Parkinson’s disease(PD)is a common neurodegenerative disorder with profound impact on patients’quality of life and long-term health,and early detection and intervention are particularly critical.In recent years,the ...Parkinson’s disease(PD)is a common neurodegenerative disorder with profound impact on patients’quality of life and long-term health,and early detection and intervention are particularly critical.In recent years,the search for precise and reliable biomarkers has become one of the key strategies to effectively address the clinical challenges of PD.In this paper,we systematically evaluated potential biomarkers,including proteins,metabolites,epigenetic markers,and exosomes,in the peripheral blood of PD patients.Protein markers are one of the main directions of biomarker research in PD.In particular,α‑synuclein and its phosphorylated form play a key role in the pathological process of PD.It has been shown that aggregation ofα-synuclein may be associated with pathologic protein deposition in PD and may be a potential marker for early diagnosis of PD.In terms of metabolites,uric acid,as a metabolite,plays an important role in oxidative stress and neuroprotection in PD.It has been found that changes in uric acid levels may be associated with the onset and progression of PD,showing its potential as an early diagnostic marker.Epigenetic markers,such as DNA methylation modifications and miRNAs,have also attracted much attention in Parkinson’s disease research.Changes in these markers may affect the expression of PD-related genes and have an important impact on the onset and progression of the disease,providing new research perspectives for the early diagnosis of PD.In addition,exosomes,as a potential biomarker carrier for PD,are able to carry a variety of biomolecules involved in intercellular communication and pathological regulation.Studies have shown that exosomes may play an important role in the pathogenesis of PD,and their detection in blood may provide a new breakthrough for early diagnosis.It has been shown that exosomes may play an important role in the pathogenesis of PD,and their detection in blood may provide new breakthroughs in early diagnosis.In summary,through in-depth evaluation of biomarkers in the peripheral blood of PD patients,this paper demonstrates the important potential of these markers in the early diagnosis of PD and in the study of pathological mechanisms.Future studies will continue to explore the clinical application value of these biomarkers to promote the early detection of PD and individualized treatment strategies.展开更多
Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,n...Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.展开更多
Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sam...Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.展开更多
Five to ten serotyqe I Marek’s disease virus (MDV1) strains of different pathotypes were compared for their DNA sequences of gI, gE, pp38 and meq genes. The reference strains were vMDV GA and JM, vvMDV RB1B and Md11(...Five to ten serotyqe I Marek’s disease virus (MDV1) strains of different pathotypes were compared for their DNA sequences of gI, gE, pp38 and meq genes. The reference strains were vMDV GA and JM, vvMDV RB1B and Md11(p16), vv+MDV strains 648A and 584A,vaccine strain CVI988/Rispens; Chinese strains were: v MDV strain N, vvMDV strain G2, vaccine strain 814. Only random aa changes were found in 12 positions within gE of 497 aa among 10 analyzed strains and in 10 positions within gI of 355 aa among 5 strains. There was no relationship found between virus pathotypes and aa changes of both glycoproteins. The aa changes happened in 14 positions within meq of 339 aa among 5 compared strains. But a proline deletion at aa #194 in a proline-rich domain of meq