Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

厦门大学医学院、神经科学研究所张杰教授团队发现了抑郁症新的致病基因MEN1，并阐明了MEN1调控星形胶质细胞炎症导致抑郁发生发展的新机制，为抑郁症的诊治提供了新靶点和方向。抑郁症是严重威胁人类健康的重大神经系统疾病，危及全球30%的人口。但对其发病机制并不清楚。张杰教授团队发现，在慢性不可预测以及LPS处理的模拟抑郁小鼠模型中，多发性内分泌肿瘤蛋白(menin)在大脑中的表达显著降低，并且在星形胶质细胞中降低最明显。为了研究menin是否参与了小鼠抑郁表型的产生，研究团队制作了多种神经系统menin条件性敲除小鼠。通过对这些小鼠行为学的检测，锁定了只有在星形胶质细胞中敲除menin后，小鼠才会表现出抑郁样表型。证实了menin可能是通过调控星形胶质细胞的功能促进了抑郁的发生。 MEN1基因的突变会导致多发性内分泌肿瘤，而内分泌的紊乱和抑郁等精神疾病有着密切的联系。下丘脑-垂体-肾上腺轴（HPA轴）的功能紊乱直接参与了抑郁的产生。基于此研究团队推测MEN1的基因突变是否也会导致抑郁的发生。通过和中国医学科学院基础所的许琪教授合作，研究团队对1000多例重度抑郁患者和800多例对照人群进行了MEN1基因的外显子测序。通过测序发现MEN1的一个SNP s375804228和抑郁的发生有着显著关联。该SNP导致menin第503位的氨基酸由G突变成D。通过功能研究进一步证实该突变可以阻断menin和p65的结合，从而过度激活NF-κB-IL-1β通路，导致神经炎症的发生。 张杰，厦门大学特聘教授、博士生导师。国家优秀青年科学基金；教育部新世纪优秀人才；福建省杰出青年科学基金；厦门市五四青年奖章等获得者。2011年8月加入厦门大学医学院神经科学研究所担任教授至今。张杰博士主要从事重大神经系统疾病（老年痴呆、帕金森、抑郁症、自闭症、术后认知障碍、胶质瘤）等的发病机制和药物开发研究。至今以第一作者或者通讯作者在国际知名期刊发表研究论文21篇。其中回国独立开展研究工作以后，作为通讯作者在 Neuron，Cell Reports, PNAS, The Journal of Neuroscience, Clinical Cancer Research，Cell Death and Disease, JBC, Chemistry，Chem. Biol. Drug Des.等杂志上发表多篇研究论文。【Abstract】Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for providing the Men1-floxp mice. This work was supported by the National Natural Science Foundation of China (grants 81522016, 81271421, and 31571055 to J.Z.; 81625008 and 31430048 to Q.X.; 81630026 to Z.Y.; 81771163 and U1405222 to H.X.; U1505227 to G.B.; 81472725 to W.M.), the Natural Science Foundation of Fujian Province of China (grant 2013J01147 and 2014J06019 to J.Z.), the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.), the National Key Research and Development Program of China (2016YFC1305903), and CAMS Innovation Fund for Medical Sciences (grant 2016I2M1004 to Q.X.).研究工作得到国家自然科学基金项目（81522016、81271421、31571055）以及厦门大学校长基金等资助

