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Experimental primates and non-human primate(NHP) models of human diseases in China: current status and progress

Zoological Research 2014年第6期35卷 447-464页

作者： Xiao-Liang ZHANG Wei PANG Xin-Tian HU Jia-Li LI Yong-Gang YAO Yong-Tang ZHENG key laboratory of animal models and human disease mechanisms of chinese academy of sciences & yunnan province Kunming Institute of Zoology Chinese Academy of Sciences Faculty of Life Science and Technology Kunming University of Science and Technology Kunming Primate Research Center of the chinese academy of sciences Kunming Institute of Zoology Chinese Academy of Sciences

Non-human primates （NHPs） are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China＇s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China＇s life sciences and pharmaceutical industry, and enhance China＇s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective to better utilize NHP resources and further foster NHP research in China.

关键词： Non-human primates Experimental primates animal models Current status

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Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer

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animal models and Experimental Medicine 2023年第3期6卷 245-254页

作者： Yumin Wei Liping Zhang Chao Wang Zefeng Li Mingjie Luo Guomin Xie Xingjiu Yang Mengyuan Li Shuyue Ren Dongbing Zhao Ran Gao Jia-Nan Gong National human diseases animal Model Resource Center The Institute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina NHC key laboratory of human disease Comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina Beijing Engineering Research Center for Experimental animal models of human Critical diseases BeijingChina Department of Pancreatic and Gastric Surgical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-Sen UniversityGuangzhouChina

Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset o

关键词： apoptosis BCL2L1(BCL-XL) gastric cancer(GC) PROTAC-BCL-XL selective BCL-XL inhibitors

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完整猕猴脑连续亚微米分辨的三维成像

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Science Bulletin 2022年第1期67卷 85-96,M0004页

作者：周灿杨孝全吴诗昊钟秋园罗婷李安安刘广才孙庆涛罗盘邓磊倪鸿谭朝镇袁菁骆清铭胡新天李向宁龚辉 Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for OptoelectronicsMoE Key Laboratory for Biomedical PhotonicsHuazhong University of Science and TechnologyWuhan 430074China HUST-Suzhou Institute for Brainsmatics JITRISuzhou 215123China key laboratory of animal models and human disease mechanisms of chinese academy of sciences&yunnan province Kunming Institute of ZoologyKunming 650223China CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China School of Biomedical Engineering Hainan UniversityHaikou 570228China

解剖整个脑回路结构对于揭示神经系统的组织结构逻辑至关重要.然而,在庞大而复杂的灵长类大脑中绘制亚微米分辨率的神经元投影仍然具有挑战性.本文开发了高效的技术方案,以亚微米分辨率绘制整个猕猴大脑的神经元投射.该方案包括一种可... 详细信息

解剖整个脑回路结构对于揭示神经系统的组织结构逻辑至关重要.然而,在庞大而复杂的灵长类大脑中绘制亚微米分辨率的神经元投影仍然具有挑战性.本文开发了高效的技术方案,以亚微米分辨率绘制整个猕猴大脑的神经元投射.该方案包括一种可长期保存组织结构和荧光信号的新型包埋方法,高分辨率快速全脑光学成像方法和图像后处理方法.利用该方案获取完整猕猴脑的0.32μm×0.32μm×10.00μm体素分辨率数据集展示了单细胞定位、密度、形状等解剖构筑信息.结合病毒标记,追踪了猕猴半脑从前额皮质到丘脑的长距离投射神经纤维,结果显示,额叶皮层的轴突可投射到视皮层、纹状体、丘脑和中脑等多个脑区.该方案为整个猕猴大脑的亚微米级三维细胞构筑和神经元环路研究提供了有效的方法,有助于揭示大脑功能和疾病基础.

关键词：三维成像光学成像结构逻辑细胞构筑神经元视皮层额叶皮层大脑功能

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Decreased peripheral mtDNA in methamphetamine use disorder

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Science China(Life sciences) 2022年第3期65卷 648-650页

作者： Ling-Yan Su Yuan Li Qianjin Liu Lijin Jiao Jing Shen Lu-Xiu Yang Ti-Fei Yuan Yong-Gang Yao key laboratory of animal models and human disease mechanisms of the chinese academy of sciences&yunnan province and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyKunming 650204China Kunming College of Life Science University of Chinese Academy of SciencesKunming 650204China Shanghai key laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghai 200030China Hubei Shizishan Drug Rehabilitation Center Wuhan 426070China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226019China Translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s Hospital Affiliated to Tongji University School of MedicineShanghai 200434China CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China

Dear Editor,Methamphetamine(METH)is the most prevalent addictive psychostimulant in China.METH use disorder(MUD)and its associated disorders constitute a significant burden to the affected individuals and their families(Paulus and Stewart,2020).Neurotransmitter system aberrations,mitochondrial dysfunction,oxidative stress,and inflammasome activation have been involved in METH-induced neurotoxicity(Shin et al.,2018;Wang et al.,2015;Wei et al.,2020).

