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Damage effect and mechanisms of cyclophosphamide to human neuroblastoma SH-SY5Y cells

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中国药理学与毒理学杂志 2024年第8期38卷 561-574页

作者： LI Jiajia WANG Jiao XIAO Wenyi WEI Donghui ZHANG Yongxiang JIANG Ning ZHOU Wenxia State Key Laboratory of National Security Specially Needed Medicines Academy of Military Medical SciencesBeijing 100850China

OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y *** SH-SY5Y cells were treated with CTX[0(cell control),0.01,0.1,1,5,10,20,40 and 80 mmol·L^(-1)]and 4-HC[0(cell control),0.01,0.1,1,5,10,20,40 and 80μmol·L^(-1)]for 48 *** confluence and morphology were observed by the IncuCyte ZOOM *** viability was assessed by CCK-8 *** dehydrogenase(LDH)release was measured by LDH assay ***-SY5Y cells were treated with CTX(0,1,5,10 and 20 mmol·L^(-1))and 4-HC(0,1,5,10 and 20μmol·L^(-1))for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine(EdU)staining *** was employed to assess the levels of the DNA double-strand break markerγ-H2AX and to evaluate changes in mitochondrial membrane ***-SY5Y cells were treated with CTX(0,1,5 and 10 mmol·L^(-1))and 4-HC(0,1,5 and 10μmol·L^(-1))for 48 h,and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 *** Compared with the cell control group,cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups(P<0.01),and the half-maximal inhibitory concentrations(IC50)for CTX and 4-HC were 4.44 mmol·L^(-1) and 4.78μmol·L^(-1),*** release rate of LDH was signif⁃icantly increased while the percentage of EdU+cells was significantly reduced in the CTX and 4-HC groups(P<0.01).The percentage ofγ-H2AX+cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group(P<0.05).Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity,glycolytic reserve,maximal respi⁃ration,and ATP production(P<0.05).CONCLUSION CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure,impeding cell proliferation,and reducing ce

关键词： cyclophosphamide 4-hydroperoxycyclophosphamide neurotoxicity energy metabolism

mRNA vaccine technology for infectious diseases and beyond

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Science China Life sciences 2024年第10期67卷 2267-2270页

作者： Pei Hao Xiao Li Xuan Li Wu Zhong Key Laboratory of Molecular Virology and Immunology Shanghai Institute of Immunity and InfectionChinese Academy of Sciences University of Chinese academy of sciences Changchun Veterinary Research institute Chinese Academy of Agricultural Sciences Key Laboratory of Synthetic Biology CAS Center for Excellence in Molecular Plant SciencesInstitute of Plant Physiology and EcologyChinese Academy of Sciences National Engineering Research Center for the Emergency Drug Beijing Institute of Pharmacology and Toxicology

The rise of mRNA vaccine technology Vaccines stand as one of the most significant medical advancements, playing a crucial role in the prevention of infectious diseases and the improvement of global health. The triumph of smallpox vaccination stands as a towering achievement in the annals of healthcare, leading to the complete elimination of a oncedevastating disease and showcasing the efficacy of vaccination methods.

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Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

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Science China Chemistry 2007年第3期50卷 405-417页

作者： NIE AiHua XIAO JunHai WANG LiLi LIAO GuoChao LIU HongYing REN Shen LI Song beijing institute of pharmacology and toxicology Academy of Military Medical SciencesBeijing 100850China

By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Calcineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.

关键词： FKBP12 L-1 4-thiazane-3-carboxylic acid derivatives design synthesis neurotrophic activity

Anti-epitope antibody, a novel site-directed antibody against human acetylcholinesterase

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Acta Pharmacologica Sinica 2004年第4期25卷 33-37页

作者： Xing-mei ZHANG, GangLIU, Man-ji SUN2 institute of pharmacology and toxicology, academyof militarymedical sciences, beijing 100850, China institute of pharmacology and toxicology Academy of Military Medical Sciences 北京 100850

