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Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

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Neural Regeneration Research 2024年第2期19卷 360-368页

作者： Leyi Huang Wenjie Xiao Yan Wang Juan Li Jiaoe Gong Ewen Tu Lili Long Bo Xiao Xiaoxin Yan Lily Wan Department of Anatomy and neurobiology Central South University Xiangya Medical SchoolChangshaHunan ProvinceChina Department of neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of neurology Hunan Children’s HospitalChangshaHunan ProvinceChina Department of neurology Brain Hospital of Hunan ProvinceChangshaHunan ProvinceChina

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

关键词： antiepileptic drugs epileptogenesis metabotropic glutamate receptors(mGluRs) signal pathways therapeutic potentials

Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis

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Neural Regeneration Research 2024年第3期19卷 671-679页

作者： Chunyun Liu Shangde Guo Rong Liu Minfang Guo Qing Wang Zhi Chai Baoguo Xiao Cungen Ma Institute of Brain Science Shanxi Datong UniversityDatongShanxi ProvinceChina The Key Research Laboratory of Benefiting Qi for Acting Blood Cireulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of neurobiology Shanxi University of Chinese MedicineTaiyuanShanxi ProvinceChina Institute of neurology Huashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.

关键词： anti-inflammatory experimental autoimmune encephalomyelitis Fasudil macrophage multiple sclerosis pro-inflammatory Rho kinase

enOsCas12f1-mediated exon skipping for Duchenne muscular dystrophy therapy in humanized mouse model

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Journal of Genetics and Genomics 2024年第2期51卷 256-259页

作者： Ming Jin Jiajia Lin Yu Zhang Qingquan Xiao Xiangfeng Kong Xiumei Zhang Zhurui Shao Yin Wang Yuyang Yu Jinjing Li Wan-Jin Chen Guoling Li Hui Yang Ning Wang Department of neurology and Institute of neurology of First Affiliated Hospital Institute of NeuroscienceFujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian 350004China HUIDAGENE Therapeutics Co. Ltd.Shanghai 200131China Institute of Neuroscience State Key Laboratory of NeuroscienceKey Laboratory of Primate NeurobiologyCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China

Duchenne muscular dystrophy(DMD)is a severe neuromuscular disorder caused by mutations in the dystrophin gene,which encodes the essential protein dystrophin.This genetic condition,affecting approximately 1 in 5000 male births worldwide(Birnkrant et al.,2018),is characterized by progressive muscle weakness and wasting,leading to premature death in the second or third decade of life(Farini et al.,2016).The absence of dystrophin protein causes instability in the sarcolemma,which predisposes individuals to myonecrosis and activation of inflammatory signaling cascades.Unfortunately,there is currently no effective cure for DMD,and glucocorticoid steroids are commonly used in clinical settings to delay symptom development(Merlini et al.,2003).

关键词： dystrophy Duchenne

Effect of three-volt moxibustion with helium-neon laser irradiation on quality of care in patients with lumbar radiculopathy spondylosis

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World Journal of Clinical Cases 2024年第15期12卷 2522-2528页

作者： Xiu-Kun Ji Jian Li Department of Traditional Chinese Medicine The Second Hospital of Heilongjiang ProvinceHarbin 150028Heilongjiang ProvinceChina departments of Four neurology The Second Hospital of Heilongjiang ProvinceHarbin 150028Heilongjiang ProvinceChina

BACKGROUND Lumbar radiculopathy spondylosis is a relatively common orthopedic disease with a high incidence rate.It most commonly occurs in the lumbar 4-5 and lumbar 5-sacral 1 vertebrae,which account for approximately 95%of cases.It mostly occurs in people aged 30-50 years old and greatly affects their quality of life.AIM To determine the effect of triple-voltage acupuncture combined with helium-neon laser irradiation on the quality of care and improvement of symptoms in patients with lumbar radiculopathy spondylolisthesis.METHODS In this study,we selected 120 patients with lumbar radiculopathy spondylosis who were treated at our hospital between June 2019 to June 2020.The patients were divided into control and observation groups according to the random number table method,with 60 patients in each group.Patients in the observation group were treated with three-volt moxibustion combined with helium-neon laser irradiation,and those in the control group were treated with lumbar traction.After 1 month of treatment,the lumbar pain scores,lumbar spine motor functions,clinical treatment effects,and nursing satisfaction of the two groups were compared.RESULTS The results showed that acupuncture combined with laser irradiation significantly improved the patients'clinical symptoms,i.e.,reduced their low back pain,significantly lower numerical rating scale pain scores in the observation group than in the control group,and better lumbar spine motility than in the control group,compared to lumbar traction.In addition,they were cared for.The treatment effectiveness rate of the observation group was 95.5%,which was significantly higher than that of the control group(81.67%).Satisfaction with care was higher than 90 points in both groups,but the difference was not statistically significant.CONCLUSION Our study provides a clinical rationale for the future treatment of patients with lumbar spine disease.However,further extensive research is needed for validation.

