisms of intercellular communication and organ homeostasis and indicates their potential role in ischemic stroke. Inspired by the unique properties of exosomes, this review focuses on the communication, diagnosis, and therapeutic role of various derived exosomes, and their development and challenges for the treatment of cerebral ischemic stroke.
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Affiliation(s)
- Meiqi Jin
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China
| | - Shuxia Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China
| | - Mengchen Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China
| | - Qiaoyu Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China
| | - Jiahui Ren
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China,*Correspondence: Yun Luo, ; Xiaobo Sun,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China,Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China,NMPA Key Laboratory for Research and Evaluation of Pharmacovigilance, Beijing, China,*Correspondence: Yun Luo, ; Xiaobo Sun,
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18
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Cell Death Mechanisms in Cerebral Ischemia-Reperfusion Injury. Neurochem Res 2022; 47:3525-3542. [PMID: 35976487 DOI: 10.1007/s11064-022-03697-8] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/11/2022] [Accepted: 07/14/2022] [Indexed: 10/15/2022]
Abstract
Ischemic stroke is one of the major causes of morbidity and mortality, affecting millions of people worldwide. Inevitably, the interruption of cerebral blood supply after ischemia may promote a cascade of pathophysiological processes. Moreover, the subsequent restoration of blood flow and reoxygenation may further aggravate brain tissue injury. Although recombinant tissue plasminogen activator (rt-PA) is the only approved therapy for restoring blood perfusion, the reperfusion injury and the narrow therapeutic time window restrict its application for most stroke patients. Increasing evidence indicates that multiple cell death mechanisms are relevant to cerebral ischemia-reperfusion injury, including apoptosis, necrosis, necroptosis, autophagy, pyroptosis, ferroptosis, and so on. Therefore, it is crucial to comprehend various cell death mechanisms and their interactions. In this review, we summarize the various signaling pathways underlying cerebral ischemia-reperfusion injury and elaborate on the crosstalk between the different mechanisms.
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19
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Liao J, Li Y, Luo Y, Meng S, Zhang C, Xiong L, Wang T, Lu Y. Recent Advances in Targeted Nanotherapies for Ischemic Stroke. Mol Pharm 2022; 19:3026-3041. [PMID: 35905397 DOI: 10.1021/acs.molpharmaceut.2c00383] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ischemic stroke (IS) is a severe neurological disease caused by the narrowing or occlusion of cerebral blood vessels and is known for high morbidity, disability, and mortality rates. Clinically available treatments of stroke include the surgical removal of the thrombus and thrombolysis with tissue fibrinogen activator. Pharmaceuticals targeting IS are uncommon, and the development of new therapies is hindered by the low bioavailability and stability of many drugs. Nanomedicine provides new opportunities for the development of novel neuroprotective and thrombolytic strategies for the diagnosis and treatment of IS. Numerous nanotherapeutics with different physicochemical properties are currently being developed to facilitate drug delivery by accumulation and controlled release and to improve their restorative properties. In this review, we discuss recent developments in IS therapy, including assisted drug delivery and targeting, neuroprotection through regulation of the neuron environment, and sources of endogenous biomimetic specific targeting. In addition, we discuss the role and neurotoxic effects of inorganic metal nanoparticles in IS therapy. This study provides a theoretical basis for the utilization of nano-IS therapies that may contribute to the development of new strategies for a range of embolic diseases.
