PD, Parkinson's disease

PD,帕金森病
  • 文章类型: Journal Article
    为了评估阿尔茨海默病(AD)中黄斑OCT血管造影(OCTA)参数的内速可重复性,轻度认知障碍(MCI),帕金森病(PD),和正常认知(NC)。
    横断面研究。
    临床诊断为AD的患者,PD,对MCI或NC进行成像。质量差的图像和糖尿病患者的图像,青光眼,或玻璃体视网膜疾病被排除在分析之外.
    所有参与者均使用ZeissCirrusHD-5000和AngioPlex(CarlZeissMeditec,软件版本11.0.0.29946)并获得双眼的重复OCTA图像。灌注密度(PFD),血管密度(VD),使用ETDRS网格叠加从以中央凹为中心的3×3mm和6×6mmOCTA图像测量和中央凹无血管区(FAZ)面积。
    使用组内相关系数来量化PFD的可重复性,VD,和从成像获得的FAZ面积测量。
    AD22的3×3mm扫描,40MCI,21PD,26名NC参与者和29名AD的6×6mm扫描,44MCI,29PD,并对30名NC参与者进行了分析。AD参与者中6×6mmPFD的可重复性值范围为0.64(0.49-0.82),AD参与者中3×3mmPFD的可重复性值范围为0.87(0.67-0.92)。NC参与者和神经退行性疾病患者之间的可重复性没有显着差异。
    总的来说,在NC参与者和神经变性患者之间观察到相似的OCTA可重复性.无论诊断组如何,黄斑OCTA指标显示中等至良好的可重复性。
    作者对本文讨论的任何材料都没有专有或商业利益。
    UNASSIGNED: To assess the intrasession repeatability of macular OCT angiography (OCTA) parameters in Alzheimer\'s disease (AD), mild cognitive impairment (MCI), Parkinson\'s disease (PD), and normal cognition (NC).
    UNASSIGNED: Cross sectional study.
    UNASSIGNED: Patients with a clinical diagnosis of AD, PD, MCI, or NC were imaged. Images with poor quality and of those with diabetes mellitus, glaucoma, or vitreoretinal disease were excluded from analysis.
    UNASSIGNED: All participants were imaged using the Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Software Version 11.0.0.29946) and repeat OCTA images were obtained for both eyes. Perfusion density (PFD), vessel density (VD), and Foveal avascular zone (FAZ) area were measured from 3 × 3 mm and 6 × 6 mm OCTA images centered on the fovea using an ETDRS grid overlay.
    UNASSIGNED: Intraclass correlation coefficients were used to quantify repeatability of PFD, VD, and FAZ area measurements obtained from imaging.
    UNASSIGNED: 3 × 3 mm scans of 22 AD, 40 MCI, 21 PD, and 26 NC participants and 6 × 6 mm scans of 29 AD, 44 MCI, 29 PD, and 30 NC participants were analyzed. Repeatability values ranged from 0.64 (0.49-0.82) for 6 × 6 mm PFD in AD participants to 0.87 (0.67-0.92) for 3 × 3 mm PFD in AD participants. No significant differences were observed in repeatability between NC participants and those with neurodegenerative disease.
    UNASSIGNED: Overall, similar OCTA repeatability was observed between NC participants and those with neurodegeneration. Regardless of diagnostic group, macular OCTA metrics demonstrated moderate to good repeatability.
    UNASSIGNED: The authors have no proprietary or commercial interest in any materials discussed in this article.
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  • 文章类型: Journal Article
    UNASSIGNED:建议寻找一种非侵入性和可重复的工具来准确诊断阿尔茨海默病(AD)和帕金森病(PD)。
    UNASSIGNED:70名志愿者分为三组:24名患有轻度AD痴呆,24在PD的第一阶段和第二阶段,和22个健康对照。在评估认知测试的分数后,磷酸化tau(p-tau)的唾液水平,总α-突触核蛋白(α-syn),和β-淀粉样蛋白1-42(Aβ)*蛋白质已被评估。最后,截止点,接收机工作特性(ROC),灵敏度,和特异性已被计算以找到准确和可检测的生物标志物。
    UNASSIGNED:研究结果表明,PD(p<0.01)和AD(p<0.001)患者的唾液Aβ水平均高于对照组。此外,PD和AD患者的α-syn水平均低于对照组(p<0.05)。然而,AD组p-tau水平仅高于对照组(p<0.01)。60.3pg/ml截止点的唾液Aβ1-42水平显示出诊断AD的优异性能(AUC:0.81)。
    未经评估:p-tau的评估,α-syn,AD和PD患者唾液中Aβ1-42的水平有助于早期诊断。p-tau水平对于区分AD和PD可能是有价值的。因此,这些有希望的调查可以减少侵入性诊断方法的使用,仅此一项就能成功减轻AD和PD患者的痛苦。此外,应鼓励根据AD和PD的病理生理学引入准确的唾液生物标志物。
    UNASSIGNED: Finding a non-invasive and repeatable tool has been recommended to make an accurate diagnosis of Alzheimer\'s disease (AD) and Parkinson\'s disease (PD).
