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Uncoupling neurotrophic function from nociception of nerve growth factor: what can be learned from a rare human disease?

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Neural Regeneration Research 2019年第4期14卷 570-573页

作者： Kijung Sung Wanlin Yang chengbiao wu Department of Neurosciences University of California San Diego

Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V(HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100^(th) position of mature NGF resulting in a change of residue from arginine to tryptophan(R100W). Although those HSAN V patients associated with the NGF^(R100W) mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGF^(R100W) mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGF^(R100W) provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGF^(R100W) no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGF^(R100W) mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic

关键词： hereditary sensory and autonomic neuropathy V nerve growth factor NGFR100W mutation pain tyrosine receptor kinase A p75 neurotrophic factor receptor

Current advances in using neurotrophic factors to treat neurodegenerative disorders

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Translational Neurodegeneration 2012年第1期1卷 103-111页

作者： April M Weissmiller chengbiao wu Department of Neurosciences University of California San DiegoSchool of MedicineLa JollaCA 92093-0649USA Department of Neurosciences University of California San DiegoGeorge Palade Labs(GPL)Room 337 MC-06499500 Gilman DriveLa JollaCA 92093USA

Neurotrophic factors are best known for their roles in both development and continued maintenance of the nervous *** strong potential to elicit pro-survival and pro-functional responses in neurons of the peripheral and central nervous system make them good drug candidates for treatment of a multitude of neurodegenerative ***,significant obstacles remain and need to be overcome before translating the potential of neurotrophins into the therapeutic *** article addresses current efforts and advances in resolving these challenges and provides an overview of roadmaps for future translational research and neurotrophin-based drug developments.

关键词： Neurotrophin Neurotrophic factor BDNF NGF Gene delivery Mimetics

Dysfunction of the Endocytic Pathway Precedes Neurodegeneration in Alzheimer’s Disease

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Dysfunction of the Endocytic Pathway Precedes Neurodegenerat...

Upregulation of RIN3 induces endosomal dysfunction in Alzheimer’s disease

中国神经科学学会第十二届全国学术会议

作者： chengbiao wu Department of Neurosciences University of California San Diego and VA San Diego Health System

Alzheimer’s disease（AD） is an extremely complexed disorder of the brain. Recent advances in human genome sequencing and meta-analysis have identified many previously unknown new AD risk factors: ABCA7, BIN1, CASS4, CD33, CD2 AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5 D, MS4 A, MEF2 C, NME8, PICALM, PTK2 B, SLC24 H4-RIN3, SORL1, ZCWPW1, PLD3 and TREM2. These new AD risk genes further underscore the complexity of AD pathogenesis and the importance of studying early cellular pathologies for uncovering meaningful therapeutic targets for treating AD more effectively. Of the newly discovered AD risk factors, many are involved in the endo-lysosomal pathway. It is thus not surprising that dysfunction of the endo-lysosomal pathway has emerged as an important indicator of early cellular pathology underlining AD neurodegeneration. We and others have demonstrated that function of Rab5, a small GTPase regulating endocytic trafficking, is susceptible to genotoxicities of many the AD risk factors. We have demonstrated that full length amyloid precursor protein（APP） and its β-carboxylterminal fragment（β-CTF）, acts though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of trophic signals. We further investigated the functional impacts of APP and its various products. We found that the full length wildtype APP（APPWT） and β-CTF all induced endosomal enlargement and disrupted NGF signaling and axonal trafficking, leading to neuronal atrophy. Importantly, β-CTF induced atrophy of BFCNs that was rescued by the dominant negative Rab5 mutant, Rab5 S34 N. Moreover, axonal blockage in larvae of an APP-transgenic Drosophila strain was markedly relieved by Rab5S34N in vivo. Our data strongly support the emerging hypothesis that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD.

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Translational Neurodegeneration 2020年第2期9卷 290-308页

作者： Ruinan Shen Xiaobei Zhao Lu He Yongbo Ding Wei Xu Suzhen Lin Savannah Fang Wanlin Yang Kijung Sung Brian Spencer Robert A.Rissman Ming Lei Jianqing Ding chengbiao wu Institute of Neurology Ruijing HospitalShanghai JiaoTong University School of Medicine197 Ruijin Er Rd.Shanghai200025China Department of Neurosciences University of California San Diego School of MedicineRoom 312 MC-06249500 Gilman DriveLa JollaCA92093-0624USA Shanghai Institute of Precision Medicine Shanghai200125China Department of Neurology Zhuijiang HospitalSouthern Medical UniversityGuangzhouChina San Diego VA Health System San DiegoCAUSA

