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Tetramethylpyrazine nitrone improved mitochondrial dysfunction, downregulated α-synuclein, and reduced neurodegeneration in Parkinson disease models

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中国药理学与毒理学杂志 2019年第10期 843-844页

作者： GUO Bao-jian ZHENG Cheng-you QIU Xiao-ling zhang zai-jun Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardiocerebrovascular Diseases Jinan University College of Pharmacy

OBJECTIVE The peroxisome proliferatoractivated receptor γ co-activator 1α(PGC-1α) and nuclear factor(erythroid-derived 2)-like 2(Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of any of these processes has been implicated in the pathogenesis of Parkinson disease(PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein(α-syn) clearance, and attenuate degeneration of nigral dopaminergic neurons in PD. To test this, we used tetramethylpyrazine nitrone(TBN), a potent free radical scavenger, to activate PGC-1α/Nrf2 pathway. METHODS 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP)-induced mouse model, unilateral intrastriatal injection of 6-hydroxydopamine(6-OHDA)-induced rat model, and transgenic mice overexpression of human A53 T mutant α-synuclein were used to evaluate TBN's therapeutic efficacy and to explore its mechanisms of action. RESULTS TBN protected against 1-methyl-4-phenylpyridinium(MPP+) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in the cell models overexpressed human A53 T mutant α-syn. In MPTP-treated mouse and unilateral 6-OHDA-lesioned rat, as well as in α-syn transgenic mouse model, TBN improved motor impairment, increased survive of nigra dopaminergic neurons, and elevated striatal dopamine level, while decreased the products of oxidative ***, TBN down-regulated α-syn level in the brain and serum of α-syn transgenic mice. These improvements in vitro and in vivo were associated with activation of PGC-1α/Nrf2 signal pathway, resulting in reduced oxidative stress, enhanced mitochondrial function, and increased protein clearance. CONCLUSION Our work demonstrates that activation of PGC-1α/Nrf2 by TBN can maintain the survival of nigral dopaminergic neurons, and might be disease-modifying in PD models, providing the critical rationale for further devel

关键词： tetramethylpyrazine nitrone Parkinson disease peroxisome proliferator-activated receptor γ co-activator 1α nuclear factor(erythroid-derived 2)-like 2 α-synuclein

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Comparison of Tissue Transglutaminase Activity During Young Panicle Development in Honglian-type Cytoplasmic Male Sterile Rice

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Rice science 2006年第3期13卷 193-198页

作者： CHANG Xun zhang zai-jun LI Yang-sheng ZHU Ying-guo Key Laboratory of the Education Ministty of China for Developmental Biology College of Life Sciences Wuhan University Wuhan 430072 China Agricultural College Yangtze University Jingzhou 434025 China

To investigate the changes of tissue transglutaminase activity, the leaves and young panicles of rice at different developmental stages were excised from the Honglian-type cytoplasmic male sterile line, Yuetai A and its maintainer line, Yuetai B, respectively. An ELISA measurement protocol for tissue transglutaminase activity detection in rice was well established. The results indicated that the tissue transglutaminase activity was regulated positively by calcium cation, and the tissue transglutaminase activity in senescent leaves was remarkably higher than that in young leaves. No distinct difference was noted between Yuetai A and Yuetai B. Moreover, from the tetrad to binucleate stages the tissue transglutaminase activity increased gradually with the progression of the young panicle development and up to maximum at binucleate stage in Yuetai A. However, no similar changes were observed in Yuetai B. This indicates that the tissue transglutaminase is involved in cell programmed death in abortive pollen.

关键词： rice cytoplasmic male sterility young panicle development tissue transglutaminase programmed cell death

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TBN improves motor function and prolongs survival in SOD1G93A and TDP-43M337V mouse model of amyotrophic lateral sclerosis

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中国药理学与毒理学杂志 2021年第9期35卷 647-648页

作者： HUANG Chun-hui LI jun zhang Gui-liang LIN Ying-qi LI Cai-juan ZHENG Xiao SONG Xi-cheng HAN Bo-feng GUO Bao-jian TU Zhu-chi zhang jun SUN Ye-wei WANG Yu-qiang YAN Sen zhang zai-jun Institute of New Drug Research Jinan University College of PharmacyGuangzhou 510632China

OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative dis⁃ease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy,weakness and ***⁃tive stress plays a key role in the pathogenesis of ALS,including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase 1(SOD1).Moreover,although the pathogenesis of ALS is unclear,the abnormal accumulation of TAR DNA-binding pro⁃tein of 43 ku(TDP-43)is a pathological feature that exists in almost all *** far,there is no drug that can cure ALS/***⁃pyrazine nitrone(TBN)is a derivative of tetra⁃methylapyrazine,derived from the traditional Chinese medicine Ligusticum chuanxiong,which has been widely proven to have therapeutic effects on models of various neurodegenerative *** is currently under clinical investi⁃gation for several indications including a phaseⅡtrial of ***,we explored the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse *** In the SOD1G93A transgenic mouse model,TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor *** the same time,we unilaterally and bilaterally injected the TDP-43M337V virus into the striatum of the WT mouse,and gave the TBN treatment after the mice developed a *** administering these two models for a period of time,we con⁃ducted behavioral tests,including rotarod test,balance beam test,climbing pole test,etc,to evaluate the efficacy of TBN on SOD1G93A and TDP-43M337V ***,we explored the possible mechanism of action of TBN in the treatment of ALS through Western blotting and immunohistochemistry/immunofluorescence staining *** In the SOD1G93A transgenic mouse model,TBN slowed the pro⁃gression of motor neuron disease as evidenced by improved motor performance,reduced spinal motor neuron loss and the associated glial respons

关键词： amyotrophic lateral sclerosis tetra⁃methylpyrazine nitrone superoxide dismutase 1

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NP-20 Tetramethylpyrazine Nitrone Activates PGC-1α/Nrf2 Pathway to Prevent Neurodegeneration in Experimental Models of Parkinson’s Disease

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神经药理学报 2018年第4期8卷 117-118页

作者： zhang zai-jun GUO Bao-jian ZHENG Cheng-you WANG Yu-qiang Institute of New Drug Research Jinan University College of PharmacyGuangzhou510632China

Objective:Disease-modifying therapies are not available for Parkinson’s disease(PD)and several trials targeting individual pathways implicated in PD pathogenesis have *** hypothesize that a potentially more powerful strategy is the molecule targeting multiple signaling cascades involved in *** is the conjugate of natural product tetramethylpyrazine(TMP)and the nitrone group of a neuroprotective agent *** neuroprotective effects of TBN have been verifi ed in various models of transient and permanent ischemic stroke,traumatic brain injury,as well as optic nerve injury through multifunctional *** objective of present study was to inverstigate the therapeutic effi cay and mechanisms of TBN on PD ***:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model,unilateral intrastriatal injection of 6-hydroxydopamine(6-OHDA)-induced rat model,and transgenic mice overexpression of human A53T mutantα-synuclein were used to evaluate TBN’s therapeutic efficacy and elucidate its mechanisms of ***:TBN takes the best of the Chinese medicine TMP,which has superior capability penetrating the blood-brain barrier(BBB),and the nitrone,which potently scavenging free *** a result,TBN effi ciently penetrates the BBB delivering free radical scavenging nitrone to the brain to afford protection to neuronal *** treatment partially restores motor impairment,increases content of DA and its metabolites,and reduces loss of hydroxylase positive(TH+)neurons in SNpc of 6-OHDA and MPTP-induced and transgenic rodent PD *** intriguing is that TBN signifi cantly preserves motor function and reduces serum level of alpha-synuclein by 85%in A53T alpha-synuclein transgenic mice after 8 weeks’*** also specifi cally suppresses MPTP intoxication-induced serum and mRNA levels of TNF-alpha and IL-6 in both wild-type and Rag1-/-immune deficient *** studies show that TBN targeting PGC-1alpha and Nrf2 activatio

关键词： Experimental PGC-1α treatment α-synuclein multiple expression strategy effects

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激活AMPK/SIRT1/PGC-1α信号通路调控线粒体能量代谢在肌萎缩性侧索硬化症治疗中的潜力

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中国药理学通报 2022年第3期38卷 325-329页

作者：黄春辉张在军暨南大学新药研究所广东广州510632

肌萎缩性侧索硬化症(amyotrophic lateral sclerosis,ALS)是由上下层运动神经元的选择性丢失所致的神经退行性疾病,且发病机制复杂而不明确。越来越多的证据表明,能量代谢缺陷和体内稳态失衡导致ALS中运动神经元的选择性变性。已知磷酸... 详细信息