    UNASSIGNED: 70 volunteers participated in three groups: 24 with mild dementia of AD, 24 in the first and second stages of PD, and 22 healthy controls. After valuing the scores of cognitive tests, the salivary levels of phosphorylated tau (p-tau), total alpha-synuclein (α-syn), and beta-amyloid 1-42 (Aβ)‏‎ proteins have been evaluated. Finally, the cutoff points, receiver operating characteristic (ROC), sensitivity, and specificity have been calculated to find accurate and detectable biomarkers.
    UNASSIGNED: Findings showed that the salivary level of Aβ was higher in both PD (p < 0.01) and AD (p < 0.001) patients than in controls. Moreover, the level of α-syn in both PD and AD patients was similarly lower than in controls (p < 0.05). However, the level of p-tau was only ‎higher in the AD group than in the control (p < 0.01). Salivary Aβ 1-42 level at a 60.3 pg/ml cutoff point revealed an excellent performance for diagnosing AD (AUC: 0.81).
    UNASSIGNED: Evaluation of p-tau, α-syn, and Aβ 1-42 levels in the saliva of AD and PD patients could help the early diagnosis. The p-tau level might be valuable for differentiation between AD and PD. Therefore, these hopeful investigations could be done to reduce the usage of invasive diagnostic methods, which alone is a success in alleviating the suffering of AD and PD patients. Moreover, introducing accurate salivary biomarkers according to the pathophysiology of AD and PD should be encouraged.
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  • 文章类型: Journal Article
    未经批准:目前,许多研究证实,炎症在帕金森病(PD)中起着重要作用。炎症指标与疾病的预后有关,但单一的炎症指数有一定的局限性。与C反应蛋白(CRP)或白蛋白(Alb)相比,C反应蛋白-白蛋白比(CAR)是更好的炎症或营养状况标志物。但是关于CAR与PD总生存期(OS)之间的关系的研究有限。
    未经批准:研究PD患者的CAR和OS之间的关联。
    UNASSIGNED:所有这些数据都是从DryadDigitalRepository获得的,在此基础上,我们进行了二次分析。这项研究是由神经内科进行的,国家区域神经疾病中心,和Utano国家医院在2004年3月至2007年11月之间的研究。最终的分析样本包括235名PD患者,从研究注册到终点的生存或全因死亡。在这项研究中,单变量和多变量COX回归分析用于计算调整后的风险比(HR),95%置信区间(CI)。此外,本研究通过Kaplan-Meier曲线和亚组分析探讨了PD患者中CAR和OS的相关性.
    UNASSIGNED:这项研究包括235名PD患者,平均年龄为62.25岁,包括135名女性和100名男性,45人在随访期间死亡。CAR与性别有关,改良的Hoehn-Yahr阶段(MH-Y),和PD患者的简易精神状态检查(MMSE)。在COX多元回归模型中,在调整了年龄之后,性别,PD持续时间,mH-Y,MMSE,和非甾体抗炎药,发现CAR与PD中的OS相关(HR=1.54,95%CI=1.01-2.34,p=0.044)。亚组分析表明,亚组在CAR和PD患者的预后之间没有相互作用的作用(p为相互作用>0.05),结果保持稳定。
    UASSIGNED:CAR水平较高的PD患者的全因死亡率较高,这表明PD患者总体生存率差与CAR的增加有关。CAR可能是PD患者的可靠预后生物标志物。
    UNASSIGNED: At present, many studies have confirmed that inflammation plays a central role in Parkinson\'s disease (PD). The inflammatory index is related to the prognosis of the disease, but a single inflammatory index has some limitations. The C-reactive protein-albumin ratio (CAR) is a better marker of inflammation or nutritional status than C-reactive protein (CRP) or albumin (Alb), but there is limited study on the association between CAR and the overall survival (OS) of PD.
