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Genetically modified non-human primate models for research on neurodegenerative diseases

Zoological Research 2024年第2期45卷 263-274页

作者： Ming-Tian Pan Han Zhang Xiao-Jiang Li Xiang-Yu Guo Guangdong Key Laboratory of Non-human Primate Research Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong 510632China

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

关键词： Neurodegeneration Non-human primate Macaque monkey animal model Gene modification

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Therapeutic advances in atrial fibrillation based on animal models

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第2期25卷 135-152页

作者： Qian GONG Xuan LE Pengcheng YU Lenan ZHUANG Institute of Genetics and Reproduction College of Animal SciencesZhejiang UniversityHangzhou310058China Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province Department of CardiologySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China

Atrial fibrillation(AF)is the most prevalent sustained cardiac arrhythmia among humans,with its incidence increasing significantly with age.Despite the high frequency of AF in clinical practice,its etiology and management remain elusive.To develop effective treatment strategies,it is imperative to comprehend the underlying mechanisms of AF;therefore,the establishment of animal models of AF is vital to explore its pathogenesis.While spontaneous AF is rare in most animal species,several large animal models,particularly those of pigs,dogs,and horses,have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic options.This review aims to provide a comprehensive discussion of various animal models of AF,with an emphasis on the unique features of each model and its utility in AF research and treatment.The data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.

关键词： Atrial fibrillation animal model Therapeutic

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The generation and use of animal models of osteosarcoma in cancer research

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Genes & Diseases 2024年第2期11卷 664-674页

作者： Feifei Pu Haoyu Guo Deyao Shi Fengxia Chen Yizhong Peng Xin Huang Jianxiang Liu Zhicai Zhang Zengwu Shao Department of Orthopedics Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital)Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Radiation and Medical Oncology Zhongnan HospitalWuhan UniversityWuhanHubei 430071China Hubei Cancer Clinical Study Center Zhongnan HospitalWuhan UniversityWuhanHubei 430071China

Osteosarcoma is the most common malignant bone tumor affecting children and adolescents.Currently,the most common treatment is surgery combined with neoadjuvant chemotherapy.Although the survival rate of patients with osteosarcoma has improved in recent years,it remains poor when the tumor(s)progress and distant metastases develop.Therefore,better animal models that more accurately replicate the natural progression of the disease are needed to develop improved prognostic and diagnostic markers,as well as targeted therapies for both primary and metastatic osteosarcoma.The present review described animal models currently being used in research investigating osteosarcoma,and their characteristics,advantages,and disadvantages.These models may help elucidate the pathogenic mechanism(s)of osteosarcoma and provide evidence to support and develop clinical treatment strategies.

关键词： animal model Cancer Osteosarcoma Pathogenic mechanism Translational research

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Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model

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Zoological Research 2022年第3期43卷 301-318页

作者： Guang Wang Yong-Feng Wang Jiang-Lan Li Ru-Ji Peng Xin-Yin Liang Xue-Dong Chen Gui-Hua Jiang Jin-Fang Shi Yang-Hu Si-Ma Shi-Qing Xu School of Biology and Basic Medical Sciences Suzhou Medical CollegeSoochow UniversitySuzhouJiangsu 215123China Department of Clinical Laboratory First Affiliated Hospital of Soochow UniversitySuzhouJiangsu 215006China

Hyperproteinemia is a metabolic disorder associated with increased plasma protein concentration(PPC)and is often clinically complicated by malignant diseases or severe infections.At present,however,research on the molecular mechanism underlying high PPC(HPPC)is scant.Here,an animal model of primary hyperproteinemia was constructed in an invertebrate(Bombyx mori)to investigate the effects of HPPC on circulating blood cells.Results showed that HPPC affected blood cell homeostasis,leading to increased reactive oxygen species levels,and induced programmed cell death dependent on the endoplasmic reticulum-calcium ion signaling pathway.HPPC induced the proliferation of blood cells,mainly granulocytes,by activating the Janus kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathway.Supplementation with the endocrine hormone active substance 20 E significantly reduced the impact of HPPC on blood cell homeostasis.Thus,we identified a novel signaling pathway by which HPPC affects blood cell homeostasis,which differs from hyperglycemia,hyperlipidemia,and hypercholesterolemia.In addition,we showed that down-regulation of gene expression of the hematopoietic factor Gcm could be used as a potential early detection indicator for hyperproteinemia.