肌萎缩性侧索硬化症(amyotrophic lateral sclerosis,ALS)是由上下层运动神经元的选择性丢失所致的神经退行性疾病,且发病机制复杂而不明确。越来越多的证据表明,能量代谢缺陷和体内稳态失衡导致ALS中运动神经元的选择性变性。已知磷酸腺苷激活的蛋白激酶(AMPK)和沉默信息调节因子2相关酶1(SIRT1)可在细胞水平感受能量代谢状态,并在调节机体能量稳态和自噬方面起重要作用。AMPK激活SIRT1,使下游的参与能量代谢的基因过氧化物酶体增殖物激活受体γ辅活化因子1α(PGC-1α)等去乙酰化激活,从而提高线粒体生物合成水平。因此,AMPK/SIRT1协同参与能量代谢调节的机制极有可能是ALS治疗的潜力靶点。本综述,我们首先回顾了能量代谢缺陷和线粒体异常在ALS发病机制中的重要作用,并简要介绍AMPK/SIRT1/PGC-1α通路在ALS中作为治疗途径的潜力,以及如何靶向调控该信号通路使之成为ALS的有效治疗策略。

关键词：肌萎缩性侧索硬化症线粒体能量代谢 AMPK/SIRT1/PGC-1α通路靶向药物治疗策略

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Tetramethylpyrazine analogue T-006 promotes clearance of alpha-synuclein by enhancing proteasome activity in Parkinson disease models

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中国药理学与毒理学杂志 2019年第9期33卷 658-659页

作者： ZHOU He-feng SHAO Min GUO Bao-jian LI Chu-wen LU Yu-cong YANG Xuan-jun LI Sheng-nan LI Hai-tao ZHU Qi ZHONG Han-bing WANG Yu-qiang zhang zai-jun LU Jia-hong LEE Ming-yuen Simon State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences University of MacaoMacao 999078China Department of Bioengineering Zhuhai Campus of Zunyi Medical CollegeZhuhai 519041China Institute of New Drug Research College of PharmacyJinan UniversityGuangzhou 510000China Department of Biology South University of Science and TechnologyShenzhen 518000China

OBJECTIVE To investigate the effects of T-006(tetramethylpyrazine derivative)in promotingα-Synuclein(α-Syn)degradation and evaluated the neuroprotective effects in cellular and animalα-Syn model of Parkinson disease(PD).METHODS The inducible PC12 cells overexpressingα-syn and the homozygous transgenic(Tg)mice expressing A53T humanα-syn were used to evaluate the neuroprotective effects of *** cellular study,MTT,Western blotting,proteasomal activity assay and qRT-PCR were applied to analyze the pharmacological effects and underlying mecha⁃*** gene knock-down and overexpression approaches were used to dissect the molecular signaling *** animal study,ten-month-old homozygousα-Syn Tg mice were treated with T-006(3 mg·kg-1)daily by gavage for four *** Western blotting,immunohistochemistry and behavioral tests were applied to determine the neuropatho⁃logical *** T-006 promoted the degradation of WT and mutantα-Syn in PC12α-Syn inducible cells via an ubiquitin-proteasome system(UPS)dependent and autophagy-lysosome pathway independent *** mecha⁃nism of action involved the upregulation of 20S proteasome subunit LMP7 expression,which leads to activation of the chymotrypsin-like proteasomal activity for protein ***,we demonstrated that T-006 activated PKA/Akt/mTOR pathway upstream for LMP 7 up-regulation and UPS ***,we illustrated that T-006 promoted both Triton-soluble and-insoluble forms ofα-syn and protected againstα-Syn-induced neurotoxicity in A53Tα-Syn Tg *** T-006 is a potent UPS activator which promotes the degradation of pathogenic proteinα-Syn in cellular and animal PD *** study thus high-lights the therapeutic potential of small molecular UPS activator like T-006 in the treatment of PD and related conditions.

关键词： α-synuclein degradation LMP7 proteasome activity Parkinson disease

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玉米蛋白激酶基因ZmASK1表达载体的构建及遗传转化

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湖北农业科学 2007年第2期46卷 177-179页

作者：邹华文张再君长江大学农学院湖北荆州434025 湖北省农业科学院粮食作物研究所武汉430064

为了研究玉米蛋白激酶基因ZmASK1的功能,把ZmASK1的cDNA连接到植物表达载体pGreen0029中,通过农杆菌介导转入拟南芥中进行过量表达。PCR和Western-blot分析表明,ZmASK1已经转入到拟南芥中,并且在大多数转化植株中稳定表达。通过本试验,... 详细信息

为了研究玉米蛋白激酶基因ZmASK1的功能,把ZmASK1的cDNA连接到植物表达载体pGreen0029中,通过农杆菌介导转入拟南芥中进行过量表达。PCR和Western-blot分析表明,ZmASK1已经转入到拟南芥中,并且在大多数转化植株中稳定表达。通过本试验,为以后对ZmASK1的功能验证工作打下基础。