were shared by two vaccine strains CVI988/Rispens and 814, the latter was a non-pathogenic vaccine strain of serotype 1 isolated in 1983 in China. In another hand, vv+MDV strains 648A demonstrated 5 unique aa changes and 4 of them also located in the proline-rich region. The pp38 was very conservative among sequenced 10 strains, there were only two positions at #107 and #109 with aa altered in its 290 aa. All tested MDV1 strains had glutamine at #107, instead, only vaccine CVI988 had arginine at the position and lost its epitope reactive with Mab H19, to which all other tested MDV1 strains were positive. However, CVI988 and vMDV GA shared a Mab T65-recognized epitope when there was glycine at aa#109. It was glutamic acid at aa#109 in all other MDV1 strains which were not reactive with Mab T65. It seems like that there is some relationship between pathotypes and sequences of pp38 and meq, but more strains need to be compared.展开更多
Interleukin-8 homolog (vIL-8) is a chemokine encoded by the genome of Marek's disease virus. Chicken IL-8 (cIL8) is an important chemokine of chickens which plays a role in antiviral activity. To explore the relat...Interleukin-8 homolog (vIL-8) is a chemokine encoded by the genome of Marek's disease virus. Chicken IL-8 (cIL8) is an important chemokine of chickens which plays a role in antiviral activity. To explore the relationship between vIL-8 and cIL8 can help to discern the function of vIL-8. In this study, the amino acid sequences of vIL-8 and cIL8 were aligned. The cIL8 gene was expressed in E. coli and the cIL8 fusion protein was obtained, after induction with IPTG. The protein was separated by SDS-PAGE and the band of interest was excised and minced for mouse immunization. An immunofluorescence test was used to detect vIL-8 expression in insect cells. The results showed that both vIL-8 and cIL8 were typical CXC chemokines in structure, and they had similar key amino acids, known to be important for receptor binding. The result of the immunofluorescence test showed that the mouse anti-cIL8 serum could react with vIL-8 expressed by insect cells. Therefore, vIL-8 shares common antigenic determinants with cIL8, and they may have a common receptor. This feature of vIL-8 suggests that it may participate in the immune evasion of the virus.展开更多
OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.S...OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.展开更多
目的探讨针刺联合重复经颅磁刺激疗法(transcranial magnetic stimulation,TMS)对帕金森患者认知功能的改善效果。方法选择2021年5月—2023年4月于丽水市中医院就诊的87例帕金森患者,依照随机数字表法将其分为A组(43例)与B组(44例)。A...目的探讨针刺联合重复经颅磁刺激疗法(transcranial magnetic stimulation,TMS)对帕金森患者认知功能的改善效果。方法选择2021年5月—2023年4月于丽水市中医院就诊的87例帕金森患者,依照随机数字表法将其分为A组(43例)与B组(44例)。A组给予TMS治疗,B组在此基础上联合针刺治疗。两组均治疗8周,比较两组临床疗效、治疗前及治疗8周后P300潜伏期、波幅、血清脑神经递质5-羟色胺(5-hydroxytryptamine,5-HT)、去甲肾上腺(norepinephrine,NE)、神经营养因子-3(neurotrophic factor-3,NT-3)、胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)、过氧化氢酶(catalase,CAT)、丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH-px)、髓过氧化物酶(myeloperoxidase,MPO)、简易智力状态评分量表(mini-mental state rating scale,MMSE)评分、统一帕金森病评定量表(unified Parkinson′s disease rating scale,UPDRS)评分、中医证候积分。结果与A组比较,B组临床总有效率更高;与治疗前比较,治疗8周后两组P300潜伏期均缩短,B组短于A组;与治疗前比较,治疗8周后两组波幅、MMSE、UPDRS评分、5-HT、NE、NT-3、IGF-1、CAT、MDA水平均增高,B组高于A组;与治疗前比较,治疗8周后两组中医证候积分、GSH-px、MPO水平均下降,B组低于A组;差异有统计学意义(P<0.05)。结论针刺联合TMS用于帕金森治疗可有效提升临床疗效,缓解相关症状,修复神经损伤,改善认知功能,且可降低氧化应激反应。展开更多
OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its ...OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its effects on the improvement of memory deficit.In this study,the effects of DL0410 on inhibitingβ-amyloid(Aβ)aggregation and attenuating cognition and memory impairment of APP/PS1 mice were further investigated.METHODS Th-T binding test was used to determinethe effect of DL0410 on Aβ1-42 aggregation.In addition,locomotor test,object recognition test,step-down test,and Morris Water maze were performedto investigate the effect of DL0410 on the cognition and memoryfunctions of APP/PS1 mice.RESULTS In vitro results showed that DL0410(10and 30μmol·L-1)could inhibit significantly the monomer Aβ1-42 from aggregation,when incubated together with monomer Aβ1-42 for 24h(P<0.01).Several behavioral tests demonstrated that DL0410(10and 30mg·kg-1)could shortened latency time innavigation test(P<0.01),increased platform crossing-times in space probe test(P<0.05),and reduced the error times in step-down test(P<0.01).CONCLUSIONDL0410 could inhibit Aβaggregation in vitro and alleviate cognition and memory impairment of APP/PS1 mice,which make DL0410 apromising candidate for Alzheimer′s disease treatment.展开更多
Aim It has been widely accepted that autophagy plays a key role in some human diseases such as Par- kinson＇ s disease （PD）. UNC-51-1ike kinasesl （ ULK1 ） has been widely reported to initiate autophagy via its com...Aim It has been widely accepted that autophagy plays a key role in some human diseases such as Par- kinson＇ s disease （PD）. UNC-51-1ike kinasesl （ ULK1 ） has been widely reported to initiate autophagy via its com- plex ULKl-mAtg13-FIP200 at the first stage; however, targeting ULK1 as a therapeutic strategy in PD still remains in its infancy. This study aimed at developing a novel ULK1 activator as candidate drugs for PD therapy and valida- ting the possible mechanism and efficacy in vitro and in vivo. Methods Sequence alignment, phylogenetic analy- sis, homology modeling, molecular dockingand structure modificationwere applied forscreening of candidate com- pounds. Surface plasmon resonance （SPR） analysis and molecular dynamics （MD） simulations were carried outto prove the binding betweenULKland BL-UA07. Observations of cell morphology were executed through several methods including MDC staining and GFP-LC3 transfection. Flow cytometric analysis of MDC was used for quantifi- cation of autophagy ratio. Western blot and RNAi transfection were used to explore the detailed mechanisms of BL- UA07-induced autophagy. Furthermore, an in vivo PD mouse model was established for validating the PD treatment efficacy of BL-UA07. Results After a series of screening and structure modification, a novel compound BL-UA07 targeting ULK1 was obtained, which couldeffectivelybind with its target. Then, our results showed that BL-UA07 could induce autophagy via ULK1 complex and decrease damage induced by MPP ~ in SH-SY5Y cells. In addition, in vivomouse model was established to evaluate the protective effect of BL-UA07. The results demonstrated that BL- UA07 has a therapeutic effect on the in vivomouse model without apparent toxicity, which is dependent on the cyto- protective autophagy mediated by ULK1. Conclusion In this study, a novel specific ULK1 activator （BL-UA07） was computationally designed, chemically synthesized and biologically validatedthat could induce cytoprotective au- tophagy in neuroblastoma SH-SYSY cells and in vivo mouse models. Together, these results may uncover this small-molecule compound BL-UA07 as a novel ULK1 activator in autophagy and thus would provide a new clue for exploring more candidate drug targeting ULK1 for future PD therapy.展开更多
Time:December 8-11,2013Venue:Palexpo Geneva Congress Center,Geneva,Switzerland Email:Parkinson@kenes.com Website:www2.kenes.com/parkinson/Pages/Home.aspxⅩⅩ World Congress on Parkinson’s Disease and Related Disorder...Time:December 8-11,2013Venue:Palexpo Geneva Congress Center,Geneva,Switzerland Email:Parkinson@kenes.com Website:www2.kenes.com/parkinson/Pages/Home.aspxⅩⅩ World Congress on Parkinson’s Disease and Related Disorders will be held on December 8-11,2013 in Geneva,Switzerland.As the motto for this World Congress is'Integration by Translation',this Congress will deal in a most translational way with most recent research and updates on the etiology,pathogenesis,potential diagnostic markers and treatment modalities展开更多