关键词： animal model Blood cell homeostasis High plasma protein concentration(HPPC) JAK/STAT pathway Programmed cell death

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The incidence rate and histological characteristics of intimal hyperplasia in elastase-induced experimental abdominal aortic aneurysms in mice

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animal models and Experimental Medicine 2024年第3期7卷 388-395页

作者： Meng Li Panpan Wei Kexin Li Haole Liu Naqash Alam Haiwen Hou Jie Deng Baohui Xu Enqi Liu Sihai Zhao Yankui Li Laboratory animal Center Xi'an Jiaotong UniversityXi'anChina Department of Vascular Surgery The Second Hospital of Tianjin Medical UniversityTianjinChina Department of Cardiology The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina Department of Vascular Surgery Stanford University School of MedicineStanfordCaliforniaUSA

Intimal hyperplasia(IH)is a negative vascular remodeling after arterial injury.IH occasionally occurs in elastase-induced abdominal aortic aneurysm(AAA)mouse models.This study aims to clarify the incidence and histological characteristics of IH in aneurysmal mice.A retrospective study was conducted by including 42 male elastaseinduced mouse AAA models.The IH incidence,aortic diameters with or without IH,and hyperplasia lesional features of mice were analyzed.Among 42 elastase-induced AAA mouse models,10 mice developed mild IH(24%)and severe IH was found in only 2 mice(5%).The outer diameters of the AAA segments in mice with and without IH did not show significant difference.Both mild and severe IH lesions show strong smooth muscle cell positive staining,but endothelial cells were occasionally observed in severe IH lesions.There was obvious macrophage infiltration in the IH lesions of the AAA mouse models,especially in mice with severe IH.However,only a lower numbers of T cells and B cells were found in the IH lesion.Local cell-secreted matrix metalloproteinases(MMP)2 was highly expressed in all IH lesions,but MMP9 was only overexpressed in severe lesions.In conclusion,this study is the first to demonstrate the occurrence of aneurysmal IH and its histological characteristics in an elastaseinduced mouse AAA model.This will help researchers better understand this model,and optimize it for use in AAA-related research.

关键词： abdominal aortic aneurysms animal model histology intimal hyperplasia

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Selecting an Appropriate Experimental animal model for Cholangiocarcinoma Research

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Journal of Clinical and Translational Hepatology 2022年第4期10卷 700-710页

作者： Man Li Xueli Zhou Wei Wang Baoan Ji Yu Shao Qianyu Du Jinghao Yao Yan Yang Department of Medical Oncology The First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina Depart-ment of Cancer Biology Mayo ClinicJacksonvilleFloridaUSA

Cholangiocarcinoma(CCA)is a highly aggressive biliary tree malignancy with intrahepatic and extra-hepatic sub-types that differ in molecular pathogeneses,epidemiology,clinical manifestations,treatment,and prognosis.The over-all prognosis and patient survival remains poor because of lack of early diagnosis and effective treatments.Preclini-cal in vivo studies have become increasingly paramount as they are helpful not only for the study of the fundamental molecular mechanisms of CCA but also for developing novel and effective therapeutic approaches of this fatal cancer.Recent advancements in cell and molecular biology have made it possible to mimic the pathogenicity of human CCA in chemical-mechanical,infection-induced inflammatory,implantation,and genetically engineered animal models.This review is intended to help investigators understand the particular strengths and weaknesses of the currently used in vivo animal models of human CCA and their related mod-eling techniques to aid in the selection of the one that is the best for their research needs.

关键词： Cholangiocarcinoma Heterogeneity animal model Genetically engineered model Cancer cell of origin

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Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

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animal models and Experimental Medicine 2024年第3期7卷 283-296页

作者： Frazer I.Heinis Shaheed Merani Nicholas W.Markin Kim F.Duncan Michael J.Moulton Lance Fristoe William E.Thorell Raechel A.Sherrick Tami R.Wells Matthew T.Andrews Marian Urban School of Natural Resources Institute of Agriculture and Natural ResourcesUniversity of Nebraska-LincolnLincolnNebraskaUSA Division of Transplantation and Vascular Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Department of Anesthesiology University of Nebraska Medical CenterOmahaNebraskaUSA Division of Cardiothoracic Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Clinical Perfusion Nebraska Medicine-Nebraska Medical CenterOmahaNebraskaUSA Department of Neurosurgery University of Nebraska Medical CenterOmahaNebraskaUSA Nutrition and Health Sciences College of Education and Human SciencesUniversity of Nebraska-LincolnLincolnNebraskaUSA Department of Comparative Medicine University of Nebraska Medical CenterOmahaNebraskaUSA

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical transplantation.animal models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury,organ preservation strategies,and future donor-based interventions.Important considerations include cost,public opinion regarding the conduct of animal research,translational value,and relevance of the animal model for clinical practice.We present an overview of two porcine models of organ donation:donation following brain death(DBD)and donation following circulatory death(DCD).The cardiovascular anatomy and physiology of pigs closely resembles those of humans,making this species the most appropriate for pre-clinical research.Pigs are also considered a potential source of organs for human heart and kidney xenotransplantation.It is imperative to minimize animal loss during procedures that are surgically complex.We present our experience with these models and describe in detail the use cases,procedural approach,challenges,alternatives,and limitations of each model.

