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MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases

Bioactive Materials 2023年第5期23卷 409-437页

作者： Heng Zhou Yan He Wei Xiong Shuili Jing Xingxiang Duan Zhiyun Huang Gurek SNahal Youjian Peng Mingchang Li Yaoqi Zhu Qingsong Ye Center of Regenerative Medicine&Department of Stomatology Renmin Hospital of Wuhan UniversityWuhan430060China Institute of Regenerative and Translational Medicine Tianyou Hospital of Wuhan University of Science and TechnologyWuhanHubei430064China Department of Oral and Maxillofacial Surgery Massachusetts General HospitalHarvard Medical SchoolBoston02114MAUSA School of Dentistry University of QueenslandHerston4006QLDAustralia Department of Neurosurgery Renmin Hospital of Wuhan UniversityWuhan430060China Department of Oral and Maxillofacial Surgery Hospital of Taikang Tongji(Wuhan)430050WuhanChina

Mesenchymal stem cells(MSCs)are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility.They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders,including neural differentiation,immunosuppression,neurotrophy,and safety.However,the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases.To improve some of their abilities,many studies have employed genetic engineering to transfer key genes into MSCs.Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties.However,to date,different modes of gene transfer have specific drawbacks and advantages.In addition,MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation,enhancing neurotrophic and neuroprotective functions,and increasing survival and homing abilities.The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function.In this review,we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes.Further,we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.

关键词： Mesenchymal stem cells Gene delivery neurological diseases Viral vector Nonviral vectors

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Neuro faces of beneficial T cells:essential in brain,impaired in aging and neurological diseases,and activated functionally by neurotransmitters and neuropeptides

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Neural Regeneration Research 2023年第6期18卷 1165-1178页

作者： Mia Levite Faculty of Medicine The Hebrew University of JerusalemCampus Ein KaremJerusalemIsrael Institute of Gene Therapy The Hadassah University Hospital-Ein KaremJerusalemIsrael

T cells are essential for a healthy life,performing continuously:immune surveillance,recognition,protection,activation,suppression,assistance,eradication,secretion,adhesion,migration,homing,communications,and additional tasks.This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain.First,normal beneficial T cells are essential for normal healthy brain functions:cognition,spatial learning,memory,adult neurogenesis,and neuroprotection.T cells decrease secondary neuronal degeneration,increase neuronal survival after central nervous system(CNS) injury,and limit CNS inflammation and damage upon injury and infection.Second,while pathogenic T cells contribute to CNS disorders,recent studies,mostly in animal models,show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in seve ral neuroinflammatory and neurodegenerative diseases.These include M ultiple Sclerosis(MS),Alzheimer’s disease,Parkinson’s disease,Amyotrophic Lateral Sclerosis(ALS),stro ke,CNS trauma,chronic pain,and others.Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective,neuro regenerative and immunomodulato ry effects.Third,normal beneficial T cells are abnormal,impaired,and dysfunctional in aging and multiple neurological diseases.Different T cell impairments are evident in aging,brain tumors(mainly Glioblastoma),seve re viral infections(including COVID-19),chro nic stress,major depression,schizophrenia,Parkinson’s disease,Alzheimer’s disease,ALS,MS,stro ke,and other neuro-pathologies.The main detrimental mechanisms that impair T cell function are activation-induced cell death,exhaustion,senescence,and impaired T cell stemness.Fo urth,several physiological neurotransmitters and neuro peptides induce by themselves multiple direct,potent,beneficial,and therapeutically-relevant effects on normal human T cells,via their receptors in T cells.This scientific field is called "Nerve-Driven Immunity".The main neurotransmitters and neuropept

关键词： aging dopamine glutamate nerve-driven immunity neurological diseases neuropeptides neurotransmitters Personalized Adoptive Neuro-Immunotherapy T cells

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Targeting the blood-brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota,circadian rhythms,and their interplays

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4667-4687页

作者： Yanping Wang Weihong Du Xiaoyan Hu Xin Yu Chun Guo Xinchun Jin Wei Wang Department of Neurology the Second Affliated Hospital of Jiaxing CityJiaxing 314000China Beijing Key Laboratory of Cancer Invasion and Metastasis Research Department of Histology and EmbryologySchool of Basic Medical SciencesAdvanced Innovation Center for Human Brain ProtectionCapital Medical UniversityBeijing 100069China Bengbu Medical College(Department of Neurology the Second Hospital of Jiaxing City)Jiaxing 233030China School of Biosciences University of SheffieldSheffeld S102TNUK Department of Physiology and Pathophysiology Capital Medical UniversityBeijing 100069China

AbstracTthe blood-brain barrier(BBB)impairment plays a crucial role in the pathological processes of aging-accompanied neurological diseases(AAND).Meanwhile,circadian rhythms disruption and gut microbiota dysbiosis are associated with increased morbidity of neurological diseases in the accelerated aging population.Importantly,circadian rhythms disruption and gut microbiota dysbiosis are also known to induce the generation of toxic metabolites and pro-inflammatory cytokines,resulting in disruption of BBB integrity.Collectively,this provides a new perspective for exploring the relationship among circadian rhythms,gut microbes,and the BBB in aging-accompanied neurological diseases.In this review,we focus on recent advances in the interplay between circadian rhythm disturbances and gut microbiota dysbiosis,and their potential roles in the BBB disruption that occurs in AAND.Based on existing literature,we discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota,which would serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.

