A Comprehensive Review of Animal Models for Coronaviruses: SARS-CoV-2, SARS-CoV,and MERS-CoV

The recent outbreak of coronavirus disease(COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus(SARS-CoV) and Middle East respiratory syndrome coronavirus(MERSCoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.     

子宫内膜异位症动物模型研究进展

为研究子宫内膜异位症的病因、发病机制、治疗和预防对策,需要构建实验动物模型。本文通过分析各种模型的优点和缺点,为选择性应用动物模型提供指导,从而更利于对该病的研究。     

动物模型在肺部真菌病研究中的应用

真菌病成为日益严重的临床问题,深部真菌感染尤其是肺部真菌感染呈持续增多趋势。肺部真菌病往往发生于免疫低下或有基础疾病的患者,其具体发病机制尚不完全清楚。动物模型不仅为真菌病病因学研究提供有效的途径,还能在抗真菌药物、免疫调节剂及可能的疫苗的研究中提供多方面的帮助。动物实验中所观察到的病理改变可能对发病机理的探索有所帮助。实验动物研究有助于我们明晰各种参数的作用机理,比如抗原、暴露途径、基因背景即反应修饰在发病中的作用,进一步的,通过基因缺失或插入或结合,我们有可能了解某种特定的细胞、受体、介质在发病过程中的机理,其结果可能应用到人类疾病上。     

动物模型在HIV-1杀微生物剂有效性和安全性评价中的应用

HIV/AIDS的流行趋势没有减弱的迹象,人们迫切需要新的预防HIV传播的手段。杀微生物剂旨在通过局部用药于阴道或直肠从而阻止HIV的传播。鉴于目前有大量的杀微生物剂候选物,亟待能够有效评价其有效性及安全性的动物模型。通过比较非灵长类小型动物模型与非人灵长类动物模型在评价HIV杀微生物剂的有效性及安全性上的重要作用,本文总结了评价杀微生物剂有效性及安全性的动物模型的优缺点,同时指出了杀微生物剂研究与发展的方向和建议,希望能够对杀微生物剂的研发有所帮助。     

基因打靶技术在人类疾病动物模型研究中的应用

人类疾病动物模型在医学研究中起着非常重要的作用,而自然发生的人类疾病已远远不能满足医学研究的需要。利用基因打靶技术开展人类疾病动物模型的研究具有广阔的应用前景。本文就基因打靶技术及其在人类疾病动物模型研究中的应用做一介绍。     

Changes in Antioxidant Defense Enzymes after d-amphetamine Exposure: Implications as an Animal Model of Mania

Studies have demonstrated that oxidative stress is associated with amphetamine-induced neurotoxicity, but little is known about the adaptations of antioxidant enzymes in the brain after amphetamine exposure. We studied the effects of acute and chronic amphetamine administration on superoxide dismutase (SOD) and catalase (CAT) activity, in a rodent model of mania. Male Wistar rats received either a single IP injection of d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle (acute treatment). In the chronic treatment rats received a daily IP injection of either d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle for 7 days. Locomotor behavior was assessed using the open field test. SOD and CAT activities were measured in the prefrontal cortex, hippocampus, and striatum. Acute and to a greater extent chronic amphetamine treatment increased locomotor behavior and affected SOD and CAT activities in the prefrontal cortex, hippocampus and striatum. Our findings suggest that amphetamine exposure is associated with an imbalance between SOD and CAT activity in the prefrontal cortex, hippocampus and striatum.     

