The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,p...The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,particularly given the current lack of disease-modifying treatments.The glymphatic system,a recently identified perivascular fluid transport network,is crucial for clearing neurotoxic proteins.This review aims to synthesize current knowledge on the role of the glymphatic system inα-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research.The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance.It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease,as well as the effect of glymphatic dysfunction onα-synuclein accumulation in Parkinson's disease models.Subsequently,the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease,including sleep disturbances,aquaporin-4 impairment,and mitochondrial dysfunction,all of which diminish glymphatic system efficiency.This creates a vicious cycle that exacerbatesα-synuclein accumulation and worsens Parkinson's disease.The therapeutic perspectives section outlines strategies for enhancing glymphatic activity,such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization.Promising interventions include deep brain stimulation,melatonin supplementation,γ-aminobutyric acid modulation,and non-invasive methods(such as exercise and bright-light therapy),multisensoryγstimulation,and ultrasound therapy.Moreover,identifying neuroimaging biomarkers to assess glymphatic flow as an indicator ofα-synuclein burden could refine Parkinson's disease diagnosis and track disease progression.In conclusion,the review highlights the critical role of the glymphatic system inα-synuclein clearance and its potential as a therapeutic target in Parkinson's disease.It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfoldedα-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease.Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducingα-synuclein deposits and mitigating the progression of Parkinson's disease.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic ...Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.展开更多
Alzheimer’s disease(AD),the predominant form of dementia,is a progressive neurodegenerative disorder characterized by an inexorable cognitive decline and memory loss.Accounting for 50%–70%of dementia cases,it repres...Alzheimer’s disease(AD),the predominant form of dementia,is a progressive neurodegenerative disorder characterized by an inexorable cognitive decline and memory loss.Accounting for 50%–70%of dementia cases,it represents one of the most formidable challenges in modern medicine.The disease pathogenesis,while not fully deciphered,centers on theβ-amyloid cascade,a pathological sequence where misfoldedβ-amyloid peptides aggregate into neurotoxic oligomers,eventually forming characteristic amyloid plaques and neurofibrillary tangles that disrupt neuronal function and viability.Recent therapeutic advances include the Food and Drug Administration’s conditional approval of anti-amyloid monoclonal antibodies(aducanumab,2021;lecanemab,2023).However,these breakthrough therapies present significant constraints:their efficacy is confined to early stage AD,they demonstrate only modest clinical benefits,and carry a substantial risk of treatment-emergent adverse effects,particularly amyloid-related imaging abnormalities.展开更多
Exposure to some toxic compounds causes structural and behavioral anomalies associated with the neurons in the later stage of life.Those toxic compounds are termed as a neurotoxicant,which can be a physical factor,a t...Exposure to some toxic compounds causes structural and behavioral anomalies associated with the neurons in the later stage of life.Those toxic compounds are termed as a neurotoxicant,which can be a physical factor,a toxin,an infection,radiation,or maybe a drug.The incongruities caused due to a neurotoxicant further depend on the toxicity of the compound.More importantly,the neurotoxicity of the compound is associated with the concentration and the time point of exposure.The neurodevelopmental defect appears depending on the toxicity of the compound.A neurodevelopmental defect may be associated with a delay in developmental time,defective growth,structural abnormality of many organs,including sensory organs,behavioral abnormalities,or death in the fetus stage.Numerous model organisms are employed to assess the effect of neurotoxicants.The current review summarizes several methods used to check the effect of neurotoxicant and their effect using the model organism Drosophila melanogaster.展开更多
Alzheimer＇s disease（AD） is a neurodegenerative disease characterized by extracellular amyloid beta（Aβ） deposition and intracellular neurofibrillary tangle formation.Monocyte is part of the innate immune system a...Alzheimer＇s disease（AD） is a neurodegenerative disease characterized by extracellular amyloid beta（Aβ） deposition and intracellular neurofibrillary tangle formation.Monocyte is part of the innate immune system and can effectively remove dead cells and debris.It has been suggested that Aβ can recruit monocytes into brain in AD mice,resulting in restriction of cerebral amyloidosis.However,monocyte may act as a double-edged sword,either beneficial（e.g.,clearance of Aβ） or detrimental（e.g.,secretion of neurotoxic factors）.In addition,recent studies indicate that in AD patients,Aβ phagocytosis by monocytes is ineffective.The present review mainly summarized the current knowledge on monocytes and their potential roles in AD.展开更多
Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired eli...Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.展开更多
Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously exp...Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.展开更多
Biochemical, anatomical, and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the...Biochemical, anatomical, and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly suggestive that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural-free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radicals as measured by the fluorescent probe dichlorofluorescein. This article considers that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that free radicals may be common phenomena of neurotoxicity.展开更多
Curcumin(CUR), the main phenolic composition in turmeric, shows preventive effects in various diseases. CUR is commonly found in the Curcuma species and historically applied in herbal medicine. Numerous studies have i...Curcumin(CUR), the main phenolic composition in turmeric, shows preventive effects in various diseases. CUR is commonly found in the Curcuma species and historically applied in herbal medicine. Numerous studies have indicated that CUR possesses protective effects against toxic agents in the various animal tissues including the brain. This study found that CUR may be effective in nervous system problems induced by neurotoxic agents. However, due to the lack of information on human, more investigations are needed to determine the efficacy of CUR as an antidote matter. The current study aimed to critically review the recent literature data from 2014 to 2016 that regarding the therapeutic aspects of CUR versus neurotoxic agents-induced brain damage and its involved mechanisms.展开更多
Pesticides are a well-known family of chemicals that have contaminated water systems globally. Four common subfamilies of pesticides include organochlorines, organophosphates, pyrethroids, and carbamate insecticides w...Pesticides are a well-known family of chemicals that have contaminated water systems globally. Four common subfamilies of pesticides include organochlorines, organophosphates, pyrethroids, and carbamate insecticides which have been shown to adversely affect the human nervous system. Studies have shown a link between pesticide exposure and decreased viability, proliferation, migration, and differentiation of murine neural stem cells. Besides human exposure directly through water systems, additional factors such as pesticide bioaccumulation, biomagnification and potential synergism due to co-exposure to other environmental contaminants must be considered. A possible avenue to investigate the molecular mechanisms and biomolecules impacted by the various classes of pesticides includes the field of-omics. Discovery of the precise molecular mechanisms behind pesticidemediated neurodegenerative disorders may facilitate development of targeted therapeutics.Likewise, discovery of pesticide biodegradation pathways may enable novel approaches for water system bioremediation using genetically engineered microorganisms. In this minireview, we discuss recently established harmful impacts of various categories of pesticides on the nervous system and the application of-omics field for discovery, validation, and mitigation of pesticide neurotoxicity.展开更多
Objective To develop an ICR （female） mouse bioassay （MBA） for toxicity confirmation and evaluation of neurotoxins （brevetoxins）-contaminated shellfish. Methods Brevetoxins （BTX-B） as a causative agent of neuro...Objective To develop an ICR （female） mouse bioassay （MBA） for toxicity confirmation and evaluation of neurotoxins （brevetoxins）-contaminated shellfish. Methods Brevetoxins （BTX-B） as a causative agent of neurotoxic shellfish poisoning （NSP） under different shellfish matrices were intraperitoneally injected at different doses into mice to study their toxic effects and to differentiate the range of lethal and sublethal dosages. Their sensitivity and specificity were analyzed with 2 competitive ELISA kits for quantitative determination of standard BTX-B and dihydroBTX-B under different shellfish matrix-diluent combinations. Detection rates of MBA and two antibody-based assays for BTX-B from field NSP-positive shellfish samples were compared. Results BTX-B could be detected in shellfish tissues at concentration of 50-400 μg/100 g under shellfish matrix-Tween-saline media, which were appropriate to identify toxic shellfish at or above the regulatory limit （80 μg/100 g shellfish tissues）. The LD 50 identified was 455 g/kg for BTX-B under general shellfish matrices （excluding oyster matrices） dissolved in Tween-saline. The presence of shellfish matrices, of oyster matrices in particular, retarded the occurrence of death and toxicity presentation in mice. Two antibody-based assays, even in the presence of different shellfish matrix-diluent combinations, showed acceptable results in quantifying BTX-B and dihydroBTX-B well below the regulatory limit. Conclusion The two ELISA analyses agree favorably （correlation coefficient, r 0.96; Student＇s t-tests, P〉0.05） with the developed bioassay.展开更多