    UNASSIGNED: To study the association between CAR and OS in PD patients.
    UNASSIGNED: All of these data were obtained from the Dryad Digital Repository, based on which we conducted a secondary analysis. The study was conducted by the Department of Neurology, the National Regional Center for Neurological Disorders, and the National Hospital of Utano study between March 2004 to November 2007. The final analytic sample included 235 PD patients with the outcome of survival or all-cause death from the study registration to the endpoint. In this study, univariate and multivariate COX regression analyses were used to calculate the adjusted hazard ratio (HR), with a 95% confidence interval (CI). In addition, the association between CAR and OS in PD patients was explored by Kaplan-Meier curve and subgroup analysis.
    UNASSIGNED: This study included 235 PD patients with an average age of 62.25 years, including 135 females and 100 males, and 45 died during the follow-up period. CAR was associated with gender, modified Hoehn-Yahr stages (mH-Y), and Mini-Mental State Examination (MMSE) of PD patients. In the COX multivariate regression model, after adjusting the age, gender, PD duration, mH-Y, MMSE, and the non-steroidal anti-inflammatory drugs, CAR was found to be associated with the OS in PD (HR = 1.54, 95% CI = 1.01-2.34, p = 0.044). Subgroup analysis showed that the subgroup did not play an interactive role in the association between the prognosis of patients with CAR and PD (p for interaction >0.05), and the results remained stable.
    UNASSIGNED: The all-cause mortality of PD patients with a high level of CAR is higher, which indicates that the poor overall survival of PD patients is associated with the increase of CAR. The CAR may be a reliable prognostic biomarker for PD patients.
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  • 文章类型: Journal Article
    UNASSIGNED:运动障碍和便秘等非运动障碍是影响帕金森病(PD)患者生活质量的主要因素。探讨电针结合常规药物治疗对PD运动功能障碍和便秘的疗效和安全性。
    未经评估:在这项多中心随机对照试验中,2018年9月19日至2019年9月25日,我们在中国4家医院纳入了166名符合条件的参与者.参与者被随机分配(1:1)到电针(EA)组和等待名单对照组。两组均接受常规药物治疗,EA组每周接受3次电针,持续12周。主要结果是统一帕金森病评定量表(UPDRS)评分从基线到第12周的变化。次要结果包括运动症状和便秘的功能障碍评估,还记录了依从性和不良事件.在Chictr.org注册。cn,ChiCTR1800019517。
    UNASSIGNED:在第12周,EA组的UPDRS评分变化显着高于对照组,差异为-9.1点(95%CI,-11.8至-6.4),这种差异持续到第16周和第24周。从基线到第12周,39项帕金森病问题(PDQ-39)减少了10分(四分位数范围,EA组中的IQR-26.0至0.0)和对照组中的2.5点(IQR:-11.0至4.0),差异有统计学意义。第12周20米步行的时间和步数,以及EA组的基线变化,与对照组相当。但是EA组在第16周和第24周的20米步行时间比对照组的基线下降更大。从第4周到第24周,EA组每周自发排便(SBMs)的中位数高于对照组,差异均有统计学意义。治疗期间EA相关不良事件发生率较低,它们是温和和短暂的。
    UNASSIGNED:我们的研究结果表明,与常规药物治疗相比,常规药物治疗联合电针治疗可显著提高PD患者的运动功能,增加排便,电针治疗PD是一种安全有效的治疗方法。
    UNASSIGNED:上海“科技创新行动计划”临床医学领域项目(18401970700),上海市老龄化与妇女儿童健康研究专项(020YJZX0134),上海市针灸临床研究中心(20MC1920500).
    UNASSIGNED: Motor disturbances and non-motor disturbances such as constipation are the main factors affecting the quality of life in patients with Parkinson\'s disease (PD). We investigated the efficacy and safety of electroacupuncture combined with conventional pharmacological treatment on motor dysfunction and constipation in PD.