目的利用自适应合成抽样(adaptive synthetic sampling,ADASYN)与类别逆比例加权法处理类别不平衡数据,结合分类器构建模型对阿尔茨海默病(alzheimer′s disease,AD)患者疾病进程进行分类预测。方法数据源自阿尔茨海默病神经影像学计划(...目的利用自适应合成抽样(adaptive synthetic sampling,ADASYN)与类别逆比例加权法处理类别不平衡数据,结合分类器构建模型对阿尔茨海默病(alzheimer′s disease,AD)患者疾病进程进行分类预测。方法数据源自阿尔茨海默病神经影像学计划(Alzheimer′s disease neuroimaging initiative,ADNI),经随机森林填补缺失值,弹性网络筛选特征子集后,利用ADASYN与类别逆比例加权法处理类别不平衡数据。分别结合随机森林(random forest,RF)、支持向量机(support vector machine,SVM)构建四种模型:ADASYN-RF、ADASYN-SVM、加权随机森林(weighted random forest,WRF)、加权支持向量机(weighted support vector machine,WSVM),与RF、SVM比较分类性能。模型评价指标为宏观平均精确率(macro-average of precision,macro-P)、宏观平均召回率(macro-average of recall,macro-R)、宏观平均F1值(macro-average of F1-score,macro-F1)、准确率(accuracy,ACC)、Kappa值和AUC(area under the ROC curve)。结果ADASYN-RF的分类性能最优(Kappa值为0.938,AUC为0.980),ADASYN-SVM次之。利用ADASYN-RF预测得到的重要分类特征分别为CDRSB、LDELTOTAL、MMSE,在临床上均可得到证实。结论ADASYN与类别逆比例加权法都能辅助提升分类器性能,但ADASYN算法更优。展开更多
文摘Parkinson’s disease(PD)is a common neurodegenerative disorder with profound impact on patients’quality of life and long-term health,and early detection and intervention are particularly critical.In recent years,the search for precise and reliable biomarkers has become one of the key strategies to effectively address the clinical challenges of PD.In this paper,we systematically evaluated potential biomarkers,including proteins,metabolites,epigenetic markers,and exosomes,in the peripheral blood of PD patients.Protein markers are one of the main directions of biomarker research in PD.In particular,α‑synuclein and its phosphorylated form play a key role in the pathological process of PD.It has been shown that aggregation ofα-synuclein may be associated with pathologic protein deposition in PD and may be a potential marker for early diagnosis of PD.In terms of metabolites,uric acid,as a metabolite,plays an important role in oxidative stress and neuroprotection in PD.It has been found that changes in uric acid levels may be associated with the onset and progression of PD,showing its potential as an early diagnostic marker.Epigenetic markers,such as DNA methylation modifications and miRNAs,have also attracted much attention in Parkinson’s disease research.Changes in these markers may affect the expression of PD-related genes and have an important impact on the onset and progression of the disease,providing new research perspectives for the early diagnosis of PD.In addition,exosomes,as a potential biomarker carrier for PD,are able to carry a variety of biomolecules involved in intercellular communication and pathological regulation.Studies have shown that exosomes may play an important role in the pathogenesis of PD,and their detection in blood may provide a new breakthrough for early diagnosis.It has been shown that exosomes may play an important role in the pathogenesis of PD,and their detection in blood may provide new breakthroughs in early diagnosis.In summary,through in-depth evaluation of biomarkers in the peripheral blood of PD patients,this paper demonstrates the important potential of these markers in the early diagnosis of PD and in the study of pathological mechanisms.Future studies will continue to explore the clinical application value of these biomarkers to promote the early detection of PD and individualized treatment strategies.
文摘Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.
基金This work was supported by the National Natural Science Foundation (82273506,82273508)the Hunan Provincial Health Commission Scientific Research Plan Project (D202304128334),China。
文摘Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.
