NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation

Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.

集束化护理预防血液净化患儿下肢深静脉血栓形成的效果研究

目的探讨集束化护理对预防血液净化患儿下肢深静脉血栓形成的效果。方法选择2017年长春市某三级甲等医院小儿重症监护病房收治的315例需要进行血液净化治疗的患儿作为实验组,实施集束化护理干预措施,护理措施包括评估筛查、血管保护、评估腿围、营养支持、体液管理、体温管理、肢体运动、体位管理等;选择2016年该小儿重症监护病房行血液净化治疗的患儿202例作为对照组,采用常规护理措施。比较两组下肢静脉血栓形成的发生情况。结果实验组40例(12.7%)发生下肢深静脉血栓,其中0～6岁36例(16.5%),7～14岁4例(4.12%);治疗时间≥24 h 22例(11.3%),治疗<24 h 18例(15%)。对照组49例(24.3%)发生下肢深静脉血栓,其中0～6岁39例(30.7%),7～14岁10例(13.3%);治疗时间≥24 h 25例(22.5%),治疗<24 h 24例(26.4%)。两组血栓发生情况比较,差异均有统计学意义(P<0.05)。结论集束化护理干预可有效降低血液净化治疗患儿下肢深静脉血栓形成的发生率,尤其对年龄>7岁,上机时长≥24 h的患儿效果更佳。

Deregulation of brain insulin signaling in Alzheimer's disease

Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer＇s disease （AD）. In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid 13 precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.

The recommendations of Chinese Parkinson’s disease and movement disorder society consensus on therapeutic management of Parkinson’s disease

Background:Parkinson’s disease(PD)is a chronic,progressive and debilitating disease,which affects over 2.5 million people in China.PD is characterized clinically by resting tremor,muscular rigidity,bradykinesia and postural instability.As the disease progresses,additional complications can arise such as non-motor and neurobehavioral symptoms.Pharmacological treatment and surgical intervention for PD have been implemented in China.Until 10 years ago,there was lack of standardization for the management of PD in different regions and among different physicians,leading to different treatment levels in different regions and different physicians.Since then,the Chinese Parkinson’s Disease and Movement Disorder Society have published three versions of guidelines for the management of PD in China,in 2006,2009 and 2014,respectively.Correspondingly,the overall level of treatment for PD in China improved.Objectives:To update the treatment guidelines based on current foreign and domestic practice guidelines and clinical evidence,and to improve the treatment options available to physicians in the management of PD.Summary:A variety of treatment recommendations in the treatment guidelines have been proposed,including physical activity and disease-modifying medication,which should be initiated at the early-stage of the disease.The principles of dosage titration should be followed to avoid acute adverse reactions to the drugs,to achieve a satisfactory clinical effect with a low dose and to reduce the incidence of long-term motor complications.Moreover,different treatment strategies should be considered at different stages of the disease.Importantly,treatment guidelines and personalized treatments should be valued equally.A set of treatment recommendations has been developed to assist physicians to improve and optimize clinical outcomes for patients with PD in China.

Efficacy and safety of rasagiline in Chinese patients with early Parkinson’s disease:a randomized, double-blind,parallel,placebo-controlled,fixed-dose study