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Affiliation(s)
- Jun Liao
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yi Li
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yunchun Luo
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Sha Meng
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Chuan Zhang
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Liyan Xiong
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Tingfang Wang
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Ying Lu
- School of Pharmacy, Naval Medical University, Shanghai 200433, China
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20
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Mohan Viswanathan T, Krishnakumar V, Senthilkumar D, Chitradevi K, Vijayabhaskar R, Rajesh Kannan V, Senthil Kumar N, Sundar K, Kunjiappan S, Babkiewicz E, Maszczyk P, Kathiresan T. Combinatorial Delivery of Gallium (III) Nitrate and Curcumin Complex-Loaded Hollow Mesoporous Silica Nanoparticles for Breast Cancer Treatment. NANOMATERIALS 2022; 12:nano12091472. [PMID: 35564180 PMCID: PMC9105406 DOI: 10.3390/nano12091472] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/13/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022]
Abstract
The main aims in the development of a novel drug delivery vehicle is to efficiently carry therapeutic drugs in the body's circulatory system and successfully deliver them to the targeted site as needed to safely achieve the desired therapeutic effect. In the present study, a passive targeted functionalised nanocarrier was fabricated or wrapped the hollow mesoporous silica nanoparticles with 3-aminopropyl triethoxysilane (APTES) to prepare APTES-coated hollow mesoporous silica nanoparticles (HMSNAP). A nitrogen sorption analysis confirmed that the shape of hysteresis loops is altered, and subsequently the pore volume and pore diameters of GaC-HMSNAP was reduced by around 56 and 37%, respectively, when compared with HMSNAP. The physico-chemical characterisation studies of fabricated HMSNAP, Ga-HMSNAP and GaC-HMSNAP have confirmed their stability. The drug release capacity of the fabricated Ga-HMSNAP and GaC-HMSNAP for delivery of gallium and curcumin was evaluated in the phosphate buffered saline (pH 3.0, 6.0 and 7.4). In an in silico molecular docking study of the gallium-curcumin complex in PDI, calnexin, HSP60, PDK, caspase 9, Akt1 and PTEN were found to be strong binding. In vitro antitumor activity of both Ga-HMSNAP and GaC-HMSNAP treated MCF-7 cells was investigated in a dose and time-dependent manner. The IC50 values of GaC-HMSNAP (25 µM) were significantly reduced when compared with free gallium concentration (40 µM). The mechanism of gallium-mediated apoptosis was analyzed through western blotting and GaC-HMSNAP has increased caspases 9, 6, cleaved caspase 6, PARP, and GSK 3β(S9) in MCF-7 cells. Similarly, GaC-HMSNAP is reduced mitochondrial proteins such as prohibitin1, HSP60, and SOD1. The phosphorylation of oncogenic proteins such as Akt (S473), c-Raf (S249) PDK1 (S241) and induced cell death in MCF-7 cells. Furthermore, the findings revealed that Ga-HMSNAP and GaC-HMSNAP provide a controlled release of loaded gallium, curcumin and their complex. Altogether, our results depicted that GaC-HMNSAP induced cell death through the mitochondrial intrinsic cell death pathway, which could lead to novel therapeutic strategies for breast adenocarcinoma therapy.
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Affiliation(s)
- Thimma Mohan Viswanathan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Vaithilingam Krishnakumar
- Department of Microbiology, Bharathidasan University, Tiruchirappalli 620024, India; (V.K.); (V.R.K.)
| | - Dharmaraj Senthilkumar
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Kaniraja Chitradevi
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | | | - Velu Rajesh Kannan
- Department of Microbiology, Bharathidasan University, Tiruchirappalli 620024, India; (V.K.); (V.R.K.)
| | | | - Krishnan Sundar
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
| | - Ewa Babkiewicz
- Department of Hydrobiology, Faculty of Biology, University of Warsaw, 02-089 Warsaw, Poland; (E.B.); (P.M.)
| | - Piotr Maszczyk
- Department of Hydrobiology, Faculty of Biology, University of Warsaw, 02-089 Warsaw, Poland; (E.B.); (P.M.)
| | - Thandavarayan Kathiresan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil 626126, India; (T.M.V.); (D.S.); (K.C.); (K.S.); (S.K.)
- Correspondence: ; Tel.: +91-4563-289042; Fax: +91-4563-289322
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21
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Exosomes and Other Extracellular Vesicles with High Therapeutic Potential: Their Applications in Oncology, Neurology, and Dermatology. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041303. [PMID: 35209095 PMCID: PMC8879284 DOI: 10.3390/molecules27041303] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/28/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
Until thirty years ago, it was believed that extracellular vesicles (EVs) were used to remove unnecessary compounds from the cell. Today, we know about their enormous potential in diagnosing and treating various diseases. EVs are essential mediators of intercellular communication, enabling the functional transfer of bioactive molecules from one cell to another. Compared to laboratory-created drug nanocarriers, they are stable in physiological conditions. Furthermore, they are less immunogenic and cytotoxic compared to polymerized vectors. Finally, EVs can transfer cargo to particular cells due to their membrane proteins and lipids, which can implement them to specific receptors in the target cells. Recently, new strategies to produce ad hoc exosomes have been devised. Cells delivering exosomes have been genetically engineered to overexpress particular macromolecules, or transformed to release exosomes with appropriate targeting molecules. In this way, we can say tailor-made therapeutic EVs are created. Nevertheless, there are significant difficulties to solve during the application of EVs as drug-delivery agents in the clinic. This review explores the diversity of EVs and the potential therapeutic options for exosomes as natural drug-delivery vehicles in oncology, neurology, and dermatology. It also reflects future challenges in clinical translation.