A cross sectional epidemiological study of 93 arc welders in a shipyard was conducted to observe the adverse effect of exposure to manganese welding fumes. Among them, 37 workers with paired controls were given the ne...A cross sectional epidemiological study of 93 arc welders in a shipyard was conducted to observe the adverse effect of exposure to manganese welding fumes. Among them, 37 workers with paired controls were given the neurobehavioral tests. Air concentration of manganese in working place, hair manganese and platelet 5 hydroxytryptamine in both exposed workers and controls was also measured. The higher percentage of respiratory symptoms including sour throat and dyspnea in the welders were observed as compared with the controls. The results of neurobehavioral tests showed that the welders exhibited poorer performance in simple reaction time and Santa Ana dexterity tests than that in the controls. The hair manganese concentration was higher and the blood platelet 5 HT level decreased in the welders. In conclusion, symptoms in the welders might be related to the exposure of manganese. Long term exposure to manganese welding fume could cause the change in simple reaction time and Santa Ana dexterity tests. The hair manganese concentration could be used as a biological monitoring index of exposure to manganese.展开更多
The inhibition and the recovery of brain AChE, BuChE, and NTE activities after acute and subacute administration of DFP were studied in the rat. DFP displayed different specificities in inhibiting these enzymes; inhib...The inhibition and the recovery of brain AChE, BuChE, and NTE activities after acute and subacute administration of DFP were studied in the rat. DFP displayed different specificities in inhibiting these enzymes; inhibition was greatest for BuChE followed by AChE and NTE. Recovery was most rapid for BuChE followed by NTE and AChE. The recovery rates of AChE and BuChE following acute and subacute treatment were similar. However, the recovery rate of NTE in subacutely treated rats was significantly faster than that in acutely treated rats. The results suggest that DFP inhibits these three enzymes and the rates of regeneration of these enzymes are significantly different. (c)1989 Academic Press, Inc.展开更多
BACKGROUND ： To summarize the metabolic pathway of 1-methyl-4-phenyl-1,2,3,6-tetradropyridine （MPTP） and its mechanism in inducing Parkinson disease. DATA SOURCES： A computer-based online search of Medline databas...BACKGROUND ： To summarize the metabolic pathway of 1-methyl-4-phenyl-1,2,3,6-tetradropyridine （MPTP） and its mechanism in inducing Parkinson disease. DATA SOURCES： A computer-based online search of Medline database was undertaken to identify articles about the metabolic pathway of MPTP and its mechanism in inducing Parkinson disease published in English between January 1996 and August 2004, the keywords were ＂MPTP, Parkinson disease＂. Meanwhile, Chinese relevant articles published between January 2000 and August 2004 were searched in Wanfang database with the keywords of ＂MPTP, Parkinson disease＂. STUDY SELECTION： More than 300 relevant literatures were retrieved, and the full-texts were further searched, those about the establishment of animal models, molecular mechanism of MPTP neurotoxicity and the metabolism were selected, and the obviously repetitive ones, case report and reviews were excluded, finally 18 of them were selected for summarization. DATA EXTRACTION： The 18 literatures were categorized according to MPTP induced animal models of Parkinson disease, mechanism of MPTP in inducing apoptosis in models of Parkinson disease, role of dopamine in the neurotoxic mechanism of MPTP, the role of reactive oxygen species and nitric oxide in the neurotoxicity of MPTP. DATA SYNTHESIS： Animal models of Parkinson disease induced by MPTP can not only produce the clinical characters of Parkinson disease, also duplicate the main biochemical and pathological changes of Parkinson disease. The metabolic pathway of MPTP and its mechanism in inducing Parkinson disease included producing free oxygen and nitric oxide, damaging mitochondrial respiratory chain, and inducing apoptosis, etc. which could all lead to the degeneration and loss of dopaminergic neurons. CONCLUSION ： Although some aspects of the models of Parkinson disease are different from that in human beings, we can still know the neurodegeneration of Parkinson disease through studying the molecular mechanism of MPTP.展开更多