CDK5-dependent BAG3 degradation modulates synaptic protein turnover

阿尔茨海默病（AD）是严重威胁人类健康的重大神经系统疾病，AD的发生发展与衰老密切相关，目前临床治疗方法十分有限。因此迫切需要从AD致病早期入手，发现和鉴定导致AD神经功能紊乱的机制和靶点，为AD的早期防治提供基础。张杰教授及其团队从高通量磷酸化蛋白质组学入手，系统研究了CDK5在神经细胞中的磷酸化底物，鉴定出了在蛋白质量控制中发挥重要功能的BAG3蛋白是CDK5的全新底物。课题组从磷酸化蛋白质组学入手，发现和阐明了细胞周期蛋白激酶5（CDK5）通过调控BAG3在维持突触蛋白水平调控中的作用机制，及其在阿尔茨海默病（AD）发生发展中的机理。 该研究是多个团队历时8年合作完成的，香港中文大学的周熙文教授、美国匹兹堡大学的Karl Herrup教授、美国Sanford-Burnham研究所的许华曦教授、美国梅奥医学中心的卜国军教授，厦门大学医学院的文磊教授、张云武教授、赵颖俊教授、薛茂强教授，军事医学科学院的袁增强教授等都参与了该工作。 厦门大学医学院2012级博士生周杰超等为文章的第一作者，张杰教授为通讯作者。Background Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer’s disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were re-examined in search for candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. Methods Quantitative phospho-proteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays were used to investigate the associated regulatory signaling networks. Histological, electrochemical and behavioral assays were performed in conditional knockout, shRNA-mediated knockdown and AD-related mice models to evaluate its relevance to synaptic homeostasis and functions. Results Among candidates with known implications in synaptic modulations, BCL2-associated athanogene-3 (BAG3) ranked the highest. CDK5-mediated phosphorylation on Ser297/Ser291 (Mouse/Human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related-mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such were reversed by ectopic BAG3 re-expression. Conclusions Our results highlight that neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.This work was supported by the National Science Foundation in China (Grant: 31571055, 81522016, 81271421 to J.Z.; 81801337 to L.L; 81774377 and 81373999 to L.W.); Fundamental Research Funds for the Central Universities of China-Xiamen University (Grant: 20720150062, 20720180049 and 20720160075 to J.Z.); Fundamental Research Funds for Fujian Province University Leading Talents (Grant JAT170003 to L.L); Hong Kong Research Grants Council (HKUST12/CRF/13G, GRF660813, GRF16101315, AoE/M-05/12 to K.H.; GRF16103317, GRF16100718 and GRF16100219 to H.-M,C.); Offices of Provost, VPRG and Dean of Science, HKUST (VPRGO12SC02 to K.H.); Chinese University of Hong Kong (CUHK) Improvement on Competitiveness in Hiring New Faculty Funding Scheme (Ref. 133), CUHK Faculty Startup Fund and Alzheimer’s Association Research Fellowship (AARF-17-531566) to H.-M, C. 该研究受到了国家自然科学基金、厦门大学校长基金、福建省卫生教育联合攻关基金等的资助

Affinity electromembrane with covalently coupled heparin for thrombin adsorption

A new composite membrane with electrical conductivity and reactive groups (-COOH) was synthesized by copolymerizing pyrrole-3-carboxylic acid and pyrrole onto nylon membrane via the template method. The ligand, heparin, was covalently coupled onto the composite membrane by activating with N-hydroxysuccinimide and 1-ethyl-3[-3-(dimethylamino)propyl]carbodiimide and modified with ethylenediamine. The as-synthesized affinity electromembrane exhibited a uniform conductivity value of 3.7 x 10(-7) S/cm and the content of heparin was approximately 1.897 mg/g membrane. By applying an electrical stimulation (-0.5 V) to the affinity electromembrane, the adsorption capacity and rate were greatly enhanced. Elution of protein showed desorption ratio was up to 92.7% using 2.0 M NaSCN solution as the desorption agent. To investigate the performance of dynamic adsorption of heparin-coupled affinity electromembrane, a membrane cartridge to which electrical stimulation can be applied was designed. The result of dynamic separation showed that the time of breakthrough was delayed from 22 min in the absence of electrical stimulation to 31 min in the presence of electrical stimulation. (C) 2012 Elsevier B.V. All rights reserved

Functionalized anodic aluminum oxide (AAO) membranes for affinity protein separation

National Nature Science Foundation of China [30500127]; Natural Science Foundation of Fujian Province [C0510005]An ideal affinity membrane should own well uniformities. However, most existing microporous membranes used as affinity matrices generally have wide pore size distribution and some thickness variation. In this paper, chitosan (CS)-anodic aluminum oxide (AAO) composite membrane with excellent uniformities, such as narrow pore size and porosity distribution, as well as uniform membrane thickness, was fabricated. for the first time. Cu(2+)-attached affinity membrane was obtained by immobilizing Cu(2+) on the CS-AAO membrane. The contents of CS and Cu(2+) of affinity membranes were similar to 49.7 and 27.15 mg/g membrane. respectively. The Cu(2+)-attached affinity membranes were used to recover a model protein, hemoglobin, from hemoglobin-phosphate solution (batch manner) and from the hemolysate (dynamic manner). The protein adsorption indicated that the adsorption capacity of hemoglobin was similar to 17.5 mg/g membrane, and the adsorption isotherm fitted the Freundlich model well. Elution of protein showed desorption ratio was up to 91.2% using 0.5 M imidazole aqueous solution as the desorption agent. The adsorption capacities of all the tested affinity membranes did not significantly change during the repeated adsorption-desorption operations. The result of dynamic experiment showed Cu(2+)-attached affinity membranes can well purify the hemoglobin from the red cell lysate. (C) 2008 Elsevier B.V. All rights reserved

Surface-modified anodic aluminum oxide membrane with hydroxyethyl celluloses as a matrix for bilirubin removal