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22
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Jiang L, Chen W, Ye J, Wang Y. Potential Role of Exosomes in Ischemic Stroke Treatment. Biomolecules 2022; 12:115. [PMID: 35053263 PMCID: PMC8773818 DOI: 10.3390/biom12010115] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is a life-threatening cerebral vascular disease and accounts for high disability and mortality worldwide. Currently, no efficient therapeutic strategies are available for promoting neurological recovery in clinical practice, except rehabilitation. The majority of neuroprotective drugs showed positive impact in pre-clinical studies but failed in clinical trials. Therefore, there is an urgent demand for new promising therapeutic approaches for ischemic stroke treatment. Emerging evidence suggests that exosomes mediate communication between cells in both physiological and pathological conditions. Exosomes have received extensive attention for therapy following a stroke, because of their unique characteristics, such as the ability to cross the blood brain-barrier, low immunogenicity, and low toxicity. An increasing number of studies have demonstrated positively neurorestorative effects of exosome-based therapy, which are largely mediated by the microRNA cargo. Herein, we review the current knowledge of exosomes, the relationships between exosomes and stroke, and the therapeutic effects of exosome-based treatments in neurovascular remodeling processes after stroke. Exosomes provide a viable and prospective treatment strategy for ischemic stroke patients.
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Affiliation(s)
- Lingling Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Weiqi Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Jinyi Ye
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Yilong Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
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Hurd MD, Goel I, Sakai Y, Teramura Y. Current status of ischemic stroke treatment: From thrombolysis to potential regenerative medicine. Regen Ther 2021; 18:408-417. [PMID: 34722837 PMCID: PMC8517544 DOI: 10.1016/j.reth.2021.09.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/16/2021] [Accepted: 09/29/2021] [Indexed: 12/22/2022] Open
Abstract
Ischemic stroke is a major cause of death and disability worldwide and is expected to increase in the future with the aging population. Currently, there are no clinically available treatments for damage sustained during an ischemic stroke, but much research is being conducted in this area. In this review, we will introduce current ischemic stroke treatments along with their limitations, as well as research on potential short and long-term future treatments. There are advantages and disadvantages in these potential treatments, but our understanding of these methods and their effectiveness in clinical trials are improving. We are confident that some future treatments introduced in this review will become commonly used in clinical settings in the future.
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Affiliation(s)
- Mason Daniel Hurd
- Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Isha Goel
- Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Yuji Teramura
- Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central fifth, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8565, Japan
- Department of Immunology, Genetics and Pathology (IGP), Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden
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24
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Xin WQ, Wei W, Pan YL, Cui BL, Yang XY, Bähr M, Doeppner TR. Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia. World J Stem Cells 2021; 13:1030-1048. [PMID: 34567423 PMCID: PMC8422926 DOI: 10.4252/wjsc.v13.i8.1030] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation plays an important role in the pathological process of ischemic stroke, and systemic inflammation affects patient prognosis. As resident immune cells in the brain, microglia are significantly involved in immune defense and tissue repair under various pathological conditions, including cerebral ischemia. Although the differentiation of M1 and M2 microglia is certainly oversimplified, changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia. Recent evidence indicates that both mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) regulate inflammation and modify tissue repair under preclinical stroke conditions. However, the precise mechanisms of these signaling pathways, especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia, have not been sufficiently unveiled. Hence, this review summarizes the state-of-the-art knowledge on MSC- and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways, including cytokines, neurotrophic factors, transcription factors, and microRNAs.