Background In Alzheimer’s Disease(AD),about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic *** them,the Ras and Rab Interactor 3(RIN3)is a guanine nucleotide exchange factor(GEF)for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD(LOAD)and sporadic early onset AD(sEOAD).However,how RIN3 is linked to AD pathogenesis is currently *** Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron(BFCNs).Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 *** flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass ***3-interacting partners were validated by co-immunoprecipitation,immunofluorescence and yeast two hybrid *** imaging of primary neurons was used to examine axonal transport of amyloid precursor protein(APP)andβ-secretase 1(BACE1).Immunoblotting was used to detect protein expression,processing of APP and phosphorylated forms of *** We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse *** forebrain cholinergic neurons(BFCNs)cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome *** addition,via its proline rich domain,RIN3 recruited BIN1(bridging integrator 1)and CD2AP(CD2 associated protein),two other AD risk factors,to early ***,overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments(CTFs)in PC12 *** of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau ***,upregulation of RIN3 expression promoted accumulation of APP CTFs and increased

关键词： Alzheimer's disease(AD) AD risk factors Endosomes Trafficking RIN3 BIN1 CD2AP Tau

Ag^+、Ni^(2+)改性复合钛铌酸钾盐对二甲基硫和乙硫醇吸附与光催化氧化研究

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石油与天然气化工 2009年第5期38卷 375-377,382页

作者：何杰刘娟邬成彪安徽理工大学化学工程学院

由高温固相法制备复合钛铌酸钾盐,通过Ag+和Ni2+离子交换对其进行改性。采用红外光谱方法考察Ag+与Ni2+离子改性的复合钛铌酸盐对二甲基硫(DMS)和乙硫醇(EM)的吸附特征与光催化氧化作用。结果表明,复合钛铌酸盐对DMS与EM的吸附与光催化... 详细信息

由高温固相法制备复合钛铌酸钾盐,通过Ag+和Ni2+离子交换对其进行改性。采用红外光谱方法考察Ag+与Ni2+离子改性的复合钛铌酸盐对二甲基硫(DMS)和乙硫醇(EM)的吸附特征与光催化氧化作用。结果表明,复合钛铌酸盐对DMS与EM的吸附与光催化氧化行为取决于分子中S原子的环境与复合钛铌酸盐中阳离子的性质。DMS同Ag+与Ni2+离子改性的钛铌酸钾盐表面相互作用较弱,在自然光辐射下稳定,而EM同Ag+离子改性的钛铌酸盐具有明显的相互作用,即使在自然光辐射下也可被氧化。在紫外光辐射下,DMS和EM在两种离子改性的钛铌酸钾盐上均被催化氧化,DMS被氧化至亚砜、砜和硫酸酯,而EM被氧化至磺酸。

关键词：复合钛铌酸钾盐离子交换二甲基硫乙硫醇吸附光催化

Cold air plasma:A potential strategy for inducing apoptosis of rheumatoid arthritis fibroblast‐like synoviocytes

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High Voltage 2022年第1期7卷 106-116页

作者： chengbiao Ding Chao Chen Wenchong Ouyang Qi Liu Lin Lin Zhengwei wu School of Nuclear Science and Technology University of Science and Technology of ChinaHefeiChina Department of Rehabilitation Medicine The Second Hospital of Anhui Medical UniversityHefeiAnhuiChina Department of Medical Oncology Division of Life Sciences and MedicineThe First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiAnhuiChina CAS Key Laboratory of Geospace Environment University of Science and Technology of ChinaHefeiChina

Rheumatoid arthritis(RA)is an autoimmune disease of the joints characterised by synovial hyperplasia and chronic *** arthritis fibroblast‐like synoviocytes(RA‐FLS)cells are the dominant cell type in the hyperplastic synovial membrane,which play a key role in the pathogenesis of *** can invade cartilage,cause inflammation,destroy joints,and show tumour‐like anti‐apoptosis ***,the purpose of this study is to investigate the effect of cold air plasma(CAP)on RA‐FLS *** results showed that CAP treatment for 120 s could significantly reduce the viability of RA‐FLS cells,increase the content of intracellular reactive ox-ygen species(ROS),and significantly down‐regulate the ratio of apoptosis‐related protein Bcl‐2 to *** this study,a novel approach of inducing apoptosis in RA‐FLS cells using CAP was proposed,which may provide a new choice for joint tar-geting therapy of RA.