关键词： animal model brain death circulatory death organ transplantation

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Development of an experimental method for well-controlled blast induced traumatic limb fracture in rats

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Defence Technology（防务技术） 2024年第4期34卷 168-176页

作者： Luyang Xu Xiancheng Yu Clement DFavier Ibidumo Igah Thuy-Tien Nguyen Warren Macdonald Anthony MJ.Bull Centre for Blast Injury Studies Imperial College LondonLondonUnited Kingdom Department of Bioengineering Imperial College LondonLondonUnited Kingdom Dyson School of Design Engineering Imperial College LondonLondonUnited Kingdom Department of Trauma and Orthopaedics Royal Free London National Health Service Foundation TrustLondonUnited Kingdom

Heterotopic ossification(HO)is a consequence of traumatic bone and tissue damage,which occurs in 65%of military casualties with blast-associated amputations.However,the mechanisms behind blast-induced HO remain unclear.animal models are used to study blast-induced HO,but developing such models is challenging,particularly in how to use a pure blast wave(primary blast)to induce limb fracture that then requires an amputation.Several studies,including our recent study,have developed platforms to induce limb fractures in rats with blast loading or a mixture of blast and impact loading.However,these models are limited by the survivability of the animal and repeatability of the model.In this study,we developed an improved platform,aiming to improve the animal's survivability and injury repeatability as well as focusing on primary blast only.The platform exposed only one limb of the rat to a blast wave while providing proper protection to the rest of the rat's body.We obtained very consistent fracture outcome in the tibia(location and pattern)in cadaveric rats with a large range of size and weight.Importantly,the rats did not obviously move during the test,where movement is a potential cause of uncontrolled injury.We further conducted parametric studies by varying the features of the design of the platform.These factors,such as how the limb is fixed and how the cavity through which the limb is placed is sealed,significantly affect the resulting injury.This platform and test setups enable well-controlled limb fracture induced directly by pure blast wave,which is the fundamental step towards a complete in vivo animal model for blast-induced HO induced by primary blast alone,excluding secondary and tertiary blast injury.In addition,the platform design and the findings presented here,particularly regarding the proper protection of the animal,have implications for future studies investigating localized blast injuries,such as blast induced brain and lung injuries.

关键词： Blast injury Biomechanics Heterotopic ossification Limb fracture Blast wave animal model

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Enzymatic hydrolysis of silkworm pupa and its allergenicity evaluation by animal model with different immunization routes

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Food Science and Human Wellness 2023年第3期12卷 774-782页

作者： Yan Dai Meijia Huang Yujuan Xu Lixia Mu Jingyan Gao Hongbing Chen Zhihua Wu Anshu Yang Yong Wu Xin Li State Key Laboratory of Food Science and Technology Nanchang UniversityNanchang 330047China School of Food Science and Technology Nanchang UniversityNanchang 330047China Sericultural and Agri-Food Research Institute Guangdong Academy of Agricultural Sciences Key Laboratory of Functional FoodsMinistry of Agriculture and Rural AffairsGuangdong Key Laboratory of Agricultural Products ProcessingGuangzhou 510610China Sino-German Joint Research Institute Nanchang UniversityNanchang 330047China

Silkworm pupa is a nourishing food with high nutritional value,but its consumption has been greatly limited given its allergenicity.Enzyme hydrolytic technique is recognized as an effective method to reduce the allergenicity of protein.In this study,we aimed to investigate the effect of enzymolysis on the allergenicity of silkworm pupa.Crude silkworm pupa protein was extracted through alkali extraction and acid precipitation,which included 5 proteins with the molecular weights ranging from 34 kDa to 76 kDa,and silkworm pupa were then hydrolyzed by alkaline protease.The allergenicity of silkworm pupa protein and its enzymatic hydrolysates was evaluated by establishing BALB/c mice model,and the mice were immunized via intragastric gavage and intraperitoneal injection,respectively.The results indicated that the intraperitoneal inj ection immunization route induced more by detecting with antibodies,histamine and Th2-related cytokines.Moreover,mice treated with silkworm pupa protein peptide displayed no obvious allergic symptoms,indicating that enzyme hydrolytic technique could significantly reduce the allergenicity of silkworm pupa.

关键词： Silkworm pupa Silkworm pupa peptides Enzymatic hydrolysis Allergenicity Immunization animal model

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Preliminary exploration of animal models of congenital choledochal cysts

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World Journal of Gastroenterology 2024年第10期30卷 1420-1430页

作者： Shu-Hao Zhang Yue-Bin Zhang Duo-Te Cai Tao Pan Ken Chen Yi Jin Wen-Juan Luo Zong-Wei Huang Qing-Jiang Chen Zhi-Gang Gao Department of General Surgery Children’s HospitalZhejiang University School of MedicineHangzhou 310000Zhejiang ProvinceChina

BACKGROUND Various animal models have been used to explore the pathogenesis of choledochal cysts(CCs),but with little convincing results.Current surgical techniques can achieve satisfactory outcomes for treatment of CCs.Consequently,recent studies have focused more on clinical issues rather than basic research.Therefore,we need appropriate animal models to further basic research.AIM To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs.METHODS Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group,sham surgical group,or control group.A rat model of CC was established by partial ligation of the bile duct.The reliability of the model was confirmed by measurements of serum biochemical indices,morpho-logy of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues.RESULTS Dilation classified as mild(diameter,≥1 mm tomodel was consistent with the human CC tissues.CONCLUSION The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC,which may contribute to investigating the pathogenesis of CC.

关键词： Choledochal cyst animal model Partial ligation Cystic and fusiform dilation Juvenile rats

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