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Affiliation(s)
- Wen-Qiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Yong-Li Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Bao-Long Cui
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Xin-Yu Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mathias Bähr
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
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25
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Xu M, Feng T, Liu B, Qiu F, Xu Y, Zhao Y, Zheng Y. Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies. Theranostics 2021; 11:8926-8944. [PMID: 34522219 PMCID: PMC8419041 DOI: 10.7150/thno.62330] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
As extracellular vesicles secreted by cells, exosomes are intercellular signalosomes for cell communication and pharmacological effectors. Because of their special properties, including low toxicity and immunogenicity, biodegradability, ability to encapsulate endogenous biologically active molecules and cross the blood-brain barrier (BBB), exosomes have great therapeutic potential in cerebrovascular and neurodegenerative diseases. However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect. Using engineering technology, exosomes can obtain active targeting ability to accumulate in specific cell types and tissues by attaching targeting units to the membrane surface or loading them into cavities. In this review, we outline the improved targeting functions of bioengineered exosomes, tracing and imaging techniques, administration methods, internalization in the BBB, and therapeutic effects of exosomes in cerebrovascular and neurodegenerative diseases and further evaluate the clinical opportunities and challenges in this research field.
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Affiliation(s)
- Meng Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Tao Feng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Bowen Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Fen Qiu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, China
| | - Yonghua Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
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26
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Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases. Drug Deliv Transl Res 2021; 12:1047-1079. [PMID: 34365576 PMCID: PMC8942947 DOI: 10.1007/s13346-021-01026-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 02/08/2023]
Abstract
Exosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood–brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases.
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Liu Y, Wu X, Du D, Liu J, Zhang W, Gao Y, Zhang H. p53 Inhibition Provides a Pivotal Protective Effect against Cerebral Ischemia-Reperfusion Injury via the Wnt Signaling Pathway. Cerebrovasc Dis 2021; 50:682-690. [PMID: 34340236 DOI: 10.1159/000516889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 04/26/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cerebral ischemia-reperfusion injury enhances brain injury and increases its morbidity and mortality. The purpose of our study was to further explore the specific pathogenesis of cerebral ischemia disease by studying the role of p53 in cerebral ischemia-reperfusion injury and its mechanism to provide a new target for the treatment of cerebral ischemia. METHODS Middle cerebral artery occlusion (MCAo) was established in rats. The changes in p53 and apoptotic proteins in the rat model were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The effects of p53 inhibitors on cerebral is-chemia-reperfusion injury in rats were evaluated by modified neurological severity score (mNSS) and infarct area. Subsequently, neural stem cells (NSCs) were isolated and cultured in vitro, and oxygen and glucose deprivation (OGD) was induced to establish an in vitro ischemia-reperfusion injury model. Cell viability and migration were detected by CCK-8 and transwell assays. Apoptosis of NSCs was detected by flow cytometry. Finally, protein expression in the Wnt pathway activated by p53 was detected by Western blotting. RESULTS Compared with the sham group, p53 levels, mNSS, cerebral infarction area, and apoptosis were significantly increased in the MCAo group (p < 0.05). When the p53 inhibitor PFT-α was injected, the increase in these levels was reversed. Also, the viability and migration of cells decreased and apo-ptosis increased in the in vitro OGD model, whereas the viability, migration, and apoptosis were significantly reversed after the addition of p53 inhibitors (p < 0.05). Finally, p53 induced Wnt signaling pathway proteins β-catenin and cyclin D1 decrease in the MCAo group, while p53 inhibitors reversed their inhibitory effect on the Wnt signaling pathway. CONCLUSION We confirmed in vivo and in vitro that inhibition of p53 has a protective effect on the cerebral ischemia-reperfusion injury, which may be related to the activation of the Wnt signaling pathway.