    UNASSIGNED: In this multi-centre randomised controlled trial, we enrolled 166 eligible participants between September 19, 2018 and September 25, 2019 in four hospitals in China. Participants were randomly assigned (1:1) to the electroacupuncture (EA) group and the waitlist control group. Each participant in both groups received the conventional pharmacological treatment, EA group received 3 sessions of electroacupuncture per week for 12 weeks. The primary outcome was the change in the Unified Parkinson\'s Disease Rating Scale (UPDRS) score from baseline to week 12. The secondary outcomes included the evaluation of functional disability in motor symptoms and constipation, the adherence and adverse events were also recorded. Registered with Chictr.org.cn, ChiCTR1800019517.
    UNASSIGNED: At week 12, the change in the UPDRS score of the EA group was significantly higher than that of the control group, with a difference of -9.1 points (95% CI, -11.8 to -6.4), and this difference continued into weeks 16 and 24. From baseline to week 12, the 39-item Parkinson Disease Question (PDQ-39) decreased by 10 points (interquartile range, IQR -26.0 to 0.0) in the EA group and 2.5 points (IQR: -11.0 to 4.0) in the control group, the difference was statistically significant. The time and steps for the 20-m walk at week 12, as well as the changes from baseline in the EA group, were comparable with that in the control group. But the EA group had a greater decrease than the control group from baseline in the times for 20-m walks at weeks 16 and 24. From week 4 to week 24, the median values of spontaneous bowel movements (SBMs) per week in the EA group were higher than that in the control group, the differences were all statistically significant. The incidence of EA-related adverse events during treatment was low, and they are mild and transient.
    UNASSIGNED: The findings of our study suggested that compared with conventional pharmacological treatment, conventional pharmacological treatment combined with electroacupuncture significantly enhances motor function and increased bowel movements in patients with PD, electroacupuncture is a safe and effective treatment for PD.
    UNASSIGNED: Shanghai \"Science and Technology Innovation Action Plan\" Clinical Medicine Field Project (18401970700), Shanghai Special Project on Aging and Women\'s and Children\'s Health Research (020YJZX0134), Shanghai Clinical Research Centre for Acupuncture and Moxibustion (20MC1920500).
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  • 文章类型: Journal Article
    近年来,科学研究已经确定神经和免疫系统具有共享的分子信号传导成分。免疫细胞的天然蛋白质,它们也存在于大脑中,在神经系统中具有神经元功能,它们会影响突触可塑性,轴突再生,神经发生,和神经传递。某些天然免疫分子,如主要组织相容性复合物I(MHC-I),配对免疫球蛋白受体B(PirB),toll样受体(TLR),分化簇-3ζ(CD3ζ),CD4共受体,和T细胞受体β(TCR-β)在神经元中的表达已被广泛记录。在这次审查中,我们提供了我们的观点,并讨论了T细胞受体β亚基在调节中枢神经系统神经元功能中的可能作用。基于Syken和Shatz之前的发现。,2003;Nishiyori等人。,2004年;罗德里格斯等。,1993年和Komal等人。,2014年;我们讨论了在选定的大脑区域中TCR-β亚基的限制性表达是否可能与神经系统疾病的病理学有关,以及它们的表达异常增强是否可以被认为是衰老或神经退行性疾病如亨廷顿病(HD)的合适生物标志物。
    In recent years scientific research has established that the nervous and immune systems have shared molecular signaling components. Proteins native to immune cells, which are also found in the brain, have neuronal functions in the nervous system where they affect synaptic plasticity, axonal regeneration, neurogenesis, and neurotransmission. Certain native immune molecules like major histocompatibility complex I (MHC-I), paired immunoglobulin receptor B (PirB), toll-like receptor (TLR), cluster of differentiation-3 zeta (CD3ζ), CD4 co-receptor, and T-cell receptor beta (TCR-β) expression in neurons have been extensively documented. In this review, we provide our opinion and discussed the possible roles of T-cell receptor beta subunits in modulating the function of neurons in the central nervous system. Based on the previous findings of Syken and Shatz., 2003; Nishiyori et al., 2004; Rodriguez et., 1993 and Komal et., 2014; we discuss whether restrictive expression of TCR-β subunits in selected brain regions could be involved in the pathology of neurological disorders and whether their aberrant enhancement in expression may be considered as a suitable biomarker for aging or neurodegenerative diseases like Huntington\'s disease (HD).