Insect-specific neurotoxic peptides derived from the venoms of scorpions and spiders can cause acute paralysis and death when injected into insects,offering a promising insecticidal component for insect pest control.H...Insect-specific neurotoxic peptides derived from the venoms of scorpions and spiders can cause acute paralysis and death when injected into insects,offering a promising insecticidal component for insect pest control.However,effective delivery systems are required to help neurotoxic peptides pass through the gut barrier into the hemolymph,where they can act.Here,we investigated the potential of a novel nanocarrier,Drosophila X virus-like particle(DXV-VLP),for delivering a neurotoxin from the scorpion Androctonus australis Hector(AaIT)against the invasive pest fruit fly,Drosophila suzuki.Our results show that the fusion proteins of DXV polyproteins with AalT peptide at their Ctermini could be sufficiently produced in Lepidoptera Hi5 cells in a soluble form using the recombinant baculovirus expression system,and could self-assemble into VLPs with similar particle morphology and size to authentic DXV virions.In addition,the AalT peptides displayed on DXV-VLPs retained their toxicity,as demonstrated in injection bioassays that resulted in severe mortality(72%)in adults after 72 h.When fed to adults,mild mortality was observed in the group treated with DXV-AalT(38%),while no mortality occurred in the group treated with AaIT peptide,thus indicating the significant role of DXV-VLPs in delivering AalT peptides.Overall,this proof-of-concept study demonstrates for the first time that VLPs can be exploited to enhance oral delivery of insect-specific neurotoxic peptides in the context of pest control.Moreover,it provides insights for further improvements and potentially the development of neurotoxin-based bioinsecticides and/or transgenic crops for insect pest control.展开更多
基金supported by the National Natural Science Foundation of China,No.81971031(to ZL)the National Key Research and Development Program of China,No.2022YFE0210100(to JFC)+7 种基金the National Natural Science Foundation of China(Original Exploration Project),No.82151308(to JFC)the National Natural Science Foundation of China(Research Fund for International Senior Scientists),No.82150710558(to JFC)Science&Technology Initiative STI2030-Major Projects,No.2021ZD0203400(to JFC)Key Research and Development Program of Zhejiang Province,No.2023C03079(to JFC)Scientific Research Starting Foundation of Oujiang Laboratory(Zhejiang Laboratory for Regenerative Medicine,Vision and Brain Health),No.OJQDSP2022007(to JFC)Project of State Key Laboratory of Ophthalmology,Optometry and Visual Science,Wenzhou Medical University,No.J01-20190101(to JFC)Scientific Research Starting Foundation of Wenzhou Medical University,No.QTJ12003(to JFC)Department of Science and Technology of Zhejiang Province,No.2023ZY1011(to JFC)。
文摘The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,particularly given the current lack of disease-modifying treatments.The glymphatic system,a recently identified perivascular fluid transport network,is crucial for clearing neurotoxic proteins.This review aims to synthesize current knowledge on the role of the glymphatic system inα-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research.The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance.It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease,as well as the effect of glymphatic dysfunction onα-synuclein accumulation in Parkinson's disease models.Subsequently,the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease,including sleep disturbances,aquaporin-4 impairment,and mitochondrial dysfunction,all of which diminish glymphatic system efficiency.This creates a vicious cycle that exacerbatesα-synuclein accumulation and worsens Parkinson's disease.The therapeutic perspectives section outlines strategies for enhancing glymphatic activity,such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization.Promising interventions include deep brain stimulation,melatonin supplementation,γ-aminobutyric acid modulation,and non-invasive methods(such as exercise and bright-light therapy),multisensoryγstimulation,and ultrasound therapy.Moreover,identifying neuroimaging biomarkers to assess glymphatic flow as an indicator ofα-synuclein burden could refine Parkinson's disease diagnosis and track disease progression.In conclusion,the review highlights the critical role of the glymphatic system inα-synuclein clearance and its potential as a therapeutic target in Parkinson's disease.It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfoldedα-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease.Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducingα-synuclein deposits and mitigating the progression of Parkinson's disease.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by Fondo Nacional de Desarrollo Científico y Tecnológico(FONDECYT)#1200836,#1210644,and#1240888,and Agencia Nacional de Investigación y Desarrollo(ANID)-FONDAP#15130011(to LL)FONDECYT#3230227(to MFG).