关键词：玉米蛋白激酶 ZmASK1 表达载体遗传转化

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表高油菜素内酯对玉米幼苗根系内源激素的影响

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湖北农业科学 2007年第1期46卷 43-45页

作者：邹华文张再君长江大学农学院湖北荆州434025

用表高油菜素内酯浸种试验结果表明,玉米品种铁单10幼苗的根长、根数、根干重增加;与对照相比,根系内的IAA、GA1,3含量升高,ZRs含量则降低,同时IAA/ZRs比值增加。

关键词：玉米表高油菜素内酯内源激素

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Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer disease

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中国药理学与毒理学杂志 2021年第9期35卷 646-647页

作者： WU Liang-miao ZHOU Xin-hua CAO Yi-wan Shing Hung MAK ZHA Ling LI Ning SU Zhi-yang HAN Yi-fan WANG Yu-qiang Maggie Pui Man Hoi SUN Ye-wei zhang Gao-xiao YANG Xi-fei zhang zai-jun Institute of New Drug Research Jinan University College of PharmacyGuangzhou 510632China

OBJECTIVE Alzheimer disease(AD)is a leading cause of dementia in elderly individuals and therapeutic options for AD are very ***-activation of N-methyl-D-aspar⁃tate(NMDA)receptors,amyloidβ(Aβ)aggrega⁃tion,a decrease in cerebral blood flow(CBF),and downstream pathological events play impor⁃tant roles in the disease progression of *** study seeks to explore the efficacy and mecha⁃nism of action of MN-08,a novel memantine ni⁃trate,in established animal models of *** MN-08′s effectiveness as a preventative and therapeutic agent was tested in 2-to 8-month-old APP/PS1 transgenic mice and 9-to 12-month-old 3×Tg-AD mice,*** neuroprotective mechanism of MN-08 was tested in the glutamate cell *** pharmacokinet⁃ics and safety of MN-08 in vivo were determined in normal rats and beagle *** the behavioral test,Western blotting analysis,pathology,ELISA test and in vitro cell tests,investigators were blinded to the experimental grouping and drug *** MN-08,a novel meman⁃tine nitrate,was found to inhibit Aβaccumulation,prevent neuronal and dendritic spine loss,and consequently attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice(for a 6-month preventative course)and in the 8-month-old triple-transgenic(3×Tg-AD)mice(for a 4-month therapeutic course).In vitro,MN-08 could bind to and antagonize NMDA receptors,inhibit the calcium influx,and reverse the dysregula⁃tions of ERK and PI3K/Akt/GSK3βpathway,sub⁃sequently preventing glutamate-induced neuro⁃nal *** addition,MN-08 had favorable phar⁃macokinetics,blood-brain barrier penetration,and safety profiles in rats and beagle ***⁃CLUSION The novel memantine nitrate MN-08 may be a useful therapeutic agent for AD.

关键词： Alzheimer disease MN-08 meman⁃tine nitrate

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牛乳中主要过敏原组分的分离纯化及鉴定

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食品科学 2007年第5期28卷 305-308页

作者：毛露甜向军俭张在军暨南大学分子免疫学与抗体工程研究中心

目的:分离纯化并鉴定牛乳中引起过敏反应的主要致敏组分。方法:采用聚丙烯酰胺凝胶电泳(SDS- PAGE)分析了脱脂乳和乳清的蛋白组分,用饱和硫酸铵分段盐析-DEAE离子交换柱层析纯化过敏原蛋白,脱脂乳和乳清蛋白皮下注射Balb/c小鼠获得高效... 详细信息

目的:分离纯化并鉴定牛乳中引起过敏反应的主要致敏组分。方法:采用聚丙烯酰胺凝胶电泳(SDS- PAGE)分析了脱脂乳和乳清的蛋白组分,用饱和硫酸铵分段盐析-DEAE离子交换柱层析纯化过敏原蛋白,脱脂乳和乳清蛋白皮下注射Balb/c小鼠获得高效价特异性IgE抗血清用于免疫印迹分析。结果:免疫印迹分析显示β-乳球蛋白(β-Lg)是引起牛乳过敏的主要过敏原,建立了牛乳过敏小鼠模型。结论:明确了牛乳过敏的主要过敏组分,对牛乳过敏症的诊断治疗以及无过敏原牛乳的制备提供了实验依据。

关键词：牛乳食物过敏原免疫印迹 DEAE离子交换层析

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