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目的探索利用短期高脂饮食结合球囊损伤的造模方式，快速建立载脂蛋白E基因敲除（ApoE-/-小）大鼠动脉粥样硬化（As）动物模型。方法选择8周雄性SD大鼠（n=10）及ApoE-/-大鼠（n=10），高脂饮食2周后分别检测两组血常规、肝肾功能、血脂谱及C反应蛋白（CRP）等指标。随后行大鼠左侧颈总动脉球囊损伤术，2周后采用过量水合氯醛处死大鼠，取术侧颈总动脉进行HE、Masson及油红O染色，并行CD68、α平滑肌蛋白（α-SMA）免疫荧光染色。结果ApoE-/-大鼠血脂水平明显高于sD大鼠[总胆固醇（TC）：18．56±2．82mmol／Lvs5．69±1.98mmol／L，P〈0．01；低密度脂蛋白（LDL）：6．86±1．47mmol／Lvs 1．92±0．76mmol／L，P〈0．01]；与SD大鼠比较，在严重血脂紊乱状态下，ApoE-/-手大鼠全身处于显著炎症状态[CRP：4．66±0．57mg／L1）so．39±0．21mg／L，P〈0．05；白细胞：（21．79±5．10）×10^9／Lvs（14．82±2．41）×10^9／L，P〈0．01；中性粒细胞：（9．28±3．35）×10^9／Lvs（2．10±0．96）×10^9／L，P〈0．01]。HE及Masson染色结果显示，两组均有显著增生形成，并伴随着胶原纤维的轻度沉积；油红O染色可见ApoE-/-大鼠斑块增生明显，而SD大鼠呈阴性。免疫荧光染色结果显示，ApoE-/-大鼠斑块内CD68呈显著阳性，α-SMA呈弱阳性，而sD大鼠α-SMA呈阳性，无明显CD68显色。结论通过短期高脂饮食结合球囊损伤的造模方式，可以快速建立ApoE-/-小大鼠AS模型。

NF-κBp50/p52 double knockout （dKO） and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism. In contrast, Op/Op mice, which form few osteoclasts, and Src KO mice, which have osteoclasts with defective resorptive function, are osteopetrotic, but they are not dwarfed. Here, we compared the morphologic features of long bones from p50/p52 dKO, RANK KO, Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths. We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2-3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone. This growth plate abnormality disappears when animals become older, but their dwarfism persists. Op/Op or Src KO mice have relatively normal growth plate morphology. In-situ hybridization study of long bones from pS0/ p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-express

目的利用低密度脂蛋白受体基因敲除（LDLR一）小鼠作为高血脂动物模型，研究山楂对小鼠脂代谢的影响，并探讨其可能的作用机制。方法将LDLR叫一小鼠随机分为正常对照组和山楂干预组（n=10只／组）。饮食干预20周后取血并解剖。采用氯仿（V）：甲醇（V）（2：1）混合液抽提肝脏总脂质，酶法分别测定甘油三酯（TG）和总胆固醇（Tc）含量。利用快速蛋白层析（FPI。c）法分离血清脂蛋白，酶法测定各馏分中TG和TC含量。Real—time检测HMG-CoAR、FAS、PPARa、SREBP—lc脂代谢相关基因的mRNA表达水平。结果山楂干预组小鼠血清中TG和TC含量，肝脏总脂质、肝脏中TG和TC含量均低于对照组（P〈O．05）。与对照组比较，山楂干预组血清中的极低密度脂蛋白甘油三酯（VLDL—TG）、胆固醇（VLDL-c）和低密度脂蛋白／中密度脂蛋白甘油三酯（LDL／IDL—TG）、胆固醇（LDL／IDL-C）明显降低。山楂干预组的脂代谢相关基因mRNA表达水平与对照组相比均有统计学差异。结论山楂能调节脂质代谢，具有明显的降血脂作用。

目的探讨3-羟-3-甲基戊二酰辅酶A（HMG-Co A）还原酶抑制剂瑞舒伐他汀对载脂蛋白E（Apo E）基因缺陷小鼠动脉粥样硬化及主动脉凝集素样氧化型低密度脂蛋白受体-1（LOX-1）、核因子-κB p65（NF-κB p65）表达的影响。方法 20只6周龄雄性Apo E基因缺陷小鼠随机分为高脂模型组（n=10）、瑞舒伐他汀药物干预组（n=10）,高脂饮食喂养13周;10只6周龄C57BL/6J（野生型,W T）雄性小鼠作为正常对照组,正常饮食喂养13周。13周后,摘眼球取血测定血浆总胆固醇（TCH）、甘油三酯（TG）、低密度脂蛋白（LDL-C）的水平。处死小鼠取主动脉,行HE染色;采用Western blotting和RT-PCR检测定量分析主动脉组织LOX-1、NF-κB p65表达变化。结果与高脂模型组比较,瑞舒伐他汀药物干预组血清中TCH、TG、LDL-C水平明显降低（P〈0.05）。HE染色结果显示,与正常对照组相比,高脂模型组主动脉粥样硬化病变程度明显加重,瑞舒伐他汀药物干预组主动脉粥样硬化病变程度减轻。与正常对照组相比,高脂模型组主动脉LOX-1、NF-κB p65蛋白和m RNA的表达均明显增加（P〈0.05）,瑞舒伐他汀药物干预组LOX-1、NF-κB p65蛋白和m RNA的表达均减少（P〈0.05）。结论瑞舒伐他汀可明显降低血脂,减轻Apo E基因缺陷小鼠主动脉组织粥样硬化病变程度,其抗动脉粥样硬化作用可能与下调LOX-1、NF-κB p65的表达有关。