文摘Five to ten serotyqe I Marek’s disease virus (MDV1) strains of different pathotypes were compared for their DNA sequences of gI, gE, pp38 and meq genes. The reference strains were vMDV GA and JM, vvMDV RB1B and Md11(p16), vv+MDV strains 648A and 584A,vaccine strain CVI988/Rispens; Chinese strains were: v MDV strain N, vvMDV strain G2, vaccine strain 814. Only random aa changes were found in 12 positions within gE of 497 aa among 10 analyzed strains and in 10 positions within gI of 355 aa among 5 strains. There was no relationship found between virus pathotypes and aa changes of both glycoproteins. The aa changes happened in 14 positions within meq of 339 aa among 5 compared strains. But a proline deletion at aa #194 in a proline-rich domain of meq were shared by two vaccine strains CVI988/Rispens and 814, the latter was a non-pathogenic vaccine strain of serotype 1 isolated in 1983 in China. In another hand, vv+MDV strains 648A demonstrated 5 unique aa changes and 4 of them also located in the proline-rich region. The pp38 was very conservative among sequenced 10 strains, there were only two positions at #107 and #109 with aa altered in its 290 aa. All tested MDV1 strains had glutamine at #107, instead, only vaccine CVI988 had arginine at the position and lost its epitope reactive with Mab H19, to which all other tested MDV1 strains were positive. However, CVI988 and vMDV GA shared a Mab T65-recognized epitope when there was glycine at aa#109. It was glutamic acid at aa#109 in all other MDV1 strains which were not reactive with Mab T65. It seems like that there is some relationship between pathotypes and sequences of pp38 and meq, but more strains need to be compared.
基金funded by Program for Changjiang Scholars and Innovative Research Team in University(IRT0978,PCSIRT)the National Natural Science Foundation of China(30270982)
文摘Interleukin-8 homolog (vIL-8) is a chemokine encoded by the genome of Marek's disease virus. Chicken IL-8 (cIL8) is an important chemokine of chickens which plays a role in antiviral activity. To explore the relationship between vIL-8 and cIL8 can help to discern the function of vIL-8. In this study, the amino acid sequences of vIL-8 and cIL8 were aligned. The cIL8 gene was expressed in E. coli and the cIL8 fusion protein was obtained, after induction with IPTG. The protein was separated by SDS-PAGE and the band of interest was excised and minced for mouse immunization. An immunofluorescence test was used to detect vIL-8 expression in insect cells. The results showed that both vIL-8 and cIL8 were typical CXC chemokines in structure, and they had similar key amino acids, known to be important for receptor binding. The result of the immunofluorescence test showed that the mouse anti-cIL8 serum could react with vIL-8 expressed by insect cells. Therefore, vIL-8 shares common antigenic determinants with cIL8, and they may have a common receptor. This feature of vIL-8 suggests that it may participate in the immune evasion of the virus.
基金Chinese Academy of Engi⁃neering Strategic Consulting Project(2022-XY-45)S&T Program of Hebei(22372502D)+1 种基金Scien⁃tific Research Project of Hebei Provincial Admin⁃istration of Traditional Chinese Medicine(023172)and Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine(2021273)。
文摘OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.
基金The project supported by Ministry of Science and Technology 11th Five-Year Plan(2008ZX09401)
文摘OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its effects on the improvement of memory deficit.In this study,the effects of DL0410 on inhibitingβ-amyloid(Aβ)aggregation and attenuating cognition and memory impairment of APP/PS1 mice were further investigated.METHODS Th-T binding test was used to determinethe effect of DL0410 on Aβ1-42 aggregation.In addition,locomotor test,object recognition test,step-down test,and Morris Water maze were performedto investigate the effect of DL0410 on the cognition and memoryfunctions of APP/PS1 mice.RESULTS In vitro results showed that DL0410(10and 30μmol·L-1)could inhibit significantly the monomer Aβ1-42 from aggregation,when incubated together with monomer Aβ1-42 for 24h(P<0.01).Several behavioral tests demonstrated that DL0410(10and 30mg·kg-1)could shortened latency time innavigation test(P<0.01),increased platform crossing-times in space probe test(P<0.05),and reduced the error times in step-down test(P<0.01).CONCLUSIONDL0410 could inhibit Aβaggregation in vitro and alleviate cognition and memory impairment of APP/PS1 mice,which make DL0410 apromising candidate for Alzheimer′s disease treatment.