关键词： China Stewart

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Bioactive peptides from scorpion venoms:therapeutic scaffolds and pharmacological tools

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chinese Journal of Natural Medicines 2023年第1期21卷 19-35页

作者： Peter Muiruri Kamau ZHONG Jian YAO Bing LAI Ren LUO Lei key laboratory of animal models and human disease mechanisms of the chinese academy of sciences/key laboratory of Bioactive Peptides of yunnan province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesNational Resource Center for Non-Human PrimatesKunming Primate Research CenterNational Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Sino-African Joint Research Centerand Engineering Laboratory of PeptidesKunming Institute of ZoologyKunming 650107China Kunming College of Life sciences University of Chinese Academy of SciencesBeijing 100049China Department of Reproductive Medicine Affiliated Jinling HospitalNanjing Medical UniversityNanjing 210002China Department of Gynecology Women’s Hospital of Nanjing Medical UniversityNanjing 210004China Center for Evolution and Conservation Biology Southern Marine Science and Engineering Guangdong LaboratoryGuangzhou 511458China

Evolution and natural selection have endowed animal venoms,including scorpion venoms,with a wide range of pharmacological properties.Consequently,scorpions,their venoms,and/or their body parts have been used since time immemorial in traditional medicines,especially in Africa and Asia.With respect to their pharmacological potential,bioactive peptides from scorpion venoms have become an important source of scientific research.With the rapid increase in the characterization of various components from scorpion venoms,a large number of peptides are identified with an aim of combating a myriad of emerging global health problems.Moreover,some scorpion venom-derived peptides have been established as potential scaffolds helpful for drug development.In this review,we summarize the promising scorpion venoms-derived peptides as drug candidates.Accordingly,we highlight the data and knowledge needed for continuous characterization and development of additional natural peptides from scorpion venoms,as potential drugs that can treat related diseases.

关键词： Scorpion venoms Scorpion venom-derived peptides Pharmacological properties Drug development

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Understanding and modeling human traits and diseases:Insights from the comparative genomics resources of Zoonomia

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The Innovation 2023年第4期4卷 5-6页

作者： Maosen Ye Deng-Feng Zhang key laboratory of animal models and human disease mechanisms of the chinese academy of sciences and yunnan province Kunming Institute of ZoologyChinese Academy of SciencesKunming 650201China Kunming College of Life Science University of Chinese Academy of SciencesKunming 650204China Center for Excellence in animal Evolution and Genetics Chinese Academy of SciencesKunming 650204China National Research Facility for Phenotypic&Genetic Analysis of Model animals(Primate Facility) Kunming Institute of ZoologyChinese Academy of SciencesKunming 650107China KIZ/CUHK Joint laboratory of Bioresources and Molecular Research in Common diseases Kunming Institute of ZoologyChinese Academy of SciencesKunming 650201China

Understanding the genetic architecture of complex human traits and diseases is one of the major aims of biomedical research.Genetic research,such as genome-wide association studies(GWASs)of large-scale,wellphenotyped cohorts,has identified tens of thousands of genomic variants associated with human traits and diseases.The remaining challenge is how to translate the statistical association of genomic loci to biological mechanisms and clinical strategies.

关键词： diseases clinical translate

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Structural variation during dog domestication: insights from gray wolf and dhole genomes

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National Science Review 2019年第1期6卷 110-122页

作者： Guo-Dong Wang Xiu-Juan Shao Bing Bai Junlong Wang Xiaobo Wang Xue Cao Yan-Hu Liu Xuan Wang Ting-Ting Yin Shao-Jie Zhang Yan Lu Zechong Wang Lu Wang Wenming Zhao Bing Zhang Jue Ruan Ya-Ping Zhang Kunming College of Life Science University of Chinese Academy of Sciences Beijing Zoo Core Genomic Facility Beijing Institute of GenomicsChinese Academy of Sciences State key laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of Sciences Center for Excellence in animal Evolution and Genetics Chinese Academy of Sciences Agricultural Genomics Institute Chinese Academy of Agricultural Sciences Medical Faculty Kunming University of Science and Technology Department of Pediatrics the First People's Hospital of Yunnan Province College of Pharmacology Soochow University key laboratory of animal models and human disease mechanisms of the chinese academy of sciences and yunnan province Kunming Institute of ZoologyChinese Academy of Sciences Department of laboratory animal Science Kunming Medical University laboratory for Conservation and Utilization of Bio-Resources and key laboratory for Microbial Resources of the Ministry of Education Yunnan University