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  • 文章类型: Case Reports
    一个有舌根癌症病史的人,表现为咯血,复发性肺炎和CT上的疯狂铺路模式最终被诊断为类脂肺炎,随后发现与使用鱼油胶囊和可能的帕金森病有关。考虑并驳回了肺泡蛋白沉积症和浸润性黏液腺癌作为鉴别诊断。具有相似放射学发现和病史的患者应考虑误吸和类脂肺炎的风险。
    A man with a history of cancer of the base of the tongue presenting with hemoptysis, recurrent pneumonia and crazy-paving patterns on CT was ultimately diagnosed with lipoid pneumonia, subsequently found to be associated with use of fish oil capsules and possible Parkinson\'s disease. Pulmonary alveolar proteinosis and invasive mucinous adenocarcinoma as differential diagnoses were considered and dismissed. Risk of aspiration and lipoid pneumonia should be considered in patients with similar radiological findings and history.
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  • 文章类型: Journal Article
    重建神经导管是改善周围神经修复功能的一种有前途的方法。除了选择合适的聚合物用于导管结构外,添加牛磺酸等因子可以改善缺损神经再生的更有利的微环境。显示牛磺酸的几个主要生物学特性,例如,渗透压的调节,神经发生的调节,和钙止血,使其成为修复缺损神经的适当选择。对此,我们研究了与人内皮干细胞(hEnSCs)培养的负载牛磺酸的PCL导管对切除的坐骨神经的修复作用。PCL/牛磺酸/细胞导管移植到10毫米的坐骨神经间隙。将42只Wistar大鼠随机分为7组:(1)正常组,(2)阴性对照(NC),(3)阳性对照(自体神经移植组),(4)PCL导管组(PCL),(5)含牛磺酸的PCL导管组(PCL/牛磺酸),(6)在PCL导管(PCL/细胞)上培养的hEnSCs,(7)在PCL/牛磺酸导管(PCL/牛磺酸/细胞)上培养的hEnSC。运动和感觉神经的功能恢复,在PCL/牛磺酸/细胞导管中观察到兴奋肌肉和运动远端潜伏期的动作电位。组织学研究表明,该组中还出现了显着的神经再生和明显的桥接。总之,PCL/牛磺酸/细胞导管显示出合适的机械性能和生物相容性可以改善坐骨神经的再生。
    Reconstruction of nerve conduits is a promising method for functional improvement in peripheral nerve repair. Besides choosing of a suitable polymer for conduit construction, adding factors such as Taurine improve a more advantageous microenvironment for defect nerve regeneration. Showing several major biological properties of Taurine, for example, regulation of the osmotic pressure, modulation of neurogenesis, and calcium hemostasis, makes it an appropriate option for repairing of defected nerves. To this, we examined repairing effects of Taurine-loading PCL conduits cultured with human endothelial stem cells (hEnSCs) on resected sciatic nerves. PCL/Taurine/Cell conduits transplanted to a 10-mm sciatic nerve gap. Forty-two wistar rats were randomly divided to seven groups: (1) Normal group, (2) Negative control (NC), (3) Positive control (nerve Autograft group), (4) PCL conduits group (PCL), (5) Taurine loaded PCL conduits group (PCL/Taurine), (6) hEnSCs cultured on the PCL conduits (PCL/Cell), (7) hEnSCs cultured on the PCL/Taurine conduits (PCL/Taurine/Cell). Functional recovery of motor and sensory nerves, the action potential of exciting muscle and motor distal latency has seen in PCL/Taurine/Cell conduits. Histological studies showed also remarkable nerve regeneration and obvious bridging has seen in this group. In conclusion, PCL/Taurine/Cell conduits showing suitable mechanical properties and biocompatibility may improve sciatic nerve regeneration.