鼠疫动物模型:经典与问题

一直以来,鼠疫菌的研究多围绕致病机制、疫苗效果评价及鼠疫治疗方案选择展开,而合理有效的鼠疫动物模型正是这些实验研究的基础与前提。研究者构建了包括小鼠、豚鼠及非人灵长类模型在内的多种动物模型,而这些模型也为人类认识、防御及治疗鼠疫菌提供了帮助,特别是一些经典动物模型沿用至今。但随着研究的深入,有些动物模型由于存在某种问题而逐渐被淘汰。本文就鼠疫菌动物模型构建以来,不同模型的优势与不足及其应用展开综述,以期为研究者提供参考。     

时空表达可控的转基因动物模型调控体系的研究

目的在血管内皮细胞建立时空表达可控的转基因动物模型调控体系。方法培育两个配套的转基因动物品系,利用组织专一性启动子确保转基因表达的空间专一性,利用四环素诱导系统对转基因表达在时间上实施调控。结果将血管内皮细胞特异性表达的VE cadherin基因启动子与人工融合的转录因子tTA基因连接,建立转基因小鼠品系VE cadherin:tTA;将tetoperon的启动子与myrAkt1连接,建立转基因小鼠品系TET:myrAkt1。两系鼠杂交的子代,筛选的阳性纯合子,能可控性地在血管内皮细胞特异性表达目的基因Akt1PKB。结论利用VE cadherin基因启动子和tet off诱导表达系统,可以达到在时间上和空间上都能人为控制目的基因在血管内皮细胞上特异性表达的目的。     

痔疮动物模型的研究进展

随着对痔疮新药药效评价的需求,痔疮模型的建立有了初步的发展。目前,大鼠、小鼠、家兔、卷尾猴等动物已被成功的用于痔疮模型的建立。所用方法主要有:巴豆油法、醋酸法、感染法、创伤法、静脉阻断法等,动物模型的成功建立和合理应用将有利于推动痔疮新药的研发,本文将现有痔疮模型创建的原理和方法进行了归纳、总结。     

慢性阻塞性肺疾病基因工程动物模型研究进展

慢性阻塞性肺疾病(COPD,简称慢阻肺)是我国常见的高发病率和死亡率的慢性气道炎症性疾病,造成沉重社会经济负担。其发病与遗传及环境因素息息相关。动物模型是研究其发病机制、预防、治疗方案并鉴定潜在治疗靶点及生物标志物的重要工具。随着基因工程技术的发展和慢阻肺相关靶点及基因的不断发现,基因修饰动物模型越来越多地用于慢阻肺的研究。通过检索PubMed中已发表论文,分析了慢阻肺相关动物模型的动物种类及造模方法。然后通过文献检索及数据库挖掘等方法,分析了主要的慢阻肺易感基因及在不同物种中的区别。最后总结了慢阻肺基因工程小鼠和大鼠模型的信息和研究进展,供科研和临床人员参考使用,以便更好地开展慢阻肺的发病机制和防治方法的研究。     

A genome-wide association analysis for porcine serum lipid traits reveals the existence of age-specific genetic determinants

Background

The genetic determinism of blood lipid concentrations, the main risk factor for atherosclerosis, is practically unknown in species other than human and mouse. Even in model organisms, little is known about how the genetic determinants of lipid traits are modulated by age-specific factors. To gain new insights into this issue, we have carried out a genome-wide association study (GWAS) for cholesterol (CHOL), triglyceride (TRIG) and low (LDL) and high (HDL) density lipoprotein concentrations measured in Duroc pigs at two time points (45 and 190 days).

Results

Analysis of data with mixed-model methods (EMMAX, GEMMA, GenABEL) and PLINK showed a low positional concordance between trait-associated regions (TARs) for serum lipids at 45 and 190 days. Besides, the proportion of phenotypic variance explained by SNPs at these two time points was also substantially different. The four analyses consistently detected two regions on SSC3 (124 Mb, CHOL and LDL at 190 days) and SSC6 (135 Mb, CHOL and TRIG at 190 days) with highly significant effects on the porcine blood lipid profile. Moreover, we have found that SNP variation within SSC3, SSC6, SSC10, SSC13 and SSC16 TARs is associated with the expression of several genes mapping to other chromosomes and related to lipid metabolism.

Conclusions

Our data demonstrate that the effects of genomic determinants influencing lipid concentrations in pigs, as well as the amount of phenotypic variance they explain, are influenced by age-related factors.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-758) contains supplementary material, which is available to authorized users.     