Background:Rasagiline is a monoamine oxidase-B inhibitor used for Parkinson’s disease(PD)treatment,but its effectiveness on Chinese patients is unclear.This study aimed to evaluate the efficacy and safety of rasagiline monotherapy in Chinese patients with early PD.Methods:A 26-weeks,randomized,double-blind,placebo-controlled study has been performed at 15 sites in China and enrolled outpatients(≥35 years old)with idiopathic PD without a history of using any dopaminergic drugs.Participants were randomized 1:1 to receive rasagiline 1 mg once daily or placebo.The primary endpoint was the change of the Unified Parkinson’s Disease Rating Scale(UPDRS)total score from baseline to 26 weeks treatment.Secondary endpoints included changes in UPDRS subscale scores from part Ⅰ to Ⅲ.Health status was assessed with the PD Questionnaire(PDQ)-39 and EuroQol-Five-Dimension(EQ-5D)questionnaire.Safety profile was collected until 30 weeks after randomization.Results:A total of 130 patients(n=65/group)were recruited,and 127(rasagiline,n=64;placebo,n=63)were included in the full analysis set.Baseline characteristics were comparable between the two groups.The decrease in the mean UPDRS total score was greater in the rasagiline group than in the placebo group(−3.18±0.95 vs.−0.18±0.98,P=0.025),and the mean UPDRS part I non-motor symptoms score(−0.54±0.15 vs.-0.08±0.15,P=0.003)were significantly decreased in the rasagiline group compared with placebo treated patients.An improvement trend was observed in the active treatment group for the subscales evaluation with parts Ⅱ and Ⅲ,while the difference to placebo was not statistically significant.Life quality assessed by the EQ-5D visual analog scale improved in the rasagiline group but worsened in placebo treated patients.The overall incidence of treatment-emergent adverse events(AEs)was slightly lower in the rasagiline group(41.5%)than in the placebo group(46.2%).Conclusions:Rasagiline is effective,safe,and well tolerated as monotherapy for the treatment of Chinese PD patients.

Exosomes in Parkinson's Disease

Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system（CNS）. The proposed functions of these vesicles include roles in cell–cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids,and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson＇s disease（PD）. Exosomes have been shown to spread toxic a-synuclein（asyn） between cells and induce apoptosis, which suggests a key mechanism underlying the spread of asyn aggregates in the brain and the acceleration of pathology in PD. However, potential neuroprotective roles of exosomes in PD have also been reported. On the treatment side, as drug delivery vehicles, exosomes have been used to deliver small interfering RNAs and catalase to the brain, and have shown clear therapeutic effects in a mouse model of PD. These features of exosomes in PD make them extremely interesting from the point of view of developing novel diagnostic and therapeutic approaches.

cFos-ANAB:A cFos-based Web Tool for Exploring Activated Neurons and Associated Behaviors

cFos is one of the most widely-studied genes in the field of neuroscience.Currently,there is no systematic database focusing on cFos in neuroscience.We developed a curated database-cFos-ANAB-a cFos-based web tool for exploring activated neurons and associated behaviors in rats and mice,comprising 398 brain nuclei and sub-nuclei,and five associated behaviors:pain,fear,feeding,aggression,and sexual behavior.Direct relationships among behaviors and nuclei(even cell types)under specific stimulating conditions were constructed based on cFos expression profiles extracted from original publications.Moreover,overlapping nuclei and sub-nuclei with potentially complex functions among different associated behaviors were emphasized,leading to results serving as important clues to the development of valid hypotheses for exploring as yet unknown circuits.Using the analysis function of cFos-ANAB,multi-layered pictures of networks and their relationships can quickly be explored depending on users’purposes.These features provide a useful tool and good reference for early exploration in neuroscience.The cFos-ANAB database is available at www.cfos-db.net.

Oscillation-specific nodal alterations in early to middle stages Parkinson’s disease

Background:Different oscillations of brain networks could carry different dimensions of brain integration.We aimed to investigate oscillation-specific nodal alterations in patients with Parkinson’s disease(PD)across early stage to middle stage by using graph theory-based analysis.Methods:Eighty-eight PD patients including 39 PD patients in the early stage(EPD)and 49 patients in the middle stage(MPD)and 36 controls were recruited in the present study.Graph theory-based network analyses from three oscillation frequencies(slow-5:0.01–0.027 Hz;slow-4:0.027–0.073 Hz;slow-3:0.073–0.198 Hz)were analyzed.Nodal metrics(e.g.nodal degree centrality,betweenness centrality and nodal efficiency)were calculated.Results:Our results showed that(1)a divergent effect of oscillation frequencies on nodal metrics,especially on nodal degree centrality and nodal efficiency,that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed,which visually showed that network was perturbed in PD;(2)PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities,which was consistently detected within all three oscillation frequencies;(3)the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients;(4)logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level;(5)occipital disruption within high frequency(slow-3)made a significant influence on motor impairment which was dominated by akinesia and rigidity.Conclusions:Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages.