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  • 文章类型: Journal Article
    未经证实:我们先前报道了阿尔茨海默病(AD)患者的血清25-羟基维生素D浓度较低,与健康对照(HC)相比,帕金森病(PD)和多系统萎缩(MSA),而1,25-二羟基维生素D水平仅在MSA患者中较低。我们研究了参与维生素D(VD)羟化的P450血清浓度,以阐明VD代谢物低血清浓度的负责羟化酶。
    UNASISIGNED:共有79个人参加了研究,其中包括20例HC,公元20年,19例PD和20例MSA患者。通过ELISA测定参与VD羟基化的P450的血清浓度。数据通过组间的非参数Kruskal-Wallis检验进行分析。
    未经批准:尽管CYP2R1和CYP27A1介导VD的25-羟基化,CYP2R1是主要的羟化酶,和CYP27A1也参与VD合成。CYP2R1浓度在各组之间没有差异,与HC相比,PD(p<0.05)和MSA(p<0.005)中的CYP27A1浓度较低,而AD和MSA之间的差异(p<0.05),然而PD和MSA之间没有差异。CYP27B1是25-羟基维生素D的主要1α-羟化酶,在HC和PD之间显示出差异(p<0.05),HC和MSA之间(p<0.005)以及PD和MSA之间(p=0.055)。CYP24A1,使1,25-二羟基维生素D失活,组间无差异。
    未经证实:CYP27A1可能会影响VD合成并导致AD患者25-羟基维生素D水平低,PD和MSA患者。MSA患者的1,25-二羟基维生素D水平低可能是由CYP27B1介导的反馈受损引起的。
    UNASSIGNED: We previously reported lower serum 25-hydroxyvitamin D concentrations in patients with Alzheimer\'s disease (AD), Parkinson\'s disease (PD) and Multiple system atrophy (MSA) compared to healthy controls (HC), whereas 1,25-di-hydroxyvitamin D levels were solely lower in MSA patients. We investigate serum concentrations of P450 involved in Vitamin D(VD) hydroxylation to clarify the responsible hydroxylase for the low serum concentrations of VD metabolites.
    UNASSIGNED: A total of 79 individuals were enrolled including 20 HC, 20 AD, 19 PD and 20 MSA patients. The serum concentrations of P450 involved in VD hydroxylation were assayed by ELISA. The data were analyzed by the nonparametric Kruskal-Wallis test between groups.
    UNASSIGNED: Though CYP2R1 and CYP27A1 mediate 25-hydroxylation for VD, CYP2R1 is the main hydroxylase, and CYP27A1 is also involved in VD synthesis. CYP2R1 concentrations showed no differences among groups, while lower CYP27A1 concentrations were found in PD (p < 0.05) and MSA (p < 0.005) compared to HC and differences between AD and MSA (p < 0.05), however no differences between PD and MSA. CYP27B1 is the main 1α-hydroxylase for 25-hydroxyvitamin D and showed differences between HC and PD (p < 0.05), between HC and MSA (p < 0.005) and between PD and MSA (p = 0.055). CYP24A1, which inactivate 1,25-di-hydroxyvitamin D, showed no differences among groups.
    UNASSIGNED: CYP27A1 might affect VD synthesis and cause low 25-hydroxyvitamin D levels in AD, PD and MSA patients. Low 1,25-di-hydroxyvitamin D levels in MSA patients might be caused by impaired feedback mediated by CYP27B1.
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  • 文章类型: Journal Article
    帕金森病(PD)已被指定为世界范围内的优先神经退行性疾病之一。尽管已经确定了诊断生物标志物,早期发现和靶向治疗仍然有限.采用集成系统和结构生物学方法来确定PD的治疗靶标。从一组49个PD相关基因中,构建了一个紧密相连的相互作用体。基于中心性指数,互动程度和功能丰富,LRRK2、PARK2、PARK7、PINK1和SNCA被鉴定为hub基因。PARK2(Parkin)由于其与α-突触核蛋白(SNCA)的强烈关联(评分>0.99)而被最终确定为有效的治疗诊断候选标记,直接调节PD进展。此外,Parkin结构的建模和验证,广泛的虚拟筛选显示了针对Parkin的小型(市售)抑制剂。分子-258(ZINC5022267)被选择为基于药代动力学特征的有效候选物,密度泛函理论(DFT)能量计算(ΔE=6.93eV)和对Parkin的高结合亲和力(结合能=-6.57±0.1kcal/mol;抑制常数=15.35µM)。蛋白质-抑制剂复合物的分子动力学模拟进一步加强了具有稳定轨迹(低结构波动)的治疗主张,氢键模式和相互作用能(>0kJ/mol)。我们的研究鼓励对新型候选药物进行实验验证,以防止PD中Parkin介导的泛素化的自动抑制。
    Parkinson\'s disease (PD) has been designated as one of the priority neurodegenerative disorders worldwide. Although diagnostic biomarkers have been identified, early onset detection and targeted therapy are still limited. An integrated systems and structural biology approach were adopted to identify therapeutic targets for PD. From a set of 49 PD associated genes, a densely connected interactome was constructed. Based on centrality indices, degree of interaction and functional enrichments, LRRK2, PARK2, PARK7, PINK1 and SNCA were identified as the hub-genes. PARK2 (Parkin) was finalized as a potent theranostic candidate marker due to its strong association (score > 0.99) with α-synuclein (SNCA), which directly regulates PD progression. Besides, modeling and validation of Parkin structure, an extensive virtual-screening revealed small (commercially available) inhibitors against Parkin. Molecule-258 (ZINC5022267) was selected as a potent candidate based on pharmacokinetic profiles, Density Functional Theory (DFT) energy calculations (ΔE = 6.93 eV) and high binding affinity (Binding energy = -6.57 ± 0.1 kcal/mol; Inhibition constant = 15.35 µM) against Parkin. Molecular dynamics simulation of protein-inhibitor complexes further strengthened the therapeutic propositions with stable trajectories (low structural fluctuations), hydrogen bonding patterns and interactive energies (>0kJ/mol). Our study encourages experimental validations of the novel drug candidate to prevent the auto-inhibition of Parkin mediated ubiquitination in PD.