多囊卵巢综合征动物模型与中医药干预研究进展

多囊卵巢综合征（PCOS）是涉及多系统的生殖、代谢障碍疾病,临床表现有高雄激素血症、排卵障碍、高胰岛素血症和高LH血症以及肥胖、不孕等,卵巢呈多囊样改变。因其病因病理复杂,生化改变、临床表现多样,为临床研究带来一定困难。因此,利用动物模型进行相关研究显得尤为必要。近年来所采用的PCOS动物模型造模方法主要有雄激素造模法、胰岛素联合人绒毛膜促性腺激素造模法、雌激素造模法、孕激素联合人绒毛膜促性腺激素造模法和芳香化酶抑制剂造模法等。本文对上述造模方法及相关研究进展进行了综述,并探讨了中药、针灸对模型动物的干预作用。     

慢性粒细胞白血病小鼠动物模型建立的研究进展*

慢性粒细胞白血病(chronic myeloid leukemia,CML)是造血干细胞(hematopoietic stem cells,HSC)恶性克隆性增殖引起的一种血液系统疾病。动物模型是研究CML发病机制及药物靶向治疗的重要载体和工具。研究表明,CML小鼠模型可以通过逆转录病毒介导、转基因和白血病细胞移植的方法建立。三种方法建立的CML小鼠模型均可用于CML发病机制及药物疗效评估研究。实验动物模型进一步通过血常规、血涂片和骨髓涂片、免疫学、分子生物学及病理学等检测手段,判断模型是否建立成功。本文就近年来CML小鼠模型的建立、鉴定及研究应用进展进行综述。     

Amphetamine Increases Extracellular Concentrations of Glutamate in the Prefrontal Cortex of the Awake Rat: A Microdialysis Study

Using microdialysis, the effect was investigated of intracerebral infusions of different doses of amphetamine (1.25, 2.5, 5, 10, and 20 g/l) on the extracellular concentrations of glutamate in the medial prefrontal cortex of the rat. Amphetamine produced a dose-related increase in extracellular concentrations of glutamate. At the highest dose, amphetamine increased extracellular glutamate by 445% of baseline as well as extracellular concentrations of taurine, and reduced extracellular concentrations of glutamine. Amphetamine did not modify other amino acids such as arginine. Increases in extracellular concentrations of glutamate and taurine were independent of calcium in the perfusion medium. This is the first study showing that amphetamine produces a calcium-independent increase in extracellular concentrations of glutamate and taurine in the medial prefrontal cortex of the rat.     

Anti-Tumor Effects of Metformin in Animal Models of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Background

Several studies have reported that metformin can reduce the risk of hepatocellular carcinoma (HCC) in diabetes patients. However, the direct anti-HCC effects of metformin have hardly been studied in patients, but have been extensively investigated in animal models of HCC. We therefore performed a systematic review and meta-analysis of animal studies evaluating the effects of metformin on HCC.

Methods

We collected the relevant studies by searching EMBASE, Medline (OvidSP), Web of Science, Scopus, PubMed Publisher, and Google Scholar. Studies were included according to the following inclusion criteria: HCC, animal study, and metformin intervention. Study quality was assessed using SYRCLE’s risk of bias tool. A meta-analysis was performed for the outcome measures: tumor growth (tumor volume, weight and size), tumor number and incidence.

Results

The search resulted in 573 references, of which 13 could be included in the review and 12 included in the meta-analysis. The study characteristics of the included studies varied considerably. Two studies used rats, while the others used mice. Only one study used female animals, nine used male, and three studies didn’t mention the gender of animals in their experiments. The quality of the included studies was low to moderate based on the assessment of their risk of bias. The meta-analysis showed that metformin significantly inhibited the growth of HCC tumour (SMD -2.20[-2.96,-1.43]; n=16), but no significant effect on the number of tumors (SMD-1.05[-2.13,0.03]; n=5) or the incidence of HCC was observed (RR 0.62[0.33,1.16]; n=6). To investigate the potential sources of significant heterogeneities found in outcome of tumor growth (I²=81%), subgroup analyses of scales of growth measures and of types of animal models used were performed.