关键词： cytes inflammation apoptosis

Sensitivity of two drug-resistant bacteria to low-temperature air plasma in catheterassociated urinary tract infections under different environments

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Plasma Science and Technology 2020年第6期22卷 137-143页

作者： Yuanyuan HE chengbiao DING Tao JIN Yueyao FAN Zhengwei wu Mengwen SUN Kun WANG Tuo JI Department of Geriatrics The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001People's Republic of China Department of Rehabilitation Medicine The Second Hospital of Anhui Medical UniversityHefei 230001People's Republic of China Department of Engineering and Applied Physics University of Science and Technology of ChinaHefei 230026People's Republic of China School of Food and Biological Engineering Hefei University of TechnologyHefei 230009People's Republic of China Polar Research Institute of China Shanghai 200136People’s Republic of China Science Island Branch University of Science and Technology of ChinaHefei 230026People's Republic of China

The high incidence of catheter-associated urinary tract infections,which are dominated by drugresistant bacteria,has attracted an increasing number of researchers interested in solving this public health *** purpose of this study was to explore the killing effect of lowtemperature air plasma(LTAP)on extended-spectrum beta-lactamase-producing Escherichia coli and high level gentamycin resistance enterococci under two simulated environments in *** results showed that the survival rate of these two kinds of bacteria decreased to less than20%after being treated by LTAP in different environments for 5 min.A comparison of the LTAP treatments showed that the killing efficacy of the two kinds of bacteria in the early stage(0-1 min)was up to 50%.Moreover,the results of transmission electron microscopy,reactive nitrogen species measurement,and a temperature test indicated that the bactericidal effect of the LTAP treatment on the two kinds of bacteria worked through the destruction of the ribosome and other organelles inside the bacteria,rather than the thermal effect,to achieve sterilization.

关键词： CAUTI low-temperature air plasma antibacterial transmission electron microscopy

Lipid rafts mediates ATP-induced endocytosis,signal transduction and retrograde transport of P2X3 receptor

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Lipid rafts mediates ATP-induced endocytosis,signal transduc...

Appoptosin介导的caspase对tau蛋白的剪切在进行性核上性麻痹致病过程中的作用机制

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xu-Qiao CHEN~(1,#),Bin WANG~(1,#),chengbiao wu~2,Jin PAN~1,Bo YUAN~3,Yuan-Yuan SU~1,Xing-Yu JIANG~3,Xu ZHANG~4 Lan BAO~(1,*) 1 Laboratory of Molecular Cell Biology,Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China 2 Department of Neurosciences,School of Medicine,University of California,San Diego,La Jolla,California,USA 3National Center of Nanoscience and Technology,Beijing 100190,China 4 Institute of Neuroscience and State Key Laboratory of Neuroscience,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai 200031,China

P2X receptors are a family of cation channels expressed in neurons and nonneuronal *** play a variety of roles including synaptic transmission,muscle contraction,neuronal secretion and inflammation response. Among P2X receptors,the P2X subtype is selectively expressed in dorsal root ganglion *** raft is a specialized membrane microdomain and participate many signal transduction *** report showed that P2X receptor is localized in the lipid rafts of DRG *** have found P2X receptor engaged in retrograde transport in the form of signaling *** we investigated the role of lipid rafts in a,B-MeATP-dependent endocytosis and signal transduction,and retrograde transport of P2X *** of lipid raft with MBCD or nystatin abolished ATP-dependent endocytosis of P2X receptor and ATP-induced ERK activation in P2X receptor-expressing HEK293 *** vivo sucrose gradient fractionation with vesicular pellets prepared from sciatic nerve axoplasm showed that abundant P2X receptor was localized in lipid raft *** transported P2X receptors were colocalized with the lipid raft marker caveolinla in sciatic *** terminal treatment with MPCD attenuated retrograde transport of P2X receptor in axon of dorsal root ganglion ***,lipid raft mediates ATP-induced endocytosis,signal transduction and retrograde transport of P2X receptor.

关键词： P2X3 receptor lipid raft endocytosis ERK retrograde transport

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科学新闻 2016年第1期 75-75页

作者： Yingjun Zhao I-Chu Tseng Charles J.Heyser Edward Rockenstein Michael Mante Anthony Adame Qiuyang Zheng Timothy Huang Xin Wang Pharhad E.Arslan Paramita Chakrabarty chengbiao wu Guojun Bu William C.Mobley Yun-wu Zhang Peter St.George-Hyslop Eliezer Masliah Paul Fraser 许华曦厦门大学神经科学研究所

文章简介进行性核上性麻痹(Progressive Supranuclear Palsy,PSP)是一种以Tau蛋白异常聚集和缠结为特征的运动障碍疾病。迄今为止人们对该疾病的致病机制知之甚少。之前的研究发现单核苷酸突变(SNP)(rs1768208 C/T)是PSP发病的高风险因... 详细信息

文章简介进行性核上性麻痹(Progressive Supranuclear Palsy,PSP)是一种以Tau蛋白异常聚集和缠结为特征的运动障碍疾病。迄今为止人们对该疾病的致病机制知之甚少。之前的研究发现单核苷酸突变(SNP)(rs1768208 C/T)是PSP发病的高风险因子。本研究通过对正常人和PSP患者的大脑样品进行检测,发现rs1768208 C/T中高的T等位基因频率与促凋亡蛋白appoptosin水平增高相关联,而appoptosin水平的增高与caspase-3的激活及caspase对tau蛋白的剪切相关。

关键词：蛋白 tau 介导 caspase Appoptosin