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Affiliation(s)
- Yanwei Liu
- Department of Emergency Internal Medicine, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinning Wu
- Department of Cardiovascular Medicine, People's Hospital of Rizhao, Rizhao, China
| | - Deyong Du
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Jing Liu
- Bincheng Municipal Hospital, Binzhou, China
| | - Wensheng Zhang
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yang Gao
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
| | - Haitao Zhang
- Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, China
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Butreddy A, Kommineni N, Dudhipala N. Exosomes as Naturally Occurring Vehicles for Delivery of Biopharmaceuticals: Insights from Drug Delivery to Clinical Perspectives. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:1481. [PMID: 34204903 PMCID: PMC8229362 DOI: 10.3390/nano11061481] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/28/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022]
Abstract
Exosomes as nanosized vesicles are emerging as drug delivery systems for therapeutics owing to their natural origin, their ability to mediate intercellular communication, and their potential to encapsulate various biological molecules such as proteins and nucleic acids within the lipid bilayer membrane or in the lumen. Exosomes contain endogenous components (proteins, lipids, RNA) that could be used to deliver cargoes to target cells, offering an opportunity to diagnose and treat various diseases. Owing to their ability to travel safely in extracellular fluid and to transport cargoes to target cells with high efficacy, exosomes offer enhanced delivery of cargoes in vivo. However, several challenges related to the stabilization of the exosomes, the production of sufficient amounts of exosomes with safety and efficacy, the efficient loading of drugs into exosomes, the clearance of exosomes from circulation, and the transition from the bench scale to clinical production may limit their development and clinical use. For the clinical use of exosomes, it is important to understand the molecular mechanisms behind the transport and function of exosome vesicles. This review exploits techniques related to the isolation and characterization of exosomes and their drug delivery potential to enhance the therapeutic outcome and stabilization methods. Further, routes of administration, clinical trials, and regulatory aspects of exosomes will be discussed in this review.
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Affiliation(s)
- Arun Butreddy
- Formulation R&D, Biological E. Limited, IKP Knowledge Park, Shameerpet, Hyderabad 500078, Telangana State, India;
| | - Nagavendra Kommineni
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA;
| | - Narendar Dudhipala
- Depratment of Pharmaceutics, Vaagdevi College of Pharmacy, Warangal 506005, Telangana State, India
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Therapeutic Nanoparticles for the Different Phases of Ischemic Stroke. Life (Basel) 2021; 11:life11060482. [PMID: 34073229 PMCID: PMC8227304 DOI: 10.3390/life11060482] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/27/2022] Open
Abstract
Stroke represents the second leading cause of mortality and morbidity worldwide. Ischemic strokes are the most prevalent type of stroke, and they are characterized by a series of pathological events prompted by an arterial occlusion that leads to a heterogeneous pathophysiological response through different hemodynamic phases, namely the hyperacute, acute, subacute, and chronic phases. Stroke treatment is highly reliant on recanalization therapies, which are limited to only a subset of patients due to their narrow therapeutic window; hence, there is a huge need for new stroke treatments. Nonetheless, the vast majority of promising treatments are not effective in the clinical setting due to their inability to cross the blood-brain barrier and reach the brain. In this context, nanotechnology-based approaches such as nanoparticle drug delivery emerge as the most promising option. In this review, we will discuss the current status of nanotechnology in the setting of stroke, focusing on the diverse available nanoparticle approaches targeted to the different pathological and physiological repair mechanisms involved in each of the stroke phases.
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30
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Extracellular Vesicle Application as a Novel Therapeutic Strategy for Ischemic Stroke. Transl Stroke Res 2021; 13:171-187. [PMID: 33982152 DOI: 10.1007/s12975-021-00915-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022]
Abstract
Ischemic stroke (IS) accounts for most of the cases of stroke onset, and due to short therapeutic time window for thrombolysis and numerous limited treatment measures and contraindications, lots of patients cannot receive satisfying therapeutic effects resulting in high disability and mortality worldly. In recent years, extracellular vesicles (EVs), as nanosized membrane-structured vesicles secreted from almost all cells, especially from stem/progenitor cells, have been reported to exert significant beneficial effects on IS from multiple approaches and notably ameliorate neurological outcome. Moreover, based on nano-size and lipid bilayer structure, EVs can easily penetrate the blood-brain barrier and migrate into the brain. In this review, we mainly systematically summarize the therapeutic effects of EVs on IS and explore their potential applications. Simultaneously, we also discuss administration routines, dosages, experimental observation time, and some key issues of EV application during IS treatment. It contributes to a comprehensive understanding of the progress of EV treatment for IS and providing confident evidence for further EV clinical application widely.
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31
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Ueno Y, Hira K, Miyamoto N, Kijima C, Inaba T, Hattori N. Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery. Int J Mol Sci 2020; 21:ijms21186894. [PMID: 32962207 PMCID: PMC7555640 DOI: 10.3390/ijms21186894] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.