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  • 文章类型: Journal Article
    步态冻结(FOG)是帕金森氏病(PD)的一种高度致残症状,口服多巴胺能药物和几种具有不同药物状态的亚型具有不同程度的益处(例如,离开雾,在雾上,伪上雾,上一篇:FOG)。左旋多巴-卡比多巴肠凝胶(LCIG)通过连续的左旋多巴肠输注,极大地降低了口服疗法固有的脑多巴胺替代的变异性。虽然LCIG在治疗运动波动和最小化休息时间方面可能优于口服治疗,对于LCIG治疗PD患者FOG的总体有效性尚无共识.
    进行了系统的文献综述,以了解LCIG治疗PD患者FOG的疗效。使用搜索查询“肠和(左旋多巴或左旋多巴)和冻结步态和帕金森病”进行PubMed搜索。“其他资格标准包括用英文撰写的文章和当前发表的期刊文章。如果文章没有临床设计或未提供有关FOG的可报告数据,则将其排除。
    文献检索产生了16篇文章,其中包括10篇文章。在包括的10项研究中,有3项回顾性研究,6例病例报告或病例系列,和1个开放标签研究。(n=449例患者和318例FOG患者)。10项研究中有9项得出结论,LCIG对FOG有良好的影响,尽管评估LCIG对FOG的益处的指标在不同的文章中有所不同。
    LCIG可能是患有FOG的PD患者的有效治疗方法,包括对口服药物反应不佳的患者,可能是因为它有能力维持稳定的多巴胺水平。需要进一步研究LCIG作为难治性FOG的治疗方法,特别注意FOG的不同亚型。
    UNASSIGNED: Freezing of gait (FOG) is a highly disabling symptom in Parkinson\'s Disease (PD) with varying degree of benefits from oral dopaminergic medications and several subtypes that present with different medication states (e.g., off FOG, on FOG, pseudo-on FOG, supra-on FOG). Levodopa-Carbidopa Intestinal Gel (LCIG) greately reduces the variability of cerebral dopamine replacement inherent to oral therapies by continuous levodopa intestinal infusion. While LCIG may be superior to oral therapy in its ability to treat motor fluctuations and minimize off-time, there is no consensus regarding the overall effectiveness of LCIG specifically for the treatment of FOG in PD patients.
    UNASSIGNED: A systematic literature review was conducted to understand the efficacy of LCIG to treat FOG in PD patients. A PubMed search was conducted using the search query \"Intestinal AND (Levodopa OR L-dopa) AND Freezing of Gait AND Parkinson.\" Additional eligibility criteria included articles written in English and currently published journal articles. Articles were excluded if they did not have a clinical design or if they did not yield reportable data on FOG.
    UNASSIGNED: The literature search yielded 16 articles, of which 10 articles were included. Of the 10 studies included, there were 3 retrospective studies, 6 case reports or case series, and 1 open-label study. (n = 449 patients total and 318 FOG patients). Nine of the 10 studies concluded that LCIG has a favorable effect on FOG, though the metrics to evaluate benefits of LCIG on FOG varied among the articles.
    UNASSIGNED: LCIG may be an effective treatment for PD patients suffering from FOG including those with poor response to oral medication, likely because of its ability to maintain steadier dopamine levels. Further research is necessary on LCIG as a therapy for refractory FOG, with particular attention to the different subtypes of FOG.
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