The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates ...The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.展开更多
Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic ...Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.展开更多
The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral bloo...The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.展开更多
背景:纳米细胞囊泡具有再上皮化、抗氧化、抗炎以及调节细胞外基质重塑等功能,凋亡小体具有免疫调节作用,因此二者结合所形成的纳米融合囊泡可协同促进糖尿病皮肤创面愈合。目的:探讨纳米融合囊泡对糖尿病小鼠皮肤创面的愈合作用。方法...背景:纳米细胞囊泡具有再上皮化、抗氧化、抗炎以及调节细胞外基质重塑等功能,凋亡小体具有免疫调节作用,因此二者结合所形成的纳米融合囊泡可协同促进糖尿病皮肤创面愈合。目的:探讨纳米融合囊泡对糖尿病小鼠皮肤创面的愈合作用。方法:①材料制备及表征:分离提取C57BL/6J乳鼠原代骨髓间充质干细胞纳米囊泡和C57BL/6J小鼠骨髓来源中性粒细胞凋亡小体,将二者结合采用微型挤出机制备纳米融合囊泡。②体外实验:采用MTT检测不同浓度纳米融合囊泡对NIH-3T3细胞和人脐静脉内皮细胞的增殖作用;采用活性氧荧光探针检测纳米融合囊泡对过氧化氢干预的NIH-3T3细胞的抗氧化作用;采用实时定量RT-qPCR法检测纳米融合囊泡对脂多糖引发的RAW 264.7巨噬细胞炎症反应的抑制效果。③体内实验:36只雄性C57BL/6J小鼠构建糖尿病小鼠模型,造模成功后在糖尿病小鼠脊柱两侧使用打孔机分别制备直径6 mm的2个圆形创面,采用随机数字表法分为3组,对照组创缘皮下注射0.1 mL磷酸盐缓冲液,纳米囊泡组注射0.1 mL 25μg/mL纳米囊泡,纳米融合囊泡组注射0.1 mL 25μg/mL纳米融合囊泡,连续治疗3 d,观察创面愈合情况与组织形态学变化。结果与结论:①体外实验:纳米融合囊泡在质量浓度为0-100μg/mL时均无毒性作用,且可促进NIH-3T3细胞和人脐静脉内皮细胞的增殖,其中25μg/mL纳米融合囊泡促进NIH-3T3细胞增殖的效果最明显,而人脐静脉内皮细胞的存活率则随着纳米融合囊泡质量浓度的增加不断增强。纳米融合囊泡具有良好的抗氧化效果,与过氧化氢组相比,纳米囊泡组和纳米融合囊泡组的活性氧荧光信号依次减弱。此外,纳米融合囊泡还具有抗炎能力,降低了脂多糖诱导的巨噬细胞炎症反应。②体内实验:苏木精-伊红染色与Masson染色显示,与对照组相比,术后第6天纳米囊泡组和纳米融合囊泡组创面均表达出丰富的胶原纤维以及肉芽组织,其中以纳米融合囊泡组最多;术后第12天,纳米融合囊泡组创面显著缩小,且愈合速度显著快于其他组,促创面愈合效果最为显著。结果表明,纳米融合囊泡能够展现出促细胞增殖、抗氧化和抗炎特性,从而在促进糖尿病小鼠皮肤创面愈合过程中发挥积极作用。展开更多
With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of th...With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.展开更多
背景:全身振动训练已广泛应用于运动表现、康复医学及健康管理等多个领域。目的:通过CiteSpace软件对全身振动训练方法的国内外应用研究进行可视化分析,揭示该领域的研究进展、热点问题及未来发展趋势。方法:在中国知网和Web of Scienc...背景:全身振动训练已广泛应用于运动表现、康复医学及健康管理等多个领域。目的:通过CiteSpace软件对全身振动训练方法的国内外应用研究进行可视化分析,揭示该领域的研究进展、热点问题及未来发展趋势。方法:在中国知网和Web of Science数据库中选取2000-2024年期间全身振动领域的文献,利用CiteSpace V(6.2.R6)软件对文献的发表趋势、合作网络、关键词聚类及研究热点进行可视化分析。结果与结论:共纳入661篇中文文献和1005篇英文文献,国内外全身振动领域研究呈现逐年增长的趋势。国内研究主要集中于振动训练对运动表现和康复应用的影响,特别是在老年人、运动员和特定疾病患者中的应用;国外研究更加注重全身振动对神经肌肉功能、代谢综合征及慢性疾病患者的康复效果。国内全身振动相关研究的热点集中在振动频率、振动训练和振动治疗方面,国外全身振动相关研究侧重姿势控制、肌肉力量及全身振动的综合效果。未来全身振动训练的研究应加强跨国合作、优化训练参数,探索在不同人群中的个性化应用,推动全身振动技术在体育、康复及健康管理中广泛应用。展开更多
基金supported by grants PID2020-120308RB-I00 and PID2023-147802OB-I00 funded by MICIU/AEI/10.13039/501100011033FEDER,UE,by Aligning Science Across Parkinson’s(ref.ASAP-020505)through the Michael J.Fox Foundation for Parkinson’s Research+1 种基金by CiberNed Intramural Collaborative Projects(ref.PI2020/09)by the Spanish Fundación Mutua Madrile?a de Investigación Médica(to JLL)。
文摘The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.