文摘Aim It has been widely accepted that autophagy plays a key role in some human diseases such as Par- kinson＇ s disease （PD）. UNC-51-1ike kinasesl （ ULK1 ） has been widely reported to initiate autophagy via its com- plex ULKl-mAtg13-FIP200 at the first stage; however, targeting ULK1 as a therapeutic strategy in PD still remains in its infancy. This study aimed at developing a novel ULK1 activator as candidate drugs for PD therapy and valida- ting the possible mechanism and efficacy in vitro and in vivo. Methods Sequence alignment, phylogenetic analy- sis, homology modeling, molecular dockingand structure modificationwere applied forscreening of candidate com- pounds. Surface plasmon resonance （SPR） analysis and molecular dynamics （MD） simulations were carried outto prove the binding betweenULKland BL-UA07. Observations of cell morphology were executed through several methods including MDC staining and GFP-LC3 transfection. Flow cytometric analysis of MDC was used for quantifi- cation of autophagy ratio. Western blot and RNAi transfection were used to explore the detailed mechanisms of BL- UA07-induced autophagy. Furthermore, an in vivo PD mouse model was established for validating the PD treatment efficacy of BL-UA07. Results After a series of screening and structure modification, a novel compound BL-UA07 targeting ULK1 was obtained, which couldeffectivelybind with its target. Then, our results showed that BL-UA07 could induce autophagy via ULK1 complex and decrease damage induced by MPP ~ in SH-SY5Y cells. In addition, in vivomouse model was established to evaluate the protective effect of BL-UA07. The results demonstrated that BL- UA07 has a therapeutic effect on the in vivomouse model without apparent toxicity, which is dependent on the cyto- protective autophagy mediated by ULK1. Conclusion In this study, a novel specific ULK1 activator （BL-UA07） was computationally designed, chemically synthesized and biologically validatedthat could induce cytoprotective au- tophagy in neuroblastoma SH-SYSY cells and in vivo mouse models. Together, these results may uncover this small-molecule compound BL-UA07 as a novel ULK1 activator in autophagy and thus would provide a new clue for exploring more candidate drug targeting ULK1 for future PD therapy.
文摘Time:December 8-11,2013Venue:Palexpo Geneva Congress Center,Geneva,Switzerland Email:Parkinson@kenes.com Website:www2.kenes.com/parkinson/Pages/Home.aspxⅩⅩ World Congress on Parkinson’s Disease and Related Disorders will be held on December 8-11,2013 in Geneva,Switzerland.As the motto for this World Congress is'Integration by Translation',this Congress will deal in a most translational way with most recent research and updates on the etiology,pathogenesis,potential diagnostic markers and treatment modalities
文摘目的利用自适应合成抽样(adaptive synthetic sampling,ADASYN)与类别逆比例加权法处理类别不平衡数据,结合分类器构建模型对阿尔茨海默病(alzheimer′s disease,AD)患者疾病进程进行分类预测。方法数据源自阿尔茨海默病神经影像学计划(Alzheimer′s disease neuroimaging initiative,ADNI),经随机森林填补缺失值,弹性网络筛选特征子集后,利用ADASYN与类别逆比例加权法处理类别不平衡数据。分别结合随机森林(random forest,RF)、支持向量机(support vector machine,SVM)构建四种模型:ADASYN-RF、ADASYN-SVM、加权随机森林(weighted random forest,WRF)、加权支持向量机(weighted support vector machine,WSVM),与RF、SVM比较分类性能。模型评价指标为宏观平均精确率(macro-average of precision,macro-P)、宏观平均召回率(macro-average of recall,macro-R)、宏观平均F1值(macro-average of F1-score,macro-F1)、准确率(accuracy,ACC)、Kappa值和AUC(area under the ROC curve)。结果ADASYN-RF的分类性能最优(Kappa值为0.938,AUC为0.980),ADASYN-SVM次之。利用ADASYN-RF预测得到的重要分类特征分别为CDRSB、LDELTOTAL、MMSE,在临床上均可得到证实。结论ADASYN与类别逆比例加权法都能辅助提升分类器性能,但ADASYN算法更优。