目的探讨胰高血糖素样肽1（GLP-1）受体激动剂艾塞那肽对ApoE-/-小鼠动脉粥样硬化模型中主动脉病变的影响。方法 ApoE-/-小鼠随机分为普通饮食组（n=14）和高脂饮食组（n=68）,喂养12周后随机抽取普通饮食组4只和高脂饮食组8只小鼠检测造模情况。将高脂饮食组小鼠再分为非药物干预组、阿托伐他汀钙片组、艾塞那肽小剂量组、艾塞那肽大剂量组、阿托伐他汀＋艾塞那肽小剂量组、阿托伐他汀＋艾塞那肽大剂量组（每组10只）。药物干预6周后,各组小鼠眶周静脉丛取血,并取主动脉弓行石蜡切片,HE染色观察。ELISA法检测血清血脂水平,Western blotting检测主动脉血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）的蛋白表达水平。结果 HE染色结果显示：普通饮食组及阿托伐他汀＋艾塞那肽大剂量组镜下观察未见异常;阿托伐他汀钙片组,艾塞那肽小、大剂量组,阿托伐他汀＋艾塞那肽小剂量组可见广泛的病理性内膜增厚;非药物干预组有脂质斑块形成,可见脂核。单独应用艾塞那肽或联合阿托伐他汀可不同程度降低血清血脂（TC、TG、LDL-C）水平（P〈0.05）。艾塞那肽不同剂量单独或联合阿托伐他汀可降低主动脉VCAM-1、ICAM-1的表达（P〈0.05）。结论艾塞那肽可能通过下调ApoE-/-小鼠主动脉VCAM-1、ICAM-1的表达,抑制ApoE-/-小鼠动脉粥样硬化病变的形成。

基因修饰（敲除、变异和过度表达）小鼠自90年代初应用于心脏学研究。近十余年来,利用这一类模型的研究发现对心血管领域所取得的重要进展有着突出的贡献,已经成为该领域里具有举足轻重地位的研究手段。目前,基因修饰小鼠模型的数量日益增多并已形成系统,有关的心脏表现型数据库日趋丰富,多种从整体到分子水平的表现型的研究手段已十分成熟。在今后的心脏研究中,小鼠模型有望对阐明疾病的分子机制和探索新的治疗途径起到很大的推动作用。

Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related （Atg） genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

The pig is an important livestock for food supply and an ideal model for various human diseases. Efficient and precise genetic engineering in pigs holds great promise in agriculture and biomedicine . Using currently available approach, generating specific gene modifications in pigs requires two steps. First, site-specific nucleases such as zinc finger nucleases （ZFNs） and transcription activator-like effector nucleases （TALENs） are used to generate targeted mutations in pig somatic cells.

Mixed lineage kinase domain-like protein （Mlkl） was recently found to interact with receptor interacting protein 3 （Rip3） and to be essential for tumor necrosis factor （TNF）-induced programmed necrosis （necroptosis） in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases （TALENs）-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell develop- ment. Mlkl-deficient mouse embryonic fibroblasts （MEFs） and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their abil- ity to activate NF-KB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides （LPS）, respectively. Consis- tently, Mlkl-deficient macrophages and mice exhibited normal interleukin-lp （IL-1β）, IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis.

Dear Editor, Technologies to achieve specific and precise genome editing, such as knock-in and knock-out, are critical for deciphering the functions of a gene and for under- standing fundamental biological processes. Compared with the zinc finger nucleases （ZFN） and transcription activator-like effector nucleases （TALEN）, which have been used for genome editing [1], the Clustered Regu- larly Interspaced Short Palindromic Repeats （CRISPR）/ CRISPR-associated （Cas） system has emerged as a new powerful tool for genome modifications. It has recently been adopted for genome editing in human cell lines [2- 4], mouse [5], zebrafisb [6], C. elegans [7-12], and plants [13].