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Affiliation(s)
- Yuji Ueno
- Correspondence: ; Tel.: +81-3-3813-3111; Fax: +81-3-5800-0547
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32
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Guy R, Offen D. Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes. Biomolecules 2020; 10:E1320. [PMID: 32942544 PMCID: PMC7564210 DOI: 10.3390/biom10091320] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/03/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
Neurodegenerative disease refers to any pathological condition in which there is a progressive decline in neuronal function resulting from brain atrophy. Despite the immense efforts invested over recent decades in developing treatments for neurodegenerative diseases, effective therapy for these conditions is still an unmet need. One of the promising options for promoting brain recovery and regeneration is mesenchymal stem cell (MSC) transplantation. The therapeutic effect of MSCs is thought to be mediated by their secretome, and specifically, by their exosomes. Research shows that MSC-derived exosomes retain some of the characteristics of their parent MSCs, such as immune system modulation, regulation of neurite outgrowth, promotion of angiogenesis, and the ability to repair damaged tissue. Here, we summarize the functional outcomes observed in animal models of neurodegenerative diseases following MSC-derived exosome treatment. We will examine the proposed mechanisms of action through which MSC-derived exosomes mediate their therapeutic effects and review advanced studies that attempt to enhance the improvement achieved using MSC-derived exosome treatment, with a view towards future clinical use.
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Affiliation(s)
| | - Daniel Offen
- Felsenstein Medical Research Center, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
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33
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Dehghani L, Hashemi SM, Saadatnia M, Zali A, Oraee-Yazdani S, Heidari Keshel S, Khojasteh A, Soleimani M. Stem Cell-Derived Exosomes as Treatment for Stroke: a Systematic Review. Stem Cell Rev Rep 2020; 17:428-438. [PMID: 32935221 DOI: 10.1007/s12015-020-10024-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The therapeutic potential of stem cells may largely be mediated by paracrine factors contained in exosomes released from intracellular endosomes. A systematic review was performed to identify the effects of stem cell-derived exosomes for their ability to induce restorative effects in animal models of stroke. METHODS PubMed, Scopus, and ISI Web of Science databases were searched for all available articles testing stem cell-derived exosomes as therapeutic interventions in animal models of stroke until April 2020. The STAIR scale was used to assess the quality of the included studies. RESULTS A total of 994 published articles were identified in the systematic search. After screening for eligibility, a total of 16 datasets were included. Type of cerebral ischemia was transient in majority studies and most studies used rat or mice adipose tissue-derived stem cells/bone marrow-derived stem cells. Eight studies indicated improved functional recovery while 8 were able to show reduced infarct volume as a result of exosome therapy. The beneficial effects were mainly attributed to reduced inflammation and oxidative stress, enhanced neurogenesis, angiogenesis, and neurite remodeling. Also, 4 studies demonstrated that exosomes hold great promise as an endogenous drug delivery nano-system. CONCLUSION In preclinical studies, use of stem cell-derived exosomes is strongly associated with improved neurological recovery and reduced brain infarct volume following stroke. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans. Graphical abstract.
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Affiliation(s)
- Leila Dehghani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Saadatnia
- Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Khojasteh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Masoud Soleimani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.,Medical Nanotechnology and Tissue engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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34
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Nelson BC, Maragh S, Ghiran IC, Jones JC, DeRose PC, Elsheikh E, Vreeland WN, Wang L. Measurement and standardization challenges for extracellular vesicle therapeutic delivery vectors. Nanomedicine (Lond) 2020; 15:2149-2170. [PMID: 32885720 PMCID: PMC7546159 DOI: 10.2217/nnm-2020-0206] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/10/2020] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs), such as exosomes and microvesicles, are nonreplicating lipid bilayer particles shed by most cell types which have the potential to revolutionize the development and efficient delivery of clinical therapeutics. This article provides an introduction to the landscape of EV-based vectors under development for the delivery of protein- and nucleic acid-based therapeutics. We highlight some of the most pressing measurement and standardization challenges that limit the translation of EVs to the clinic. Current challenges limiting development of EVs for drug delivery are the lack of: standardized cell-based platforms for the production of EV-based therapeutics; EV reference materials that allow researchers/manufacturers to validate EV measurements and standardized measurement systems for determining the molecular composition of EVs.