关键词： Moxibustion Laser irradiation Clinical rationale Lumbar spine Three-volt moxibustion

Exploring the novel role of oligodendrocyte precursor cells in phagocytosis:beyond myelinogenesis

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Neural Regeneration Research 2025年第2期20卷 473-474页

作者： Gen Hamanaka Ken Arai Neuroprotection Research Laboratories Departments of Radiology and NeurologyMassachusetts General Hospital and Harvard Medical SchoolCharlestownMAUSA

Roles of oligodendrocyte precursor cells in the central nervous system:Oligodendrocyte precursor cells(OPCs)have long been recognized for their critical role as precursors to oligodendrocytes,the primary myelin-producing cells.As precursors,OPCs mature and differentiate into oligodendrocytes,which contribute significantly to the formation of myelin sheaths around axons.This myelination,which is critical for the conduction of salutatory nerve impulses in the cerebral white matter,underscores the classical role of oligodendrocytes in central nervous system(CNS)functionality.Importantly,because oligodendrocytes are differentiated cells that cannot proliferate.

关键词： critical system conduction

Gene therapy for monogenic disorders: challenges, strategies, and perspectives

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Journal of Genetics and Genomics 2024年第2期51卷 133-143页

作者： Yi Zhang Zhi-Ying Wu Department of Medical Genetics and Center for Rare Diseases Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Department of neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Key Laboratory of Medical neurobiology of Zhejiang Province HangzhouZhejiang 310009China

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

关键词： Gene therapy Monogenic diseases Geneediting Genedelivery Challenges

The neuroscience of pain,addiction,and anesthesia

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Zoological Research 2024年第3期45卷 709-710页

作者： Ji Hu Ping Zheng School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Medical neurobiology Institutes of Brain ScienceMOE Frontier Center for Brain ScienceDepartment of Neurology of Zhongshan HospitalFudan UniversityShanghai 200032China

Researchers and clinicians have long been interested in the mechanisms of pain,anesthesia,and addiction.The International Association for the Study of Pain(IASP)defines pain as an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage(Raja et al.,2020).Drug addiction refers to a condition of reliance that develops from regular drug consumption,which may lead to withdrawal symptoms when use is halted.Anesthesia involves the complete loss of consciousness induced by an inhaled or intravenous anesthetic(Tosello et al.,2022).In this special collection,Zoological Research presents research findings focused on pain,addiction,and anesthesia.

关键词： anesthesia damage

Neural Circuitry Involving Substance P in Male Sexual Behavior

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Neuroscience Bulletin 2024年第4期40卷 544-546页

作者： Xinrong Wang Junqiang Zheng Han Xu Department of neurobiology and Department of neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine Zhejiang University School of MedicineHangzhou310058China Nanhu Brain-Computer Interface Institute Hangzhou311100China Liangzhu Laboratory MOE Frontier Science Center for Brain Science and Brain-machine IntegrationState Key Laboratory of Brain-Machine IntelligenceZhejiang UniversityHangzhou311121China NHC and CAMS Key Laboratory of Medical neurobiology Zhejiang UniversityHangzhou310058China Lingang Laboratory Shanghai200031China

Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.

关键词： behavior neural specified

Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

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The Innovation 2024年第1期5卷 118-126页

作者： Qing-Qing Tao Xue Cai Yan-Yan Xue Weigang Ge Liang Yue Xiao-Yan Li Rong-Rong Lin Guo-Ping Peng Wenhao Jiang Sainan Li Kun-Mu Zheng Bin Jiang Jian-Ping Jia Tiannan Guo Zhi-Ying Wu Department of neurology and Research Center of neurology in the Second Affiliated Hospital and Key Laboratory of Medical neurobiology of Zhejiang Province Zhejiang University School of MedicineHangzhou 310009China Liangzhu Laboratory Zhejiang UniversityHangzhou 311100China Westlake Laboratory of Life Sciences and Biomedicine Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhou 310024China Institute of Basic Medical Sciences Westlake Institute for Advanced StudyHangzho 310024China Department of neurology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Department of neurology First Affiliated HospitalSchool of MedicineXiamen UniversityXiamen 361009China Innovation Center for Neurological Disorders and Department of neurology Xuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric DiseasesBeijing 100053China MOE Frontier Science Center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhou 310058China CAS Center for Excellence in Brain Science and Intelligence Technology Shanghai 200031China

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

关键词： cerebrospinal Alzheimer fluid