关键词： Blood-brain barrier neurological diseases Aging Gut microbiota Circadian rhythms

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The gut microbiome:implications for neurogenesis and neurological diseases

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Neural Regeneration Research 2022年第1期17卷 53-58页

作者： Cheng Liu Shang-Yu Yang Long Wang Fang Zhou Department of Healthcare Administration College of Medical and Health ScienceAsia UniversityTaichungTaiwanChina Department of Anesthesiology Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina

There is an increasing recognition of the strong links between the gut microbiome and the brain,and there is persuasive evidence that the gut microbiome plays a role in a variety of physiological processes in the central nervous system.This review summarizes findings that gut microbial composition alterations are linked to hippocampal neurogenesis,as well as the possible mechanisms of action;the existing literature suggests that microbiota influence neurogenic processes,which can result in neurological disorders.We consider this evidence from the perspectives of neuroinflammation,microbial-derived metabolites,neurotrophins,and neurotransmitters.Based on the existing research,we propose that the administration of probiotics can normalize the gut microbiome.This could therefore also represent a promising treatment strategy to counteract neurological impairment.

关键词： gut microbiota microbial-derived metabolites microbiota-gut-brain axis neurogenesis neuroinflammation neurological diseases neurotrophins probiotics

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Gut microbiota:a new insight into neurological diseases

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Chinese Medical Journal 2023年第11期136卷 1261-1277页

作者： Lanxiang Liu Haiyang Wang Xueyi Chen Peng Xie Department of Neurology Yongchuan Hospital of Chongqing Medical UniversityChongqing 402160China National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional diseases The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China

In the last decade,it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host.Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases,e.g.,Parkinson’s disease,Alzheimer’s disease,and myasthenia gravis.However,the underlying molecular mechanisms are complex and remain unclear.Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation,indicating that the gut microbiota may be an important regulator of neurological diseases.However,further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases.Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders.In this review,we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases,and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.

关键词： Gut microbiota Gut-brain axis neurological diseases Parkinson’s disease Alzheimer’s disease Autism spectrum disorder Cerebrovascular disease

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neurological diseases caused by coronavirus infection of the respiratory airways

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Brain Science Advances 2020年第4期6卷 324-343页

作者： Waqas Ahmed Adeel Khan Wish Hal Sundar Humaira Naseem Wanghao Chen Jia Feng Samran Durrani Lukui Chen Department of Neurosurgery Neuroscience CenterCancer CenterIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhou 510310GuangdongChina School of Medicine Southeast UniversityNanjing 210009JiangsuChina School of Biological Science and Medical Engineering Southeast UniversityNanjing 210009JiangsuChina Department of Medicine Dow University of Health SciencesKarachiSindhPakistan Department of General Surgery Allied Hospital FaisalabadPunjabPakistan

Infections of the central nervous system(CNS)infections are critical problems for public health.They are caused by several different organisms,including the respiratory coronaviruses(Co Vs).Co Vs usually infect the upper respiratory tract causing the common cold.However,in infants,and in elderly and immunocompromised persons,they can also affect the lower respiratory tract causing pneumonia and various syndromes of respiratory distress.Co Vs also have neuroinvasive capabilities because they can spread from the respiratory tract to the CNS.Once infection begins in the CNS cells,it can cause various CNS problems such as status epilepticus,encephalitis,and long-term neurological disease.This neuroinvasive properties of Co Vs may damage the CNS as a result of misdirected host immune response,which could be associated with autoimmunity in susceptible individuals(virus-induced neuro-immunopathology)or associated with viral replication directly causing damage to the CNS cells(virus-induced neuropathology).In December 2019,a new disease named COVID-19 emerged which is caused by Co Vs.The significant clinical symptoms of COVID-19 are related to the respiratory system,but they can also affect the CNS,causing acute cerebrovascular and intracranial infections.We describe the possible invasion routes of coronavirus in this review article,and look for the most recent findings associated with the neurological complications in the recently published literature.

关键词： human coronavirus respiratory viral infection neuroinvasion CNS infection neurological diseases COVID-19

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The Discrepancy of neurological diseases between China and Western Countries in Recent Two Decades

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Chinese Medical Journal 2018年第8期131卷 886-891页

作者： Jun Ni Fei Han Jing Yuan Han Wang Dong-Chao Shen Yan Xu Li-Ying Cui Department of Neurology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China

INTRODUCTION neurological diseases are characterized by high frequency of disability and mortality with pathogenesis largely unknown. Genetic, refractory, and rare diseases account tbr a large proportion of neurological diseases： sympathetically, limited curable treatments are available. Hundreds of millions of people worldwide are affected by neurological disorders. The diagnosis and treatment of neurological disorders have made significant progress in recent years, especially in the past two decades with the rapid development of technology.