Application of the concept of continuous dopaminergic stimulation for the management of Parkinson's disease

Continuous dopaminergic stimulation（CDS）is a prominent therapeutic concept for the treatment of Parkinson＇s disease（PD）,which proposes that continuous brain dopamine-receptor stimulation,rather than intermittent doses of oral L-dopa,prevents or manages L-dopa-induced dyskinesias（LIDs）.In the normal situation,dopaminergic neurons in the substantia nigra pars compacta fire tonically to keep the dopamine receptor stimulation at a steady-state level.But when the dopaminergic pathway is impaired,the dopamine receptor stimulation becomes intermittent or pulsatile.This pulsatile stimulation causes a series of gene and protein changes in striatal neurons,leading to alterations in the firing patterns of basal ganglia neurons that result in LIDs.Studies in animal models and clinical trials of PD have shown that approaches providing CDS,currently including patches,extended-release formulations of L-dopa or dopamine agonists,continuous delivery of apomorphine and duodenal L-dopa infusion,are associated with a decreased risk of LIDs.In this review,we summarize both preclinical and clinical evidence for the five methods that may provide CDS in theory and compare the advantages and disadvantages of these methods.

Induced neural stem/precursor cells for fundamental studies and potential application in neurodegenerative diseases

Recent research has shown that defined sets of exogenous factors are sufficient to convert rodent and human somatic cells directly into induced neural stem cells or neural precursor cells（iNSCs/iNPCs）.The process of transdifferentiation bypasses the step of a pluripotent state and reduces the risk of tumorigenesis and genetic instability while retaining the self-renewing capacity.This iNSC/iNPC technology has fueled much excitement in regenerative medicine,as these cells can be differentiated into target cells for replacement therapy for neurodegenerative diseases.Patients＇ somatic cell-derived iNSCs/iNPCs have also been proposed to serve as disease models with potential value in both fundamental studies and clinical applications.This review focuses on the mechanisms,techniques,and applications of iNSCs/iNPCs from a series of related studies,as well as further efforts in designing novel strategies using iNSC/iNPC technology and its potential applications in neurodegenerative diseases.

Adjunct rasagiline to treat Parkinson’s disease with motor fluctuations:a randomized,double-blind study in China

Background:The use of adjunct rasagiline in levodopa-treated patients with Parkinson’s disease and motor fluctuations is supported by findings from large-scale clinical studies.This study is to investigate the efficacy and safety of adjunct rasagiline in Chinese patients with Parkinson’s disease,as a product registration study.Methods:This 16-week,randomized,double-blind,parallel-group,multicenter,placebo-controlled study of rasagiline 1 mg/day included levodopa-treated patients with Parkinson’s disease and motor fluctuations.The primary efficacy endpoint was mean change from baseline in total daily OFF time over 16 weeks.Secondary endpoints were Clinical Global Impressions–Improvement(CGI-I),and change in Unified Parkinson’s Disease Rating Scale(UPDRS)Activities of daily living(ADL)and Motor scores.Patient well-being(EQ-5D),and the frequency of adverse events were also assessed.Results:In total,324 levodopa-treated patients were randomized to rasagiline 1 mg/day(n=165)or placebo(n=159).Over 16 weeks,rasagiline statistically significantly reduced the mean[95% confidence interval]total daily OFF time versus placebo(−0.5 h[−0.92,−0.07];p=0.023).There were also statistically significant improvements versus placebo in CGI-I(−0.4 points[−0.61,−0.22];p<0.001),UPDRS-ADL OFF(−1.0 points[−1.75,−0.27];p=0.008),and UPDRS-Motor ON(−1.6 points[−3.05,−0.14];p=0.032)scores,as well as the EQ-5D utility index(p<0.05).Rasagiline was safe and well tolerated.Conclusions:In levodopa-treated Chinese patients with Parkinson’s disease and motor fluctuations,adjunct rasagiline 1 mg/day statistically significantly reduced OFF time,and improved daily function and overall well-being,versus placebo.Consistent with findings in other countries,adjunct rasagiline was proven efficacious and well tolerated in Chinese patients.