Several processes like phenotypic evolution, disease susceptibility and environmental adaptations, which fashion the domestication of animals, are largely attributable to structural variations(SVs) in the genome.Here, we present high-quality draft genomes of the gray wolf(Canis lupus) and dhole(Cuon alpinus) with scaffold N50 of 6.04 Mb and 3.96 Mb, respectively. Sequence alignment comprising genomes of three canid species reveals SVs specific to the dog, particularly 16 315 insertions, 2565 deletions, 443 repeats, 16 inversions and 15 translocations. Functional annotation of the dog SVs associated with genes indicates their enrichments in energy metabolisms, neurological processes and immune systems. Interestingly, we identify and verify at population level an insertion fully covering a copy of the AKR1 B1(Aldo-Keto Reductase Family 1 Member B) transcript. Transcriptome analysis reveals a high level of expression of the new AKR1 B1 copy in the small intestine and liver, implying an increase in de novo fatty acid synthesis and antioxidant ability in dog compared to gray wolf, likely in response to dietary shifts during the agricultural revolution. For the first time, we report a comprehensive analysis of the evolutionary dynamics of SVs during the domestication step of dogs. Our findings demonstrate that retroposition can birth new genes to facilitate domestication, and affirm the importance of large-scale genomic variants in domestication studies.

关键词： dog domestication genome assembly structural variation gray wolf dhole

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Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2

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Signal Transduction and Targeted Therapy 2023年第5期8卷 2384-2391页

作者： Zhijian Xu Danrong Shi Jian-Bao Han Yun Ling Xiangrui Jiang Xiangyun Lu Chuan Li Likun Gong Guangbo Ge Yani Zhang Yi Zang Tian-Zhang Song Xiao-Li Feng Ren-Rong Tian Jia Ji Miaojin Zhu Nanping Wu Chunhui Wu Zhen Wang Yechun Xu Cheng Peng Min Zheng Junling Yang Feifei Du Junliang Wu Peipei Wang Jingshan Shen Jianliang Zhang Yong-Tang Zheng Hangping Yao Weiliang Zhu State key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China Drug Discovery and Design Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Pharmacy University of Chinese Academy of SciencesBeijing100049China State key laboratory for Diagnosis and Treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesFirst Affiliated HospitalZhejiang University School of MedicineHangzhou310003China Kunming National High-level Biosafety Research Center for Non-human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan650107China Department of Infectious disease Shanghai Public Health Clinical CenterFudan UniversityShanghai201508China Center for Drug Safety Evaluation and Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China key laboratory of animal models and human disease mechanisms of the chinese academy of sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan650223China Jinan Microecological Biomedicine Shandong laboratory Jinan250117China

Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.

关键词： drugs infected treatment

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High seroprevalence of toxoplasma gondii and HIV-1 co-infection among drug users in yunnan province, southwest China

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Science China(Life sciences) 2016年第8期59卷 857-859页

作者： Xin Chen Mei Ye Yan-Heng Zhou Feng-Liang Liu Lin Duo Hong Li Wei Pang Yong-Tang Zheng key laboratory of animal models and human disease mechanisms of the chinese academy of sciences & yunnan province Kunming Institute of Zoology Chinese Academy of Sciences Kunming 650223 China The Second People's Hospital of yunnan province Kunming 650021 China yunnan Center for disease Control and Prevention Kunming 650022 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming 650204 China

Dear Editor,Toxoplasma gondii was discovered more than 100 years ago and has a broad-spectrum of intermediate hosts in addition to its definitive host,felids.Although it does not cause symptomatic illness in most adul... 详细信息

关键词： users Toxoplasma retardation illness southwest infected likely prone children conclusion

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Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

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chinese Chemical Letters 2015年第2期26卷 243-247页

作者： Yong Sun Cui-Lin Lu Chang-Yuan Wang Rui-Rui Wang Ke-Xin Liu Liu-Meng Yang Yu-Hong Zhen Hou-Li Zhang Chao Wang Yong-Tang Zheng Xiao-Dong Ma College of Pharmacy Dalian Medical University key laboratory of animal models and human disease mechanisms of chinese academy of sciences and yunnan province.Kunming Institute of Zoology Chinese Academy of Sciences Kunming College of Life Science University of Chinese Academy of Sciences

Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a new template bearing N-phenylbenzenesulfonamide（PBSA） structure was designed to enhance the interactions with HIV-1 RT.In this manuscript,a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity.The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC_（50） values ranging of 0.105-14.531 μmol/L.In particular,compound 13 f not only has high anti-HIV-1 activity（0.108 μmol/L）,but also possesses low toxicity with a Tl value of 1816.6.Furthermore,the major interactions of the inhibitor 13 f with HIV-1 RT were also investigated using the molecular modelling.Our discovered structure-activity relationships（SARs） of these analogues may serve as an important clue for further optimizations.

关键词： Benzophenone N-Phenylbenzenesulfonamide Structure modification Anti-HIV activity

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