National Nature Science Foundation of China [30500127, 31070845]; Natural Science Foundation of Fujian Province of China [2011J01331]; Fundamental Research Funds for the Central Universities [2011121001]Microporous anodic aluminum oxide (AAO) membranes were modified by 3-glycidoxypropyl-trimethoxysilane to produce terminal epoxy groups. These were used to covalently link hydroxyethyl celluloses (HEC) to amplify reactive groups of AAO membrane. The hydroxyl groups of HEC-AAO composite membrane were further modified with 1,4-butanediol diglycidyl ether to link arginine as an affinity ligand. The contents of HEC and arginine of arginine-immobilized HEC-AAO membrane were 52.1 and 19.7 mg/g membrane, respectively. As biomedical adsorbents, the arginine-immobilized HEC-AAO membranes were tested for bilirubin removal. The non-specific bilirubin adsorption on the unmodified HEC-AAO composite membranes was 0.8 mg/g membrane. Higher bilirubin adsorption values, up to 52.6 mg/g membrane, were obtained with the arginine-immobilized HEC-AAO membranes. Elution of bilirubin showed desorption ratio was up to 85% using 0.3 M NaSCN solution as the desorption agent. Comparisons equilibrium and dynamic capacities showed that dynamic capacities were lower than the equilibrium capacities. In addition, the adsorption mechanism of bilirubin and the effects of temperature, initial concentration of bilirubin, albumin concentration and ionic strength on adsorption were also investigated. (c) 2012 Elsevier B.V. All rights reserved

Nicotine activation of MAPK/ERK pathway in SH-SY5Y cells is mediated by α7 nAchR.

<p>We identified the effect of inhibition of α7 nAchRs expression by shRNA in Fig. 3. A, B) The effect of α7 shRNA by western blotting and real-time PCR. c) In the absence or presence of nicotine for 30 minutes, the EGR-1 and phosphorylated ERK1/2 levels were measured by western blot. d) When BTX, a specific α7 nAchR antagonist, was treated with nicotine, EGR-1 was detected.</p

Nicotine attenuated Aβ_25–35-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.

<p>a-c) Apoptosis analysis of SH-SY5Y cell line treated with 10^–6 M nicotine, 10^–6 M Aβ_25–35 or a combination of these drugs. Cells were exposed for 48 h. Double staining was used to distinguish between viable (lower left quadrant, annexinⅤ-negative,propidium iodide-negative), early apoptosis (lower right quadrant, annexinⅤ-positive, propidium iodide-negative), late apoptosis and necrotic (upper right quadrant, annexinⅤ-positive, propidium iodide-positive) and cell debris (upper left quadrant). Statistical analysis is shown in b. SH-SY5Y cells were exposed to 10^–6 M nicotine, 10^–6 M Aβ_25–35 or a combination of these drugs for 48 h or 72 h, cell viability is measured by MTT, *<i>P</i><0.05 verses control group.</p

Characteristics of Settings and Etiologic Agents of Foodborne Disease Outbreaks — China, 2020

INTRODUCTION: Foodborne diseases are a growing public health problem and have caused a large burden of disease in China. This study analyzed epidemiological characteristics of foodborne diseases in China in 2020 to provide a scientific basis for prevention and control measures. METHODS: Data were collected from 30 of 31 provincial-level administrative divisions (PLADs) in the mainland of China, excluding Xizang (Tibet) Autonomous Region, via the National Foodborne Disease Outbreaks Surveillance System. The number and proportion of outbreaks, illnesses, hospitalizations, deaths by setting, pathogen-food category pairs and etiology were calculated. RESULTS: In 2020, 7,073 foodborne disease outbreaks were reported, resulting in 37,454 illnesses and 143 deaths. Among the identified pathogens, microbial pathogens were the most common confirmed etiology, accounting for 41.7% of illnesses. Poisonous mushrooms caused the largest proportion of outbreaks (58.0%) and deaths (57.6%). For venues where foodborne disease outbreaks occur, household had the highest number of outbreaks (4,140) and deaths (128), and catering service locations caused the largest proportion of illnesses (59.9%). Outbreaks occurring between June and September accounted for 62.8% of total outbreaks. CONCLUSIONS: Foodborne disease outbreaks mainly occurred in households. Microbial pathogens remained the top cause of outbreak-associated illnesses. Poisonous mushrooms were ranked the top cause of deaths in private homes in China. The supervision and management of food safety and health education should be strengthened to reduce the burden of foodborne diseases. Publicity should be increased to reduce the incidence of mushroom poisonings in families, and supervision and management of food should be strengthened to reduce microbial contamination

Time course and concentration dependence of nicotine activation of EGR-1 in SH-SY5Y cells.

<p>a, b) Nicotine activates EGR-1 in the nanomolar to micromole range when SH-SY5Y cells were treated with nicotine for 30 min; the relative level of EGR1 was quantified and presented in panel b. β-actin serves as control. c-e) The SH-SY5Y cells were with 10^-6M nicotine by the indicated time, the relative level of EGR1 was quantified and presented in panel d and f respectively. β-actin serves as control. g) The mRNA level of EGR1 in SH-SY5Y cells after nicotine treatment was measured by RT-PCR. i) Immunofluorescence was shown when SH-SY5Y cells were treated by nicotine compared to control.</p