文摘Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.
文摘Alzheimer’s disease(AD),the predominant form of dementia,is a progressive neurodegenerative disorder characterized by an inexorable cognitive decline and memory loss.Accounting for 50%–70%of dementia cases,it represents one of the most formidable challenges in modern medicine.The disease pathogenesis,while not fully deciphered,centers on theβ-amyloid cascade,a pathological sequence where misfoldedβ-amyloid peptides aggregate into neurotoxic oligomers,eventually forming characteristic amyloid plaques and neurofibrillary tangles that disrupt neuronal function and viability.Recent therapeutic advances include the Food and Drug Administration’s conditional approval of anti-amyloid monoclonal antibodies(aducanumab,2021;lecanemab,2023).However,these breakthrough therapies present significant constraints:their efficacy is confined to early stage AD,they demonstrate only modest clinical benefits,and carry a substantial risk of treatment-emergent adverse effects,particularly amyloid-related imaging abnormalities.
基金MM Lab is supported by SERB/EMR/2017/003054,BT/PR21857/NNT/28/1238/2017Odisha DBT 3325/ST(BIO)-02/2017.
文摘Exposure to some toxic compounds causes structural and behavioral anomalies associated with the neurons in the later stage of life.Those toxic compounds are termed as a neurotoxicant,which can be a physical factor,a toxin,an infection,radiation,or maybe a drug.The incongruities caused due to a neurotoxicant further depend on the toxicity of the compound.More importantly,the neurotoxicity of the compound is associated with the concentration and the time point of exposure.The neurodevelopmental defect appears depending on the toxicity of the compound.A neurodevelopmental defect may be associated with a delay in developmental time,defective growth,structural abnormality of many organs,including sensory organs,behavioral abnormalities,or death in the fetus stage.Numerous model organisms are employed to assess the effect of neurotoxicants.The current review summarizes several methods used to check the effect of neurotoxicant and their effect using the model organism Drosophila melanogaster.
文摘Alzheimer＇s disease（AD） is a neurodegenerative disease characterized by extracellular amyloid beta（Aβ） deposition and intracellular neurofibrillary tangle formation.Monocyte is part of the innate immune system and can effectively remove dead cells and debris.It has been suggested that Aβ can recruit monocytes into brain in AD mice,resulting in restriction of cerebral amyloidosis.However,monocyte may act as a double-edged sword,either beneficial（e.g.,clearance of Aβ） or detrimental（e.g.,secretion of neurotoxic factors）.In addition,recent studies indicate that in AD patients,Aβ phagocytosis by monocytes is ineffective.The present review mainly summarized the current knowledge on monocytes and their potential roles in AD.
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
基金supported by the National Key R&D Program of China,No.2021YFF0702203(to HYL)the National Natural Science Foundation of China,No.82101323(to TS)Preferred Foundation of Zhejiang Postdoctors,No.ZJ2021152(to TS).
文摘Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.
基金supported by grant from the Ministry of Education,Science and Technological Development,Republic of Serbia(173051)supported by a UICC Yamagiwa-Yoshida Memorial International Cancer Study Grant(YY2/2015/381414)
文摘Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.
文摘Biochemical, anatomical, and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly suggestive that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural-free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radicals as measured by the fluorescent probe dichlorofluorescein. This article considers that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that free radicals may be common phenomena of neurotoxicity.