关键词： Discrepancy Progression neurological diseases China Western

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Efficacy and safety of nerve growth factor for the treatment of neurological diseases:a meta-analysis of 64 randomized controlled trials involving 6,297 patients

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Neural Regeneration Research 2015年第5期10卷 819-828页

作者： Meng Zhao Xiao-yan Li Chun-ying Xu Li-ping Zou Department of Pediatrics Chinese PLA General Hospital

OBJECTIVE： China is the only country where nerve growth factor is approved for large-scale use as a clinical medicine. More than 10 years ago, in 2003, nerve growth factor injection was listed as a national drug. The goal of this article is to evaluate comprehensively the efficacy and safety of nerve growth factor for the treatment of neurological diseases. DATA RETRIEVAL： A computer-based retrieval was performed from six databases, including the Cochrane Library, PubMed, EMBASE, Sino Med, CNKI, and the VIP database, searching from the clinical establishment of nerve growth factor for treatment until December 31, 2013. The key words for the searches were ＂nerve growth factor, randomized controlled trials＂ in Chinese and in English. DATA SELECTION： Inclusion criteria： any study published in English or Chinese referring to randomized controlled trials of nerve growth factor; patients with neurological diseases such as peripheral nerve injury, central nerve injury, cranial neuropathy, and nervous system infections; patients older than 7 years; similar research methods and outcomes assessing symptoms; and measurement of nerve conduction velocities. The meta-analysis was conducted using Review Manager 5.2.3 software. MAIN OUTCOME MEASURES： The total effective rate, the incidence of adverse effects, and the nerve conduction velocity were recorded for each study. RESULTS： Sixty-four studies involving 6,297 patients with neurological diseases were included. The total effective rate in the group treated with nerve growth factor was significantly higher than that in the control group （P 〈 0.0001, RR： 1.35, 95%CI： 1.30-1.40）. The average nerve conduction velocity in the nerve growth factor group was significantly higher than that in the control group （P 〈 0.00001, MD. 4.59 m/s, 95%CI： 4.12-5.06）. The incidence of pain or sclero- ma at the injection site in the nerve growth factor group was also higher than that in the control group （P 〈 0.00001, RR： 6.30, 95%CI： 3.53-11.27）, but such adverse effects were mild. CONCLUSION： N

关键词： nerve regeneration neurological diseases nerve growth factor randomized controlledtrials meta-analysis adverse effects nerve conduction velocity neural regeneration

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Potential Role of Akkermansia muciniphila in Parkinson's Disease and Other neurological/Autoimmune diseases

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Current Medical Science 2021年第6期41卷 1172-1177页

作者： Xin FANG Fang-jun LI Dao-jun HONG Department of Neurology the First Affiliated Hospital ofNanchang UniversityNanchang 330006China

The composition of the gut microbiota,including Akkermatisia muciniphila(A.muciniphila),is altered in many neurological diseases and may be involved in the pathophysiological processes of Parkinson’s disease(PD).A.muciniphila,a mucin-degrading bacterium,is a potential next-generation microbe that has anti-inflammatory properties and is responsible for keeping the body healthy.As the role of A.muciniphila in PD has become increasingly apparent,we discuss the potential link between A.muciniphila and various neurological diseases(including PD)in the current review.

关键词： Akkermansia muciniphila gut microbiota neurological diseases Parkinson’s disease

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Considerations on Intervention Goal and Efficacy Evaluation of Traditional Chinese Medicine in the Treatment of neurological diseases

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Chinese Journal of Integrative Medicine 2007年第2期13卷 148-151页

作者：谢仁明杜宝新黄燕周道友王永炎黄培新 neurological Researching Centre Guangdong Province Hospital China Academy of Chinese Medical Sciences

In the last several years, traditional Chinese medicine （TCM） has made much progress in the treatment of neurological diseases. The living space of TCM in neurological diseases lies in refractory diseases, aging and chronic diseases caused by multiple factors as well as sub-health state and chronic fatigue state. The effect model of TCM mainly consists of whole effect, self-organization, self-stable model, holographic effect and butterfly effect. The effective point of TCM in neurological diseases lies mainly in end-points and health-related events. Moreover, TCM has advantages in the evaluation of symptoms, syndrome and quality of life （QOL）. Some key indexes should be included when evaluating the efficacy of TCM in neurological diseases. Meanwhile, the advantages of TCM such as end-points, health-related events and QOL should be highlighted. Multi-subject researching methods could be adopted to make a comprehensive evaluation of subjective and objective indexes. The clinical evidence on the TCM efficacy evaluation may come from RCTs, and other types of designs can also be considered.

关键词： neurological diseases traditional Chinese medicine efficacy evaluation

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