Conclusion

Metformin appears to have a direct anti-HCC effect in animal models. Although the intrinsic limitations of animal studies, this systematic review could provide an important reference for future preclinical animal trials of good quality and clinical development.     

Efficacy of Deferoxamine in Animal Models of Intracerebral Hemorrhage: A Systematic Review and Stratified Meta-Analysis

Intracerebral hemorrhage (ICH) is a subtype of stroke associated with high morbidity and mortality rates. No proven treatments are available for this condition. Iron-mediated free radical injury is associated with secondary damage following ICH. Deferoxamine (DFX), a ferric-iron chelator, is a candidate drug for the treatment of ICH. We performed a systematic review of studies involving the administration of DFX following ICH. In total, 20 studies were identified that described the efficacy of DFX in animal models of ICH and assessed changes in the brain water content, neurobehavioral score, or both. DFX reduced the brain water content by 85.7% in animal models of ICH (-0.86, 95% CI: -.48- -0.23; P < 0.01; 23 comparisons), and improved the neurobehavioral score by -1.08 (95% CI: -1.23- -0.92; P < 0.01; 62 comparisons). DFX was most efficacious when administered 2–4 h after ICH at a dose of 10–50 mg/kg depending on species, and this beneficial effect remained for up to 24 h postinjury. The efficacy was higher with phenobarbital anesthesia, intramuscular injection, and lysed erythrocyte infusion, and in Fischer 344 rats or aged animals. Overall, although DFX was found to be effective in experimental ICH, additional confirmation is needed due to possible publication bias, poor study quality, and the limited number of studies conducting clinical trials.     

Osteoarthritis: cellular and molecular changes in degenerating cartilage

Osteoarthritis (OA) is a disease of high ethical and economical importance. In advanced stages, the patients suffer from severe pain and restriction of mobility. The consequence in many cases is an inability to work and often the substitution of the diseased joint with an artificial implant becomes inevitable. As cartilage tissue itself has only very limited capacities of self-renewing, the development of this disorder is chronic and progressive. Generally, OA is diagnosed in more advanced stages, when clinical and radiographic signs become evident. At this time point the options for therapeutic intervention without surgery are limited. It is, therefore, crucial to know about the basic incidents in the course of OA and especially in early stages to develop new diagnostic and therapeutic strategies. Numerous studies on human osteoarthritic tissue and in animal models have addressed various aspects of OA progression to get a better understanding of the pathophysiology of this disease. This review presents an overview on different aspects of OA research and the cellular and molecular alterations in degenerating cartilage.     

Gene Regulation in Continuous Cultures: A Unified Theory for Bacteria and Yeasts

During batch growth on mixtures of two growth-limiting substrates, microbes consume the substrates either sequentially (diauxie) or simultaneously. The ubiquity of these growth patterns suggests that they may be driven by a universal mechanism common to all microbial species. Recently, we showed that a minimal model accounting only for enzyme induction and dilution, the two processes that occur in all microbes, explains the phenotypes observed in batch cultures of various wild-type and mutant/recombinant cells (Narang and Pilyugin in J. Theor. Biol. 244:326–348, 2007). Here, we examine the extension of the minimal model to continuous cultures. We show that: (1) Several enzymatic trends, attributed entirely to cross-regulatory mechanisms, such as catabolite repression and inducer exclusion, can be quantitatively explained by enzyme dilution. (2) The bifurcation diagram of the minimal model for continuous cultures, which classifies the substrate consumption pattern at any given dilution rate and feed concentrations, provides a precise explanation for the empirically observed correlations between the growth patterns in batch and continuous cultures. (3) Numerical simulations of the model are in excellent agreement with the data. The model captures the variation of the steady state substrate concentrations, cell densities, and enzyme levels during the single- and mixed-substrate growth of bacteria and yeasts at various dilution rates and feed concentrations. This variation is well approximated by simple analytical expressions that furnish deep physical insights. (4) Since the minimal model describes the behavior of the cells in the absence of cross-regulatory mechanisms, it provides a rigorous framework for quantifying the effect of these mechanisms. We illustrate this by analyzing several data sets from the literature.