文摘Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.
基金supported by Department of Defense grant HT9425-24-1-0030 a grant from the Stanley Medical Research Institute(to SS).
文摘The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.
文摘背景:纳米细胞囊泡具有再上皮化、抗氧化、抗炎以及调节细胞外基质重塑等功能,凋亡小体具有免疫调节作用,因此二者结合所形成的纳米融合囊泡可协同促进糖尿病皮肤创面愈合。目的:探讨纳米融合囊泡对糖尿病小鼠皮肤创面的愈合作用。方法:①材料制备及表征:分离提取C57BL/6J乳鼠原代骨髓间充质干细胞纳米囊泡和C57BL/6J小鼠骨髓来源中性粒细胞凋亡小体,将二者结合采用微型挤出机制备纳米融合囊泡。②体外实验:采用MTT检测不同浓度纳米融合囊泡对NIH-3T3细胞和人脐静脉内皮细胞的增殖作用;采用活性氧荧光探针检测纳米融合囊泡对过氧化氢干预的NIH-3T3细胞的抗氧化作用;采用实时定量RT-qPCR法检测纳米融合囊泡对脂多糖引发的RAW 264.7巨噬细胞炎症反应的抑制效果。③体内实验:36只雄性C57BL/6J小鼠构建糖尿病小鼠模型,造模成功后在糖尿病小鼠脊柱两侧使用打孔机分别制备直径6 mm的2个圆形创面,采用随机数字表法分为3组,对照组创缘皮下注射0.1 mL磷酸盐缓冲液,纳米囊泡组注射0.1 mL 25μg/mL纳米囊泡,纳米融合囊泡组注射0.1 mL 25μg/mL纳米融合囊泡,连续治疗3 d,观察创面愈合情况与组织形态学变化。结果与结论:①体外实验:纳米融合囊泡在质量浓度为0-100μg/mL时均无毒性作用,且可促进NIH-3T3细胞和人脐静脉内皮细胞的增殖,其中25μg/mL纳米融合囊泡促进NIH-3T3细胞增殖的效果最明显,而人脐静脉内皮细胞的存活率则随着纳米融合囊泡质量浓度的增加不断增强。纳米融合囊泡具有良好的抗氧化效果,与过氧化氢组相比,纳米囊泡组和纳米融合囊泡组的活性氧荧光信号依次减弱。此外,纳米融合囊泡还具有抗炎能力,降低了脂多糖诱导的巨噬细胞炎症反应。②体内实验:苏木精-伊红染色与Masson染色显示,与对照组相比,术后第6天纳米囊泡组和纳米融合囊泡组创面均表达出丰富的胶原纤维以及肉芽组织,其中以纳米融合囊泡组最多;术后第12天,纳米融合囊泡组创面显著缩小,且愈合速度显著快于其他组,促创面愈合效果最为显著。结果表明,纳米融合囊泡能够展现出促细胞增殖、抗氧化和抗炎特性,从而在促进糖尿病小鼠皮肤创面愈合过程中发挥积极作用。
基金supported by the National Natural Science Foundation of China,No.82160255(to RX)the Natural Science Foundation of Jiangxi Province,No.20212BAB216026(to HL)+2 种基金Science and Technology Plan Project of Health Commission of Jiangxi Province,No.202110016(to HL)Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine,No.2022B975(to HL)a grant from Jiangxi Province Key Laboratory of Neurology,No.2024SSY06081(to RX).
文摘With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.
文摘背景:全身振动训练已广泛应用于运动表现、康复医学及健康管理等多个领域。目的:通过CiteSpace软件对全身振动训练方法的国内外应用研究进行可视化分析,揭示该领域的研究进展、热点问题及未来发展趋势。方法:在中国知网和Web of Science数据库中选取2000-2024年期间全身振动领域的文献,利用CiteSpace V(6.2.R6)软件对文献的发表趋势、合作网络、关键词聚类及研究热点进行可视化分析。结果与结论:共纳入661篇中文文献和1005篇英文文献,国内外全身振动领域研究呈现逐年增长的趋势。国内研究主要集中于振动训练对运动表现和康复应用的影响,特别是在老年人、运动员和特定疾病患者中的应用;国外研究更加注重全身振动对神经肌肉功能、代谢综合征及慢性疾病患者的康复效果。国内全身振动相关研究的热点集中在振动频率、振动训练和振动治疗方面,国外全身振动相关研究侧重姿势控制、肌肉力量及全身振动的综合效果。未来全身振动训练的研究应加强跨国合作、优化训练参数,探索在不同人群中的个性化应用,推动全身振动技术在体育、康复及健康管理中广泛应用。