AIM: To construct synthetic antigens using the epitope of human brain acetylcholinesterase (hbAChE) for induc- tion and detection of the specific antibody against the epitope, and to analyse the immunogenicity of the antibody. METHODS: The epitope (RTVLVSMNYR, amino acids 143-152) of hbAChEwas chemically synthesized, coupled with the carrier protein keyhole limpet hemocyanin (KLH) to construct an artificial immunogen (KLH-epitope), and injected into rabbits to raise antibody. The epitope conjugated with bovine serum albumin (BSA) was used as the detection antigen. The specificity of the antibody was tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The immunoreaction between the anti-recombinant human butyrylcholinesterase (rhBChE) polyclonal antibody and the biotinylated-epitope was examined by indirect ELISA. RESULTS: The erythrocyte AChE, the hbAChE, rhBChE and the BSA-epitope all immunoreacted with the anti-epitope antibody against the epitope (143-152) of hbAChE, whereas the torpedo AChE did not. CONCLUSION: The hbAChE, the human erythrocyte AChE and hBChE share the conservative antigenic epitope RTVLVSMNYR, hence they can all immunoreact with the anti-epitope antibody. Since the epitope of hbAChE is less similar with the aligned amino acid sequences of AChE of Torpedo californica or Torpedo marmorata, there is not any immunoreactivity between them. The R, M, and N residues in the epitope seem to be necessary radicals for the conservation of antigenicity.

关键词： acetylcholinesterase butyrylcholinesterase epitopes antibodies enzyme-linked immunosorbent assay Western blotting

Synthesis and Crystal Structure of N-[(3aR,4R,4aR,5aS,6S,6aS)-1,3-Dioxo-octahydro-4,6-ethenocyclopropa[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)phenylmethanimine Monohydrate

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Chinese Journal of Structural Chemistry 2010年第7期29卷 1043-1046页

作者： ZHOU Xin-Bo XIE Yun-De ZHONG Wu FAN Shi-Yong LI Song institute of pharmacology and toxicology Academy of Military Medical Sciences Beijing 100850 China

The crystal structure of the title compound （C19H17F3N2O4, Mr = 394.35） was determined by single-crystal X-ray diffraction. The crystal belongs to monoclinic, space group C2/c with a = 28.383（6）, b = 10.355（2）, c = 12.799（3） A, β = 111.74（3）°, V= 3493.8（12） A3, Z = 8, De = 1.499 g,/cm3, λ（MoKα） = 0.71073, F（000） = 1632,μ = 0.127 mm^-1, R = 0.0412 and wR = 0.1019. In the title compound, there exist three intermolecular hydrogen interactions （O（4）...O（1）, 0（4）...0（3） and O（4）...N（1）） between water. The neighboring molecules are linked to each other generating a two-dimensional network structure via the three intermolecular hydrogen bonds and π-π interactions shaped by phen-phen with centroid distance of 4.049 A.

关键词： ST246 monohydrate crystal structure synthesis

Enantiospecific Synthesis of Penehyclidine Hydrochloride and Its Piperidine Derivatives with R Configuration

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Chinese Journal of Chemistry 2006年第3期24卷 386-392页

作者：韩翔宇刘河刘春河吴波仲伯华刘克良 institute of pharmacology and toxicology Academy of Military Medical Science Beijing 100850 China

A novel and simple procedure for the enantiospecific synthesis of penehyclidine hydrochloride （8018） isomers and the R configuration derivatives was described. The intramolecular asymmetric cyclization of the monosulfonate of compound 1,2-diol was applied to the execution of the synthesis of the key chiral building block for the first time. The aimed products were obtained with moderate yield in〉99% ee.

关键词： enantiospecific synthesis penehyclidine hydrochloride R configuration

Production of human liver prolidase by Saccharomyces cerevisiae as host cells

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Acta Pharmacologica Sinica 2004年第6期25卷 92-98页

作者： Shu-hao WANG, Min LIU, Mu-gen CHI, Qing-ding WANG, Man-ji SUN2 institute of pharmacologyand toxicology, academy of military medical Science, beijing 100850, China institute of pharmacology and toxicology Academy of Military Medical Science 北京 100850