文摘Curcumin(CUR), the main phenolic composition in turmeric, shows preventive effects in various diseases. CUR is commonly found in the Curcuma species and historically applied in herbal medicine. Numerous studies have indicated that CUR possesses protective effects against toxic agents in the various animal tissues including the brain. This study found that CUR may be effective in nervous system problems induced by neurotoxic agents. However, due to the lack of information on human, more investigations are needed to determine the efficacy of CUR as an antidote matter. The current study aimed to critically review the recent literature data from 2014 to 2016 that regarding the therapeutic aspects of CUR versus neurotoxic agents-induced brain damage and its involved mechanisms.
文摘Pesticides are a well-known family of chemicals that have contaminated water systems globally. Four common subfamilies of pesticides include organochlorines, organophosphates, pyrethroids, and carbamate insecticides which have been shown to adversely affect the human nervous system. Studies have shown a link between pesticide exposure and decreased viability, proliferation, migration, and differentiation of murine neural stem cells. Besides human exposure directly through water systems, additional factors such as pesticide bioaccumulation, biomagnification and potential synergism due to co-exposure to other environmental contaminants must be considered. A possible avenue to investigate the molecular mechanisms and biomolecules impacted by the various classes of pesticides includes the field of-omics. Discovery of the precise molecular mechanisms behind pesticidemediated neurodegenerative disorders may facilitate development of targeted therapeutics.Likewise, discovery of pesticide biodegradation pathways may enable novel approaches for water system bioremediation using genetically engineered microorganisms. In this minireview, we discuss recently established harmful impacts of various categories of pesticides on the nervous system and the application of-omics field for discovery, validation, and mitigation of pesticide neurotoxicity.
文摘Objective To develop an ICR （female） mouse bioassay （MBA） for toxicity confirmation and evaluation of neurotoxins （brevetoxins）-contaminated shellfish. Methods Brevetoxins （BTX-B） as a causative agent of neurotoxic shellfish poisoning （NSP） under different shellfish matrices were intraperitoneally injected at different doses into mice to study their toxic effects and to differentiate the range of lethal and sublethal dosages. Their sensitivity and specificity were analyzed with 2 competitive ELISA kits for quantitative determination of standard BTX-B and dihydroBTX-B under different shellfish matrix-diluent combinations. Detection rates of MBA and two antibody-based assays for BTX-B from field NSP-positive shellfish samples were compared. Results BTX-B could be detected in shellfish tissues at concentration of 50-400 μg/100 g under shellfish matrix-Tween-saline media, which were appropriate to identify toxic shellfish at or above the regulatory limit （80 μg/100 g shellfish tissues）. The LD 50 identified was 455 g/kg for BTX-B under general shellfish matrices （excluding oyster matrices） dissolved in Tween-saline. The presence of shellfish matrices, of oyster matrices in particular, retarded the occurrence of death and toxicity presentation in mice. Two antibody-based assays, even in the presence of different shellfish matrix-diluent combinations, showed acceptable results in quantifying BTX-B and dihydroBTX-B well below the regulatory limit. Conclusion The two ELISA analyses agree favorably （correlation coefficient, r 0.96; Student＇s t-tests, P〉0.05） with the developed bioassay.
文摘A cross sectional epidemiological study of 93 arc welders in a shipyard was conducted to observe the adverse effect of exposure to manganese welding fumes. Among them, 37 workers with paired controls were given the neurobehavioral tests. Air concentration of manganese in working place, hair manganese and platelet 5 hydroxytryptamine in both exposed workers and controls was also measured. The higher percentage of respiratory symptoms including sour throat and dyspnea in the welders were observed as compared with the controls. The results of neurobehavioral tests showed that the welders exhibited poorer performance in simple reaction time and Santa Ana dexterity tests than that in the controls. The hair manganese concentration was higher and the blood platelet 5 HT level decreased in the welders. In conclusion, symptoms in the welders might be related to the exposure of manganese. Long term exposure to manganese welding fume could cause the change in simple reaction time and Santa Ana dexterity tests. The hair manganese concentration could be used as a biological monitoring index of exposure to manganese.