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Affiliation(s)
- Bryant C Nelson
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
| | - Samantha Maragh
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
| | - Ionita C Ghiran
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
| | - Jennifer C Jones
- National Institutes of Health, National Cancer Institute, Bethesda, MD 20892, USA
| | - Paul C DeRose
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
| | - Elzafir Elsheikh
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
| | - Wyatt N Vreeland
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
| | - Lili Wang
- National Institute of Standards & Technology, Material Measurement Laboratory, Gaithersburg, MD 20899, USA
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35
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Thomas JM, Cunningham CJ, Lawrence CB, Pinteaux E, Allan SM. Therapeutic potential of extracellular vesicles in preclinical stroke models: a systematic review and meta-analysis. BMJ OPEN SCIENCE 2020; 4:e100047. [PMID: 35047689 PMCID: PMC8749279 DOI: 10.1136/bmjos-2019-100047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/05/2019] [Accepted: 11/19/2019] [Indexed: 01/09/2023] Open
Abstract
Objectives Currently there is a paucity of clinically available regenerative therapies for stroke. Extracellular vesicles (EV) have been investigated for their potential as modulators of regeneration in the poststroke brain. This systematic review and meta-analysis aims to provide a summary of the efficacy of therapeutic EVs in preclinical stroke models, to inform future research in this emerging field. Methods Studies were identified by a comprehensive literature search of two online sources and subsequent screening. Studies using lesion volume or neurological score as outcome measures were included. Standardised mean difference (SMD) and 95% CIs were calculated using a restricted maximum likelihood random effects model. Publication bias was assessed with Egger’s regression and presented as funnel plots with trim and fill analysis. Subgroup analysis was performed to assess the effects of different study variables. Study quality and risk of bias were assessed using the CAMARADES checklist. Results A total of 20 publications were included in the systematic review, of which 19 were assessed in the meta-analysis (43 comparisons). Overall, EV interventions improved lesion volume (SMD: −1.95, 95% CI −2.72 to 1.18) and neurological scores (SMD: −1.26, 95% CI −1.64 to 0.87) compared with control groups. Funnel plots were asymmetrical suggesting publication bias, and trim and fill analysis predicted seven missing studies for lesion volume. Subgroup analysis suggested administration at 0–23 hours after stroke was the most effective timepoint for EV treatment. The median score on the CAMARADES checklist was 7 (IQR: 5–8). Conclusions EVs may offer a promising new avenue for stroke therapies, as EV-based interventions had positive impacts on lesion volume and neurological score in preclinical stroke models. PROSPERO registration number CRD42019134925.
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Affiliation(s)
- Josephine M Thomas
- Division of Neuroscience and Experimental Psychology and Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Catriona J Cunningham
- Division of Neuroscience and Experimental Psychology and Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Catherine B Lawrence
- Division of Neuroscience and Experimental Psychology and Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Emmanuel Pinteaux
- Division of Neuroscience and Experimental Psychology and Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology and Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
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Nozohouri S, Sifat AE, Vaidya B, Abbruscato TJ. Novel approaches for the delivery of therapeutics in ischemic stroke. Drug Discov Today 2020; 25:535-551. [PMID: 31978522 DOI: 10.1016/j.drudis.2020.01.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/20/2019] [Accepted: 01/15/2020] [Indexed: 02/06/2023]
Abstract
Here, we review novel approaches to deliver neuroprotective drugs to salvageable penumbral brain areas of stroke injury with the goals of offsetting ischemic brain injury and enhancing recovery.
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Affiliation(s)
- Saeideh Nozohouri
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Ali Ehsan Sifat
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Bhuvaneshwar Vaidya
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
| | - Thomas J Abbruscato
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
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Ghosh MK, Chakraborty D, Sarkar S, Bhowmik A, Basu M. The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports. Signal Transduct Target Ther 2019; 4:42. [PMID: 31637020 PMCID: PMC6799849 DOI: 10.1038/s41392-019-0075-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 12/16/2022] Open
Abstract
Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences, ~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.
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Affiliation(s)
- Mrinal K. Ghosh
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Dipankar Chakraborty
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Sibani Sarkar
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Arijit Bhowmik
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, 700 026 India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, South 24, Paraganas, 743372 India
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