AIM: To clone and express the recombinant human liver prolidase in yeast and explore the activities of both dipeptidaseand organophosphoric acid anhydrolase(OPAA). METHODS:The cDNAencodinghuman liver prolidase derived from healthy adult liver was cloned into the pYES2, an expression vector of S cerevisiae, and then trans- formed into S cerevisiae INVSc1 by electroporation. The transformant with the highest enzymatic activity was induced by galactose for expression. The optimal induction conditions (temperature, induction time, and the initial amount of inoculation cells) were estimated by orthogonal experimental design. The recombinant prolidase and OPAA activities were assayed by spectrocolorimetric methods. RESULTS: The recombinant enzyme catalyzed the hydrolysis of organophosphorous compound soman as well as the hydrolysis of dipeptide Gly-Pro. Under the optimal induction conditions (20 h, 25 oC, initial OD600=0.4), the maximum activities of prolidase and OPAA came to 226.5 and 578 μmol·min-1·g-1 protein in cell lysate supernatants, respectively. SDS-PAGE of the recombinant enzyme in disrupted cell supernatants showed a molecular weight of 56 kDa. Intensity scanning of the SDS-PAGE gel revealed that the enzyme accounted for 3.16 % of the total protein in the supernatant. One liter incubation medium produced 7 g of wet yeast cell containing 4.56 mg of the recombination protein. CONCLUSION: The recombinant human liver prolidase produced by yeast cell (S cerevisiae) exhibited both dipeptidase and OPAA activities.

关键词： prolidase liver human S Cerevisiae organophosphorous compounds

Detection and quantitation of PS20, a phosphorothioate oligodeoxynucleotides in monkey plasma

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Acta Pharmacologica Sinica 2004年第6期25卷 99-104页

作者： Ming-mei SHANG, Hai-feng SONG2, Xiu-wen LIU, Zhong-ming TANG Department of pharmacology and toxicology, the institute of Radiation Medicine, academy of military medical sciences, beijing 100850, China Department of pharmacology and toxicology the Institute of Radiation Medicine Academy of Military Medical Sciences 北京 100850

AIM: To establish the method for quantitation of the phosphorothioate oligodeoxynucleotides (S-ODNs) in plasma. METHODS: Two solid-phase extraction columns combined with a strong anion-exchange column were utilized to remove proteins and lipids in plasma, and the salts were removed by a reverse-phase column followed by dialysis with a 2500 Da-cutoff membrane. The concentration of the tested S-ODNs, PS20, and its metabolites extracted from the plasma were determined by the method of non-gel sieving capillary electrophoresis (NGCE) with diode array detection in the presence of internal standard (IS). RESULTS: The method was with good base number specificity. Relative standard deviation % of both intra and inter assay were all less than 10 %, and the total mean recovery was about 91 %. The methodology was successfully used to determine the PK behavior of an anti-tumor antisense S-ODNs in monkeys and identify the metabolites with single base difference. CONCLUSION: The combined method of solid-phase extraction and NGCE could be used to study the pharmacokinetics of S-ODNs, and the main parameters of the methodology met the requirement of PK study.

关键词： antisense oligodeoxyribonucleotides thionucleotides rhesus monkey plasma solid-phase extraction capillary electrophoresis non-gel sieving internal standard

TRPV4 Regulates Soman-Induced Status Epilepticus and Secondary Brain Injury via NMDA Receptor and NLRP3 Inflammasome

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Neuroscience Bulletin 2021年第7期37卷 905-920页

作者： Shuai Wang Huanhuan He Jianhai Long Xin Sui Jun Yang Guodong Lin Qian Wang Yongan Wang Yuan Luo State Key Laboratory of toxicology and medical Countermeasures Institute of Pharmacology and ToxicologyAcademy of Military Medical SciencesBeijing 100850China

Nerve agents are used in civil wars and terrorist attacks,posing a threat to public *** exposure to nerve agents such as soman(GD)causes serious brain damage,leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and ***,data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are ***,we evaluated the potential effects of transient receptor vanilloid 4(TRPV4)in the treatment of soman-induced status epilepticus(SE)and secondary brain *** demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced *** of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE ***4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman *** in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate *** protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1βand IL-18 increased in soman-exposed rat ***,TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome *** conclusion,our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated *** our knowledge,this is the first study regarding the“dual-switch”function of TRPV4 in the treatment of soman intoxication.

关键词： Nerve agents Soman TRPV4 NMDA receptor NLRP3 inflammasome