文摘The inhibition and the recovery of brain AChE, BuChE, and NTE activities after acute and subacute administration of DFP were studied in the rat. DFP displayed different specificities in inhibiting these enzymes; inhibition was greatest for BuChE followed by AChE and NTE. Recovery was most rapid for BuChE followed by NTE and AChE. The recovery rates of AChE and BuChE following acute and subacute treatment were similar. However, the recovery rate of NTE in subacutely treated rats was significantly faster than that in acutely treated rats. The results suggest that DFP inhibits these three enzymes and the rates of regeneration of these enzymes are significantly different. (c)1989 Academic Press, Inc.
基金the National Nat-ural Science Foundation of Chi-na, No. 30270433 a grant fromTechnological DevelopmentPlanning of Beijing Committeeof Education, No.KM200310025092*
文摘BACKGROUND ： To summarize the metabolic pathway of 1-methyl-4-phenyl-1,2,3,6-tetradropyridine （MPTP） and its mechanism in inducing Parkinson disease. DATA SOURCES： A computer-based online search of Medline database was undertaken to identify articles about the metabolic pathway of MPTP and its mechanism in inducing Parkinson disease published in English between January 1996 and August 2004, the keywords were ＂MPTP, Parkinson disease＂. Meanwhile, Chinese relevant articles published between January 2000 and August 2004 were searched in Wanfang database with the keywords of ＂MPTP, Parkinson disease＂. STUDY SELECTION： More than 300 relevant literatures were retrieved, and the full-texts were further searched, those about the establishment of animal models, molecular mechanism of MPTP neurotoxicity and the metabolism were selected, and the obviously repetitive ones, case report and reviews were excluded, finally 18 of them were selected for summarization. DATA EXTRACTION： The 18 literatures were categorized according to MPTP induced animal models of Parkinson disease, mechanism of MPTP in inducing apoptosis in models of Parkinson disease, role of dopamine in the neurotoxic mechanism of MPTP, the role of reactive oxygen species and nitric oxide in the neurotoxicity of MPTP. DATA SYNTHESIS： Animal models of Parkinson disease induced by MPTP can not only produce the clinical characters of Parkinson disease, also duplicate the main biochemical and pathological changes of Parkinson disease. The metabolic pathway of MPTP and its mechanism in inducing Parkinson disease included producing free oxygen and nitric oxide, damaging mitochondrial respiratory chain, and inducing apoptosis, etc. which could all lead to the degeneration and loss of dopaminergic neurons. CONCLUSION ： Although some aspects of the models of Parkinson disease are different from that in human beings, we can still know the neurodegeneration of Parkinson disease through studying the molecular mechanism of MPTP.
基金supported by the Special Research Fund of Ghent University and Research Foundation Flanders(FWO).CNTT is recipient of a senior postdoctoral fellowship from FWO(grant number 12V5722N).
文摘Insect-specific neurotoxic peptides derived from the venoms of scorpions and spiders can cause acute paralysis and death when injected into insects,offering a promising insecticidal component for insect pest control.However,effective delivery systems are required to help neurotoxic peptides pass through the gut barrier into the hemolymph,where they can act.Here,we investigated the potential of a novel nanocarrier,Drosophila X virus-like particle(DXV-VLP),for delivering a neurotoxin from the scorpion Androctonus australis Hector(AaIT)against the invasive pest fruit fly,Drosophila suzuki.Our results show that the fusion proteins of DXV polyproteins with AalT peptide at their Ctermini could be sufficiently produced in Lepidoptera Hi5 cells in a soluble form using the recombinant baculovirus expression system,and could self-assemble into VLPs with similar particle morphology and size to authentic DXV virions.In addition,the AalT peptides displayed on DXV-VLPs retained their toxicity,as demonstrated in injection bioassays that resulted in severe mortality(72%)in adults after 72 h.When fed to adults,mild mortality was observed in the group treated with DXV-AalT(38%),while no mortality occurred in the group treated with AaIT peptide,thus indicating the significant role of DXV-VLPs in delivering AalT peptides.Overall,this proof-of-concept study demonstrates for the first time that VLPs can be exploited to enhance oral delivery of insect-specific neurotoxic peptides in the context of pest control.Moreover,it provides insights for further improvements and potentially the development of neurotoxin-based bioinsecticides and/or transgenic crops for insect pest control.
